Advanced search

Vol 56, No 1 (2025)
Review article
Published online: 2025-01-22

open access

View PDF Download PDF file
Page views 364
Article views/downloads 183
Get Citation

Connect on Social Media

Connect on Social Media

KMT2a-rearranged acute leukaemias — insights and potential therapeutic options

Ogochukwu Izuegbuna1
DOI: 10.5603/ahp.102873
Acta Haematol Pol 2025;56(1):22-38.

Abstract

The lysine methyltransferase 2A (KMT2A) protein is a histone lysine 4 (H3K4) methyltransferase that is involved in
normal development through supporting certain gene transcriptions. On the other hand, it is rather a ‘promiscuous’
protein that is involved in fusion with a variety of partner proteins creating an altered mixed lineage leukaemia
complex that is not expressed in normal cells and is involved in the transformation of normal haematopoietic cells to
leukaemic ones. To date, more than 120 fusion partners have been identified. They account for 5–10% of all acute
leukaemias. Of these, infants account for more than 70% of the total cases. Another subgroup of acute leukaemia
patients with the KMT2A-rearrangement develops it as a result of exposure to certain types of chemotherapeutic
agents. The outcome of KMT2A-rearranged acute leukaemia is usually very poor especially when compared to other
patients without the KMT2A-rearrangement. They are often chemo-resistant and display cell plasticity. This has
prompted a search for better therapies. At the same time, more research has led to elucidation of the KMT2A fusion
protein complexes and its involvement in leukaemic transformation.
This article reviews the biology of the KMT2A protein and the role played by some of the partner proteins in the development
of acute leukaemias. It also considers cell plasticity in KMT2A-rearranged leukaemia, and finally some
promising therapeutics that could impact upon the management landscape of KMT2A-rearranged acute leukaemias.

Keywords: mixed-lineage leukaemiaacute leukaemiacell plasticityepigeneticstargeted therapy

Article available in PDF format

View PDF Download PDF file

References

  1. Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007; 115(1): 138–145.
    CrossRefPubMed
  2. Iacobucci I, Mullighan CG. Genetic Basis of Acute Lymphoblastic Leukemia. J Clin Oncol. 2017; 35(9): 975–983.
    CrossRefPubMed
  3. Masetti R, Castelli I, Astolfi A, et al. Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing. Oncotarget. 2016; 7(35): 56746–56757.
    CrossRefPubMed
  4. Kaspers GJL, Zimmermann M, Reinhardt D, et al. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013; 31(5): 599–607.
    CrossRefPubMed
  5. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010; 376(9757): 2009–2017.
    CrossRefPubMed
  6. Mullighan CG, Phillips LA, Su X, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008; 322(5906): 1377–1380.
    CrossRefPubMed
  7. Farrar JE, Schuback HL, Ries RE, et al. Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse. Cancer Res. 2016; 76(8): 2197–2205.
    CrossRefPubMed
  8. Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013; 152(4): 714–726.
    CrossRefPubMed
  9. Hinohara K, Polyak K. Intratumoral Heterogeneity: More Than Just Mutations. Trends Cell Biol. 2019; 29(7): 569–579.
    CrossRefPubMed
  10. Marschalek R. Mechanisms of leukemogenesis by MLL fusion proteins. Br J Haematol. 2011; 152(2): 141–154.
    CrossRefPubMed
  11. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. 1999; 10(12): 1419–1432.
    CrossRefPubMed
  12. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022; 36(7): 1720–1748.
    CrossRefPubMed
  13. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022; 36(7): 1703–1719.
    CrossRefPubMed
  14. Meyer C, Burmeister T, Gröger D, et al. The MLL recombinome of acute leukemias in 2017. Leukemia. 2018; 32(2): 273–284.
    CrossRefPubMed
  15. Menu E, Beaufils N, Usseglio F, et al. First case of B ALL with KMT2A-MAML2 rearrangement: a case report. BMC Cancer. 2017; 17(1): 363.
    CrossRefPubMed
  16. Khabirova E, Jardine L, Coorens THH, et al. Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia. Nat Med. 2022; 28(4): 743–751.
    CrossRefPubMed
  17. Xu H, Yu H, Jin R, et al. Genetic and Epigenetic Targeting Therapy for Pediatric Acute Lymphoblastic Leukemia. Cells. 2021; 10(12).
    CrossRefPubMed
  18. Cai SF, Levine RL. Genetic and epigenetic determinants of AML pathogenesis. Semin Hematol. 2019; 56(2): 84–89.
    CrossRefPubMed
  19. Butler L, Slany R, Cui X, et al. The HRX Proto-oncogene Product Is Widely Expressed in Human Tissues and Localizes to Nuclear Structures. Blood. 1997; 89(9): 3361–3370.
    CrossRef
  20. Dogan S. Genomic characterization of mixed lineage leukemias. Cancer Research. ; 7: 1928–1928.
    CrossRef
  21. Chan AKN, Chen CW. Rewiring the Epigenetic Networks in -Rearranged Leukemias: Epigenetic Dysregulation and Pharmacological Interventions. Front Cell Dev Biol. 2019; 7: 81.
    CrossRefPubMed
  22. Muntean AG, Hess JL. The pathogenesis of mixed-lineage leukemia. Annu Rev Pathol. 2012; 7: 283–301.
    CrossRefPubMed
  23. Aplan PD. Chromosomal translocations involving the MLL gene: molecular mechanisms. DNA Repair (Amst). 2006; 5(9-10): 1265–1272.
    CrossRefPubMed
  24. Rössler T, Marschalek R. An alternative splice process renders the MLL protein either into a transcriptional activator or repressor. Pharmazie. 2013; 68(7): 601–607.
    CrossRefPubMed
  25. Meyer C, Lopes BA, Caye-Eude A, et al. Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions. Leukemia. 2019; 33(9): 2306–2340.
    CrossRefPubMed
  26. Jin S, Zhao H, Yi Y, et al. c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis. J Clin Invest. 2010; 120(2): 593–606.
    CrossRefPubMed
  27. Milne TA, Kim J, Wang GG, et al. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell. 2010; 38(6): 853–863.
    CrossRefPubMed
  28. Li X, Song Y. Structure, function and inhibition of critical protein-protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins. J Hematol Oncol. 2021; 14(1): 56.
    CrossRefPubMed
  29. Bhatlekar S, Fields JZ, Boman BM. Role of HOX Genes in Stem Cell Differentiation and Cancer. Stem Cells Int. 2018; 2018: 3569493.
    CrossRefPubMed
  30. Ariki R, Morikawa S, Mabuchi Yo, et al. Homeodomain transcription factor Meis1 is a critical regulator of adult bone marrow hematopoiesis. PLoS One. 2014; 9(2): e87646.
    CrossRefPubMed
  31. Li Z, Huang H, Chen P, et al. miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. Nat Commun. 2012; 3: 688.
    CrossRefPubMed
  32. Adamaki M, Lambrou GI, Athanasiadou A, et al. HOXA9 and MEIS1 gene overexpression in the diagnosis of childhood acute leukemias: Significant correlation with relapse and overall survival. Leuk Res. 2015; 39(8): 874–882.
    CrossRefPubMed
  33. Collins CT, Hess JL. Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets. Oncogene. 2016; 35(9): 1090–1098.
    CrossRefPubMed
  34. Li Z, Zhang Z, Li Y, et al. PBX3 is an important cofactor of HOXA9 in leukemogenesis. Blood. 2013; 121(8): 1422–1431.
    CrossRefPubMed
  35. Bach C, Buhl S, Mueller D, et al. Leukemogenic transformation by HOXA cluster genes. Blood. 2010; 115(14): 2910–2918.
    CrossRefPubMed
  36. Britten O, Ragusa D, Tosi S, et al. -Rearranged Acute Leukemia with t(4;11)(q21;q23)-Current Treatment Options. Is There a Role for CAR-T Cell Therapy? Cells. 2019; 8(11).
    CrossRefPubMed
  37. Qiu KY, Zhou DH, Liao XY, et al. Prognostic value and outcome for acute lymphocytic leukemia in children with MLL rearrangement: a case-control study. BMC Cancer. 2022; 22(1): 1257.
    CrossRefPubMed
  38. Siddiqui M, Konoplev S, Issa G, et al. Biologic features and clinical outcomes in newly diagnosed myelodysplastic syndrome with KMT2A rearrangements. Am J Hematol. 2023; 98(4): E91–E94.
    CrossRefPubMed
  39. Sardou-Cezar I, Lopes BA, Andrade FG, et al. Therapy-related acute myeloid leukemia with KMT2A-SNX9 gene fusion associated with a hyperdiploid karyotype after hemophagocytic lymphohistiocytosis. Cancer Genet. 2021; 256-257: 86–90.
    CrossRefPubMed
  40. Aldoss I, Stiller T, Tsai NC, et al. Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients. Haematologica. 2018; 103(10): 1662–1668.
    CrossRefPubMed
  41. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. 2020; 395(10230): 1146–1162.
    CrossRefPubMed
  42. Roberts KG, Gu Z, Payne-Turner D, et al. High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. J Clin Oncol. 2017; 35(4): 394–401.
    CrossRefPubMed
  43. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016; 374(23): 2209–2221.
    CrossRefPubMed
  44. Brown P, Pieters R, Biondi A. How I treat infant leukemia. Blood. 2019; 133(3): 205–214.
    CrossRefPubMed
  45. Zeleznik-Le NJ. One Step Forward in the Challenging Arena of MLL-AF4 Leukemia. Cancer Cell. 2016; 30(5): 657–658.
    CrossRefPubMed
  46. Andersson AK, Ma J, Wang J, et al. St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat Genet. 2015; 47(4): 330–337.
    CrossRefPubMed
  47. Meyer C, Larghero P, Almeida Lopes B, et al. The KMT2A recombinome of acute leukemias in 2023. Leukemia. 2023; 37(5): 988–1005.
    CrossRefPubMed
  48. Bataller A, Guijarro F, Caye-Eude A, et al. KMT2A-CBL rearrangements in acute leukemias: clinical characteristics and genetic breakpoints. Blood Adv. 2021; 5(24): 5617–5620.
    CrossRefPubMed
  49. Wang QF, Wu G, Mi S, et al. MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome. Blood. 2011; 117(25): 6895–6905.
    CrossRefPubMed
  50. Prange KHM, Mandoli A, Kuznetsova T, et al. MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia. Oncogene. 2017; 36(23): 3346–3356.
    CrossRefPubMed
  51. Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol. 2006; 8(8): 877–884.
    CrossRefPubMed
  52. Yokoyama A, Ficara F, Murphy MJ, et al. Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways. J Cell Sci. 2011; 124(Pt 13): 2208–2219.
    CrossRefPubMed
  53. Zhang MY, Zhao Y, Zhang JH. t(4;11) translocation in hyperdiploid adult acute myeloid leukemia: A case report. World J Clin Cases. 2022; 10(32): 11980–11986.
    CrossRefPubMed
  54. Aoki Y, Watanabe T, Saito Y, et al. Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia. Blood. 2015; 125(6): 967–980.
    CrossRefPubMed
  55. Kalina T, Flores-Montero J, van der Velden VHJ, et al. EuroFlow Consortium (EU-FP6, LSHB-CT-2006-018708). EuroFlow standardization of flow cytometer instrument settings and immunophenotyping protocols. Leukemia. 2012; 26(9): 1986–2010.
    CrossRefPubMed
  56. Marschalek R. The reciprocal world of MLL fusions: A personal view. Biochim Biophys Acta Gene Regul Mech. 2020; 1863(7): 194547.
    CrossRefPubMed
  57. Kowarz E, Burmeister T, Lo Nigro L, et al. Complex MLL rearrangements in t(4;11) leukemia patients with absent AF4.MLL fusion allele. Leukemia. 2007; 21(6): 1232–1238.
    CrossRefPubMed
  58. von Bergh A, Gargallo P, De Prijck B, et al. Cryptic t(4;11) encoding MLL-AF4 due to insertion of 5' MLL sequences in chromosome 4. Leukemia. 2001; 15(4): 595–600.
    CrossRefPubMed
  59. Montes R, Ayllón V, Prieto C, et al. Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia. Blood. 2011; 117(18): 4746–4758.
    CrossRefPubMed
  60. Bursen A, Schwabe K, Rüster B, et al. The AF4.MLL fusion protein is capable of inducing ALL in mice without requirement of MLL.AF4. Blood. 2010; 115(17): 3570–3579.
    CrossRefPubMed
  61. Sanjuan-Pla A, Bueno C, Prieto C, et al. Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia. Blood. 2015; 126(25): 2676–2685.
    CrossRefPubMed
  62. Bueno C, Calero-Nieto FJ, Wang X, et al. Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between and fusions. Haematologica. 2019; 104(6): 1189–1201.
    CrossRefPubMed
  63. Meyer C, Hofmann J, Burmeister T, et al. The MLL recombinome of acute leukemias in 2013. Leukemia. 2013; 27(11): 2165–2176.
    CrossRefPubMed
  64. Calvo C, Fenneteau O, Leverger G, et al. Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity. Cancers (Basel). 2021; 13(4).
    CrossRefPubMed
  65. Gong XY, Wang Y, Liu BC, et al. [Characteristics and prognosis in adult acute myeloid leukemia patients with MLL gene rearrangements]. Zhonghua Xue Ye Xue Za Zhi. 2018; 39(1): 9–14.
    CrossRefPubMed
  66. Kabra A, Bushweller J. The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer. J Mol Biol. 2022; 434(1): 167117.
    CrossRefPubMed
  67. Wu A, Zhi J, Tian T, et al. DOT1L complex regulates transcriptional initiation in human erythroleukemic cells. Proc Natl Acad Sci U S A. 2021; 118(27).
    CrossRefPubMed
  68. Chen Y, Vos SM, Dienemann C, et al. Allosteric transcription stimulation by RNA polymerase II super elongation complex. Mol Cell. 2021; 81(16): 3386–3399.e10.
    CrossRefPubMed
  69. Tan J, Jones M, Koseki H, et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell. 2011; 20(5): 563–575.
    CrossRefPubMed
  70. Schmidt CR, Achille NJ, Kuntimaddi A, et al. BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity. Blood Cancer Discov. 2020; 1(2): 162–177.
    CrossRefPubMed
  71. Palermo CM, Bennett CA, Winters AC, et al. The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells. Leuk Res. 2008; 32(4): 633–642.
    CrossRefPubMed
  72. Leach BI, Kuntimaddi A, Schmidt CR, et al. Leukemia fusion target AF9 is an intrinsically disordered transcriptional regulator that recruits multiple partners via coupled folding and binding. Structure. 2013; 21(1): 176–183.
    CrossRefPubMed
  73. Calvanese V, Nguyen AT, Bolan TJ, et al. MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment. Nature. 2019; 576(7786): 281–286.
    CrossRefPubMed
  74. Cui Y, Zhou M, Zou P, et al. Mature B cell acute lymphoblastic leukaemia with KMT2A-MLLT3 transcripts in children: three case reports and literature reviews. Orphanet J Rare Dis. 2021; 16(1): 331.
    CrossRefPubMed
  75. Takahashi S, Kanai A, Okuda H, et al. HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis. Elife. 2021; 10.
    CrossRefPubMed
  76. Zhao D, Li Y, Xiong X, et al. YEATS Domain-A Histone Acylation Reader in Health and Disease. J Mol Biol. 2017; 429(13): 1994–2002.
    CrossRefPubMed
  77. Erb MA, Scott TG, Li BE, et al. Transcription control by the ENL YEATS domain in acute leukaemia. Nature. 2017; 543(7644): 270–274.
    CrossRefPubMed
  78. Wan L, Wen H, Li Y, et al. ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature. 2017; 543(7644): 265–269.
    CrossRefPubMed
  79. Reimer J, Knöß S, Labuhn M, et al. CRISPR-Cas9-induced t(11;19)/MLL-ENL translocations initiate leukemia in human hematopoietic progenitor cells . Haematologica. 2017; 102(9): 1558–1566.
    CrossRefPubMed
  80. Ugale A, Norddahl GL, Wahlestedt M, et al. Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation. Cell Rep. 2014; 9(4): 1246–1255.
    CrossRefPubMed
  81. Ugale A, Säwén P, Dudenhöffer-Pfeifer M, et al. MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment. Oncogene. 2017; 36(22): 3207–3212.
    CrossRefPubMed
  82. Nakata J, Nakano K, Okumura A, et al. In vivo eradication of MLL/ENL leukemia cells by NK cells in the absence of adaptive immunity. Leukemia. 2014; 28(6): 1316–1325.
    CrossRefPubMed
  83. Yi Y, Ge S. Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias. J Hematol Oncol. 2022; 15(1): 35.
    CrossRefPubMed
  84. Mohan M, Herz HM, Takahashi YH, et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 2010; 24(6): 574–589.
    CrossRefPubMed
  85. DiMartino JF, Ayton PM, Chen EH, et al. The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10. Blood. 2002; 99(10): 3780–3785.
    CrossRefPubMed
  86. Linder B, Jones LK, Chaplin T, et al. Expression pattern and cellular distribution of the murine homologue of AF10. Biochim Biophys Acta. 1998; 1443(3): 285–296.
    CrossRefPubMed
  87. Caudell D, Pierce R, Harper D, et al. Identification of Genes That Collaborate with CALM-AF10 to Induce Leukemia by Retroviral Insertional Mutagenesis and Candidate Gene Sequencing. Blood. 2008; 112(11): 3787–3787.
    CrossRef
  88. Caudell D, Aplan PD. The role of CALM-AF10 gene fusion in acute leukemia. Leukemia. 2008; 22(4): 678–685.
    CrossRefPubMed
  89. Antonarakis ES. Targeting lineage plasticity in prostate cancer. Lancet Oncol. 2019; 20(10): 1338–1340.
    CrossRefPubMed
  90. Lounici A, Cony-Makhoul P, Dubus P, et al. Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia: report of an adult case and review of the literature. Am J Hematol. 2000; 65(4): 319–321, doi: 10.1002/1096-8652(200012)65:4<319::aid-ajh13>3.0.co;2-1.
    PubMed
  91. Jamil SF, Sharma U, Singh C, et al. Lineage switch of acute myeloid leukemia to T-Cell acute lymphoblastic leukemia - A unique case report. Indian J Pathol Microbiol. 2023; 66(1): 191–195.
    CrossRefPubMed
  92. Zhu Y, Liu H, Zhang S, et al. A case report of lineage switch from T-cell acute leukemia to B-cell acute leukemia. Medicine (Baltimore). 2020; 99(44): e22490.
    CrossRefPubMed
  93. Iacobucci I, Mullighan CG. KMT2A-rearranged leukemia: the shapeshifter. Blood. 2022; 140(17): 1833–1835.
    CrossRefPubMed
  94. Le Magnen C, Shen MM, Abate-Shen C. Lineage Plasticity in Cancer Progression and Treatment. Annu Rev Cancer Biol. 2018; 2: 271–289.
    CrossRefPubMed
  95. Davis A, Gao R, Navin N. Tumor evolution: Linear, branching, neutral or punctuated? Biochim Biophys Acta Rev Cancer. 2017; 1867(2): 151–161.
    CrossRefPubMed
  96. Hou Y, Song L, Zhu P, et al. Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm. Cell. 2012; 148(5): 873–885.
    CrossRefPubMed
  97. Kim TM, Jung SH, An CH, et al. Subclonal Genomic Architectures of Primary and Metastatic Colorectal Cancer Based on Intratumoral Genetic Heterogeneity. Clin Cancer Res. 2015; 21(19): 4461–4472.
    CrossRefPubMed
  98. Campbell PJ, Pleasance ED, Stephens PJ, et al. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci U S A. 2008; 105(35): 13081–13086.
    CrossRefPubMed
  99. Gawad C, Koh W, Quake SR. Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. Proc Natl Acad Sci U S A. 2014; 111(50): 17947–17952.
    CrossRefPubMed
  100. Ahlgren L, Pilheden M, Sturesson H, et al. The Rise and Fall of Leukemia Clones in Longitudinal Samples from Diagnosis to Relapse in KMT2A-rearranged Infant and Childhood Leukemia. Blood. 2022; 140(Supplement 1): 9189–9190.
    CrossRef
  101. Hyrenius-Wittsten A, Pilheden M, Sturesson H, et al. De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. Nat Commun. 2018; 9(1): 1770.
    CrossRefPubMed
  102. Kurzer JH, Weinberg OK. To B- or not to B-: A review of lineage switched acute leukemia. Int J Lab Hematol. 2022; 44 Suppl 1: 64–70.
    CrossRefPubMed
  103. A distinct hematopoietic differentiation state characterizes aggressive infant leukemia. Nat Med. 2022; 28(4): 641–642.
    CrossRefPubMed
  104. Morris V, Marion W, Hughes T, et al. Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells. .
    CrossRef
  105. Tirtakusuma R, Szoltysek K, Milne P, et al. Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia. Blood. 2022; 140(17): 1875–1890.
    CrossRefPubMed
  106. Lin S, Luo RT, Ptasinska A, et al. Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia. Cancer Cell. 2016; 30(5): 737–749.
    CrossRefPubMed
  107. Lin S, Luo RT, Shrestha M, et al. The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment. Blood. 2017; 130(7): 903–907.
    CrossRefPubMed
  108. Heuts BMH, Arza-Apalategi S, Alkema SG, et al. Inducible MLL-AF9 Expression Drives an AML Program during Human Pluripotent Stem Cell-Derived Hematopoietic Differentiation. Cells. 2023; 12(8).
    CrossRefPubMed
  109. Marchand T, Pinho S. Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Front Immunol. 2021; 12: 775128.
    CrossRefPubMed
  110. Schepers K, Campbell TB, Passegué E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell. 2015; 16(3): 254–267.
    CrossRefPubMed
  111. Arneth B. Tumor Microenvironment. Medicina (Kaunas). 2019; 56(1).
    CrossRefPubMed
  112. Rowe RG, Lummertz da Rocha E, Sousa P, et al. The developmental stage of the hematopoietic niche regulates lineage in rearranged leukemia. J Exp Med. 2019; 216(3): 527–538.
    CrossRefPubMed
  113. Wei J, Wunderlich M, Fox C, et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell. 2008; 13(6): 483–495.
    CrossRefPubMed
  114. Sison EA, Rau RE, McIntyre E, et al. MLL-rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism. Br J Haematol. 2013; 160(6): 785–797.
    CrossRefPubMed
  115. Bartsch L, Schroeder MP, Hänzelmann S, et al. An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse. BMC Genom Data. 2022; 23(1): 30.
    CrossRefPubMed
  116. Woodward EL, Yang M, Moura-Castro LH, et al. Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia. Nat Commun. 2023; 14(1): 1658.
    CrossRefPubMed
  117. Sayyab S, Lundmark A, Larsson M, et al. Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia. Sci Rep. 2021; 11(1): 15988.
    CrossRefPubMed
  118. Pandit S, Wasekar N, Badarkhe G, et al. Acute lymphoblastic leukemia to acute myeloid leukemia: an unusual case report of lineage switching. Hematol Transfus Cell Ther. 2022; 44(1): 112–115.
    CrossRefPubMed
  119. Qing X, Panosyan E, Yue C, et al. Therapy-related myeloid neoplasm in an 18-year-old boy with B-lymphoblastic leukemia. Exp Mol Pathol. 2017; 103(3): 263–266.
    CrossRefPubMed
  120. Park M, Koh KN, Kim BoE, et al. Lineage switch at relapse of childhood acute leukemia: a report of four cases. J Korean Med Sci. 2011; 26(6): 829–831.
    CrossRefPubMed
  121. van Binsbergen E, de Weerdt O, Buijs A. A new subtype of MLL-SEPT2 fusion transcript in therapy-related acute myeloid leukemia with t(2;11)(q37;q23): a case report and literature review. Cancer Genet Cytogenet. 2007; 176(1): 72–75.
    CrossRefPubMed
  122. Li B, Brady SW, Ma X, et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood. 2020; 135(1): 41–55.
    CrossRefPubMed
  123. Nguyen TT, Tanaka Y, Sanada M, et al. CRISPR/Cas9-Mediated Induction of Relapse-Specific and Mutations Confers Thiopurine Resistance as a Relapsed Lymphoid Leukemia Model. Mol Pharmacol. 2023; 103(4): 199–210.
    CrossRefPubMed
  124. Chen B, Zou Z, Zhang Q, et al. Efficacy and safety of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukemia: A systematic review and meta-analysis. Front Pharmacol. 2022; 13: 1032664.
    CrossRefPubMed
  125. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017; 376(9): 836–847.
    CrossRefPubMed
  126. Queudeville M, Ebinger M. Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review). J Clin Med. 2021; 10(12).
    CrossRefPubMed
  127. Yoon JH, Kwag D, Lee JH, et al. Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: a propensity score-matched cohort analysis. Ther Adv Hematol. 2023; 14: 20406207231154713.
    CrossRefPubMed
  128. van der Sluis IM, de Lorenzo P, Kotecha RS, et al. Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia. N Engl J Med. 2023; 388(17): 1572–1581.
    CrossRefPubMed
  129. Sidaway P. Blinatumomab improves outcomes in infant ALL. Nat Rev Clin Oncol. 2023; 20(7): 426.
    CrossRefPubMed
  130. Braig F, Brandt A, Goebeler M, et al. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017; 129(1): 100–104.
    CrossRefPubMed
  131. Schultz L, Gardner R. Mechanisms of and approaches to overcoming resistance to immunotherapy. Hematology Am Soc Hematol Educ Program. 2019; 2019(1): 226–232.
    CrossRefPubMed
  132. Aldoss I, Song J, Stiller T, et al. Correlates of resistance and relapse during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol. 2017; 92(9): 858–865.
    CrossRefPubMed
  133. Zoghbi A, Zur Stadt U, Winkler B, et al. Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement. Pediatr Blood Cancer. 2017; 64(11).
    CrossRefPubMed
  134. Du J, Chisholm KM, Tsuchiya K, et al. Lineage Switch in an Infant B-Lymphoblastic Leukemia With t(1;11)(p32;q23); , Following Blinatumomab Therapy. Pediatr Dev Pathol. 2021; 24(4): 378–382.
    CrossRefPubMed
  135. He RR, Nayer Z, Hogan M, et al. Immunotherapy- (Blinatumomab-) Related Lineage Switch of Rearranged B-Lymphoblastic Leukemia into Acute Myeloid Leukemia/Myeloid Sarcoma and Subsequently into B/Myeloid Mixed Phenotype Acute Leukemia. Case Rep Hematol. 2019; 2019: 7394619.
    CrossRefPubMed
  136. Liao W, Kohler ME, Fry T, et al. Does lineage plasticity enable escape from CAR-T cell therapy? Lessons from MLL-r leukemia. Exp Hematol. 2021; 100: 1–11.
    CrossRefPubMed
  137. Lamble AJ, Myers RM, Taraseviciute A, et al. Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells. Blood Adv. 2023; 7(4): 575–585.
    CrossRefPubMed
  138. Jacoby E, Nguyen SM, Fountaine TJ, et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun. 2016; 7: 12320.
    CrossRefPubMed
  139. Stutterheim J, de Lorenzo P, van der Sluis IM, et al. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol. Eur J Cancer. 2022; 160: 72–79.
    CrossRefPubMed
  140. Rice S, Roy A. MLL-rearranged infant leukaemia: A 'thorn in the side' of a remarkable success story. Biochim Biophys Acta Gene Regul Mech. 2020; 1863(8): 194564.
    CrossRefPubMed
  141. Gouache E, Greze V, Strullu M, et al. Leukemia Cutis in Childhood Acute Myeloid Leukemia: Epidemiological, Clinical, Biological, and Prognostic Characteristics of Patients Included in the ELAM02 Study. Hemasphere. 2018; 2(5): e141.
    CrossRefPubMed
  142. Prathibha JP, Lobo C. Congenital leukemia cutis in an infant. Indian Journal of Paediatric Dermatology. 2022; 23(2): 136.
    CrossRef
  143. van der Linden MH, Valsecchi MG, De Lorenzo P, et al. Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood. 2009; 114(18): 3764–3768.
    CrossRefPubMed
  144. Yin YT, Tseng JH, Liu YL, et al. Neonatal acute lymphoblastic leukemia (MLL-AF9) with leukemia cutis. Pediatr Neonatol. 2021; 62(6): 676–678.
    CrossRefPubMed
  145. Górecki M, Kozioł I, Kopystecka A, et al. Updates in Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia. Biomedicines. 2023; 11(3).
    CrossRefPubMed
  146. Chiaretti S, Zini G, Bassan R. Diagnosis and subclassification of acute lymphoblastic leukemia. Mediterr J Hematol Infect Dis. 2014; 6(1): e2014073.
    CrossRefPubMed
  147. Gao C, Liu SG, Yue ZX, et al. Clinical-biological characteristics and treatment outcomes of pediatric pro-B ALL patients enrolled in BCH-2003 and CCLG-2008 protocol: a study of 121 Chinese children. Cancer Cell Int. 2019; 19: 293.
    CrossRefPubMed
  148. Zerkalenkova E, Mikhaylova E, Lebedeva S, et al. Quantification of NG2-positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia. Genes Chromosomes Cancer. 2021; 60(2): 88–99.
    CrossRefPubMed
  149. Prieto C, López-Millán B, Roca-Ho H, et al. NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL. Leukemia. 2018; 32(3): 633–644.
    CrossRefPubMed
  150. Konoplev S, Wang X, Tang G, et al. Comprehensive immunophenotypic study of acute myeloid leukemia with KMT2A (MLL) rearrangement in adults: A single-institution experience. Cytometry B Clin Cytom. 2022; 102(2): 123–133.
    CrossRefPubMed
  151. Bain BJ, Béné MC. Morphological and Immunophenotypic Clues to the WHO Categories of Acute Myeloid Leukaemia. Acta Haematol. 2019; 141(4): 232–244.
    CrossRefPubMed
  152. Candelli T, Schneider P, Garrido Castro P, et al. Identification and characterization of relapse-initiating cells in MLL-rearranged infant ALL by single-cell transcriptomics. Leukemia. 2022; 36(1): 58–67.
    CrossRefPubMed
  153. Pieters R, De Lorenzo P, Ancliffe P, et al. Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study. J Clin Oncol. 2019; 37(25): 2246–2256.
    CrossRefPubMed
  154. Hilden JM, Dinndorf PA, Meerbaum SO, et al. Children's Oncology Group. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood. 2006; 108(2): 441–451.
    CrossRefPubMed
  155. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007; 370(9583): 240–250.
    CrossRefPubMed
  156. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016; 34(36): 4381–4389.
    CrossRefPubMed
  157. Locatelli F, Maschan A, Boissel N, et al. Pediatric patients with acute lymphoblastic leukemia treated with blinatumomab in a real-world setting: Results from the NEUF study. Pediatr Blood Cancer. 2022; 69(4): e29562.
    CrossRefPubMed
  158. Stutterheim J, van der Sluis IM, de Lorenzo P, et al. Clinical Implications of Minimal Residual Disease Detection in Infants With -Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol. J Clin Oncol. 2021; 39(6): 652–662.
    CrossRefPubMed
  159. Durer S, Durer C, Shafqat M, et al. Concomitant use of blinatumomab and donor lymphocyte infusion for mixed-phenotype acute leukemia: a case report with literature review. Immunotherapy. 2019; 11(5): 373–378.
    CrossRefPubMed
  160. El Chaer F, Ali OM, Sausville EA, et al. Treatment of CD19-positive mixed phenotype acute leukemia with blinatumomab. Am J Hematol. 2019; 94(1): E7–E8.
    CrossRefPubMed
  161. Locatelli F, Eckert C, Hrusak O, et al. Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse B-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022; 69(8): e29715.
    CrossRefPubMed
  162. Bartram J, Balasch-Carulla M, Bhojaraja S, et al. Blinatumomab for paediatric mixed phenotype acute leukaemia. Br J Haematol. 2021; 195(2): 289–292.
    CrossRefPubMed
  163. Hogan LE, Brown PA, Ji L, et al. Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol. 2023; 41(25): 4118–4129.
    CrossRefPubMed
  164. Mirfakhraie R, Dehaghi BK, Ghorbi MD, et al. All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia. Hematol Transfus Cell Ther. 2024; 46(2): 192–200.
    CrossRefPubMed
  165. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016; 127(1): 53–61.
    CrossRefPubMed
  166. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4): 424–447.
    CrossRefPubMed
  167. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018; 36(26): 2684–2692.
    CrossRefPubMed
  168. Jaramillo S, Schlenk RF. Update on current treatments for adult acute myeloid leukemia: to treat acute myeloid leukemia intensively or non-intensively? That is the question. Haematologica. 2023; 108(2): 342–352.
    CrossRefPubMed
  169. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022; 140(12): 1345–1377.
    CrossRefPubMed
  170. Lo MY, Tsai XCH, Lin CC, et al. Validation of the prognostic significance of the 2022 European LeukemiaNet risk stratification system in intensive chemotherapy treated aged 18 to 65 years patients with de novo acute myeloid leukemia. Am J Hematol. 2023; 98(5): 760–769.
    CrossRefPubMed
  171. Hunger SP, Loh KM, Baker KS, et al. Controversies of and unique issues in hematopoietic cell transplantation for infant leukemia. Biol Blood Marrow Transplant. 2009; 15(1 Suppl): 79–83.
    CrossRefPubMed
  172. Mann G, Attarbaschi A, Schrappe M, et al. Interfant-99 Study Group. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood. 2010; 116(15): 2644–2650.
    CrossRefPubMed
  173. Pieters R, De Lorenzo P, Ancliffe P, et al. Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study. J Clin Oncol. 2019; 37(25): 2246–2256.
    CrossRefPubMed
  174. Dreyer ZE, Dinndorf PA, Camitta B, et al. Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group. J Clin Oncol. 2011; 29(2): 214–222.
    CrossRefPubMed
  175. Koh K, Tomizawa D, Moriya Saito A, et al. Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia. Leukemia. 2015; 29(2): 290–296.
    CrossRefPubMed
  176. Tomizawa D, Miyamura T, Imamura T, et al. A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial. Blood. 2020; 136(16): 1813–1823.
    CrossRefPubMed
  177. Tomizawa D, Miyamura T, Imamura T, et al. A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial. Blood. 2020; 136(16): 1813–1823.
    CrossRefPubMed
  178. Takachi T, Watanabe T, Miyamura T, et al. Hematopoietic stem cell transplantation for infants with high-risk KMT2A gene-rearranged acute lymphoblastic leukemia. Blood Adv. 2021; 5(19): 3891–3899.
    CrossRefPubMed
  179. Tomizawa D, Miyamura T, Koh K, et al. Acute lymphoblastic leukemia in infants: A quarter century of nationwide efforts in Japan. Pediatr Int. 2022; 64(1): e14935.
    CrossRefPubMed
  180. Bai Lu, Cheng YF, Lu AD, et al. Prognosis of haploidentical hematopoietic stem cell transplantation in non-infant children with t(v;11q23)/MLL-rearranged B-cell acute lymphoblastic leukemia. Leuk Res. 2020; 91: 106333.
    CrossRefPubMed
  181. Bai Lu, Zhang YZ, Yan CH, et al. Outcomes of allogeneic haematopoietic stem cell transplantation for paediatric patients with MLL-rearranged acute myeloid leukaemia. BMC Cancer. 2022; 22(1): 896.
    CrossRefPubMed
  182. Pollard JA, Guest E, Alonzo TA, et al. Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric -Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 2021; 39(28): 3149–3160.
    CrossRefPubMed
  183. Wang Yu, Liu QF, Qin YZ, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of patients with mixed-lineage-leukemia-rearranged acute leukemia: Results from a prospective, multi-center study. Am J Hematol. 2014; 89(2): 130–136.
    CrossRefPubMed
  184. Marks DI, Moorman AV, Chilton L, et al. The clinical characteristics, therapy and outcome of 85 adults with acute lymphoblastic leukemia and t(4;11)(q21;q23)/MLL-AFF1 prospectively treated in the UKALLXII/ECOG2993 trial. Haematologica. 2013; 98(6): 945–952.
    CrossRefPubMed
  185. Getta BM, Roshal M, Zheng J, et al. Allogeneic Hematopoietic Stem Cell Transplantation with Myeloablative Conditioning Is Associated with Favorable Outcomes in Mixed Phenotype Acute Leukemia. Biol Blood Marrow Transplant. 2017; 23(11): 1879–1886.
    CrossRefPubMed
  186. Munker R, Brazauskas R, Wang HL, et al. Center for International Blood and Marrow Transplant Research. Allogeneic Hematopoietic Cell Transplantation for Patients with Mixed Phenotype Acute Leukemia. Biol Blood Marrow Transplant. 2016; 22(6): 1024–1029.
    CrossRefPubMed
  187. Tong J, Zhang L, Liu H, et al. Umbilical cord blood transplantation can overcome the poor prognosis of KMT2A-MLLT3 acute myeloid leukemia and can lead to good GVHD-free/relapse-free survival. Ann Hematol. 2021; 100(5): 1303–1309.
    CrossRefPubMed
  188. Abbasi S, Totmaj MA, Abbasi M, et al. Chimeric antigen receptor T (CAR-T) cells: Novel cell therapy for hematological malignancies. Cancer Med. 2023; 12(7): 7844–7858.
    CrossRefPubMed
  189. Gill S, Brudno JN. CAR T-Cell Therapy in Hematologic Malignancies: Clinical Role, Toxicity, and Unanswered Questions. Am Soc Clin Oncol Educ Book. 2021; 41: 1–20.
    CrossRefPubMed
  190. Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016; 127(20): 2406–2410.
    CrossRefPubMed
  191. Coorens THH, Collord G, Treger TD, et al. Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy. Nat Cancer. 2023; 4(8): 1095–1101.
    CrossRefPubMed
  192. https://www.fda.gov/media/106496/download. Accessed August. ; 2023.
  193. Moskop A, Pommert L, Thakrar P, et al. Chimeric antigen receptor T-cell therapy for marrow and extramedullary relapse of infant acute lymphoblastic leukemia. Pediatr Blood Cancer. 2021; 68(1): e28739.
    CrossRefPubMed
  194. Breese EH, Krupski C, Nelson AS, et al. Use of CD19-directed CAR T-Cell Therapy in an Infant With Refractory Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol. 2021; 43(4): 152–154.
    CrossRefPubMed
  195. Ghorashian S, Jacoby E, De Moerloose B, et al. Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study. Lancet Haematol. 2022; 9(10): e766–e775.
    CrossRefPubMed
  196. Moskop A, Pommert L, Baggott C, et al. Real-world use of tisagenlecleucel in infant acute lymphoblastic leukemia. Blood Adv. 2022; 6(14): 4251–4255.
    CrossRefPubMed
  197. Atilla E, Benabdellah K. The Black Hole: CAR T Cell Therapy in AML. Cancers (Basel). 2023; 15(10).
    CrossRefPubMed
  198. Marvin-Peek J, Savani BN, Olalekan OO, et al. Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia. Cancers (Basel). 2022; 14(3).
    CrossRefPubMed
  199. Fetsch V, Zeiser R. Chimeric antigen receptor T cells for acute myeloid leukemia. Eur J Haematol. 2024; 112(1): 28–35.
    CrossRefPubMed
  200. Marofi F, Rahman HS, Al-Obaidi ZM, et al. Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients. Stem Cell Res Ther. 2021; 12(1): 465.
    CrossRefPubMed
  201. Stumpel DJ, Schneider P, van Roon EHJ, et al. Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options. Blood. 2009; 114(27): 5490–5498.
    CrossRefPubMed
  202. Stumpel DJ, Schotte D, Lange-Turenhout EAM, et al. Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale. Leukemia. 2011; 25(3): 429–439.
    CrossRefPubMed
  203. Roolf C, Richter A, Konkolefski C, et al. Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements. J Hematol Oncol. 2018; 11(1): 62.
    CrossRefPubMed
  204. Schneider P, Castro PG, Pinhanços SM, et al. Decitabine mildly attenuates -rearranged acute lymphoblastic leukemia in vivo, and represents a poor chemo-sensitizer. EJHaem. 2020; 1(2): 527–536.
    CrossRefPubMed
  205. Ball B, Arslan S, Koller P, et al. Outcomes of Venetoclax and Hypomethylating Agents (HMA) in Adult Patients with KMT2A-Rearranged Leukemias. Blood. 2021; 138(Supplement 1): 3430–3430.
    CrossRef
  206. Cheung LC, Aya-Bonilla C, Cruickshank MN, et al. Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy. Leukemia. 2023; 37(1): 61–71.
    CrossRefPubMed
  207. Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018; 24(12): 1859–1866.
    CrossRefPubMed
  208. DiNardo CD, Maiti A, Rausch CR, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020; 7(10): e724–e736.
    CrossRefPubMed
  209. Ball BJ, Arslan S, Koller P, et al. Clinical experience with venetoclax and hypomethylating agents (HMA) in patients with newly diagnosed and relapsed or refractory KMT2A-Rearranged acute myeloid leukemia (AML). Leuk Lymphoma. 2022; 63(13): 3232–3236.
    CrossRefPubMed
  210. Othman TA, Tenold ME, Moskoff BN, et al. An evaluation of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine as therapy for acute myeloid leukemia. Expert Rev Hematol. 2021; 14(5): 407–417.
    CrossRefPubMed
  211. Edahiro T, Ureshino H, Chishaki R, et al. Successful combination treatment with azacitidine and venetoclax as a bridging therapy for third allogenic stem cell transplantation in a patient with 11q23/MLL-rearranged complex karyotype acute myeloid leukemia. EJHaem. 2023; 4(1): 273–275.
    CrossRefPubMed
  212. https://classic.clinicaltrials.gov/ct2/show/NCT02828358. Accessed August. ; 31: 2023.
  213. San José-Enériz E, Gimenez-Camino N, Agirre X, et al. HDAC Inhibitors in Acute Myeloid Leukemia. Cancers (Basel). 2019; 11(11).
    CrossRefPubMed
  214. Ahmadzadeh A, Khodadi E, Shahjahani M, et al. The Role of HDACs as Leukemia Therapy Targets using HDI. Int J Hematol Oncol Stem Cell Res. 2015 Oct 1;9(4):203-14. PMID: 26865932; PMCID. : PMC4748691.
  215. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007; 5(10): 981–989.
    CrossRefPubMed
  216. Moreno DA, Scrideli CA, Cortez MA, et al. Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia. Br J Haematol. 2010; 150(6): 665–673.
    CrossRefPubMed
  217. Sonnemann J, Gruhn B, Wittig S, et al. Increased activity of histone deacetylases in childhood acute lymphoblastic leukaemia and acute myeloid leukaemia: support for histone deacetylase inhibitors as antileukaemic agents. Br J Haematol. 2012; 158(5): 664–666.
    CrossRefPubMed
  218. Pal D, Raj K, Nandi SS, et al. Potential of Synthetic and Natural Compounds as Novel Histone Deacetylase Inhibitors for the Treatment of Hematological Malignancies. Cancers (Basel). 2023; 15(10).
    CrossRefPubMed
  219. Secrist JP, Zhou X, Richon VM. HDAC inhibitors for the treatment of cancer. Curr Opin Investig Drugs. 2003; 4(12): 1422–1427.
    PubMed
  220. Ouwehand K, de Ruijter AJM, van Bree C, et al. Histone deacetylase inhibitor BL1521 induces a G1-phase arrest in neuroblastoma cells through altered expression of cell cycle proteins. FEBS Lett. 2005; 579(6): 1523–1528.
    CrossRefPubMed
  221. Tonelli R, Sartini R, Fronza R, et al. G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent. Leukemia. 2006; 20(7): 1307–1310.
    CrossRefPubMed
  222. Castro PG, Roon EV, Pinhancos SM, et al. The Histone Deacetylase Inhibitor Panobinostat (LBH-589) Exerts Anti-Leukaemic Activity in a MLL-Rearranged ALL Xenograft Mouse Model. Blood. 2014; 124(21): 3709–3709.
    CrossRef
  223. Garrido Castro P, van Roon EHJ, Pinhanços SS, et al. The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. Leukemia. 2018; 32(2): 323–331.
    CrossRefPubMed
  224. Somers K, Kosciolek A, Bongers A, et al. Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia. Int J Cancer. 2020; 146(7): 1902–1916.
    CrossRefPubMed
  225. Ehteda A, Simon S, Franshaw L, et al. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG. Cell Rep. 2021; 35(2): 108994.
    CrossRefPubMed
  226. Xiao L, Somers K, Murray J, et al. Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma. Clin Cancer Res. 2021; 27(15): 4338–4352.
    CrossRefPubMed
  227. Fetisov TI, Borunova AA, Antipova AS, et al. Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo. Biomedicines. 2023; 11(1).
    CrossRefPubMed
  228. Xiao L, Karsa M, Ronca E, et al. The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression. Front Oncol. 2022; 12: 863329.
    CrossRefPubMed
  229. Mehrpouri M, Safaroghli-Azar A, Pourbagheri-Sigaroodi A, et al. Anti-leukemic effects of histone deacetylase (HDAC) inhibition in acute lymphoblastic leukemia (ALL) cells: Shedding light on mitigating effects of NF-κB and autophagy on panobinostat cytotoxicity. Eur J Pharmacol. 2020; 875: 173050.
    CrossRefPubMed
  230. Moreno DA, Junior HL, Laranjeira AB, et al. Panobinostat (LBH589) increase survival in adult xenografic model of acute lymphoblastic leukemia with t(4;11) but promotes antagonistic effects in combination with MTX and 6MP. Med Oncol. 2022; 39(12): 216.
    CrossRefPubMed
  231. Cheung LC, Cruickshank MN, Hughes AM, et al. Romidepsin enhances the efficacy of cytarabine , revealing histone deacetylase inhibition as a promising therapeutic strategy for -rearranged infant acute lymphoblastic leukemia. Haematologica. 2019; 104(7): e300–e303.
    CrossRefPubMed
  232. Cruickshank MN, Ford J, Cheung LC, et al. Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin. Leukemia. 2017; 31(1): 40–50.
    CrossRefPubMed
  233. https://clinicaltrials.gov/study/NCT02419755?tab=results&a=8. Accessed September. ; 3: 2023.
  234. https://classic.clinicaltrials.gov/ct2/show/NCT01321346. Accessed September. ; 3: 2023.
  235. https://classic.clinicaltrials.gov/ct2/show/NCT01483690. Accessed September. ; 3: 2023.
  236. https://classic.clinicaltrials.gov/ct2/show/results/NCT00723203. Accessed September. ; 3: 2023.
  237. Saliba AN, Kaufmann SH, Stein EM, et al. Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates. Blood Adv. 2023; 7(11): 2360–2363.
    CrossRefPubMed
  238. Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018; 131(13): 1415–1424.
    CrossRefPubMed
  239. Short NJ, Muftuoglu M, Ong F, et al. A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents. J Hematol Oncol. 2023; 16(1): 73.
    CrossRefPubMed
  240. Colado E, Alvarez-Fernández S, Maiso P, et al. The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype. Haematologica. 2008; 93(1): 57–66.
    CrossRefPubMed
  241. Minderman H, Zhou Y, O'Loughlin KL, et al. Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Cancer Chemother Pharmacol. 2007; 60(2): 245–255.
    CrossRefPubMed
  242. Szczepanek J, Pogorzala M, Konatkowska B, et al. Differential ex vivo activity of bortezomib in newly diagnosed paediatric acute lymphoblastic and myeloblastic leukaemia. Anticancer Res. 2010; 30(6): 2119–2124.
    PubMed
  243. Liu H, Westergard TD, Cashen A, et al. Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4. Cancer Cell. 2014; 25(4): 530–542.
    CrossRefPubMed
  244. Ge M, Li D, Qiao Z, et al. Restoring MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors. Oncogene. 2020; 39(36): 5888–5901.
    CrossRefPubMed
  245. Zhou B, Qin Y, Zhou J, et al. Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of CDK6 in MLL-rearranged myeloid leukemia. J Cell Mol Med. 2021; 25(6): 3124–3135.
    CrossRefPubMed
  246. Niewerth D, Franke NE, Jansen G, et al. Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica. 2013; 98(12): 1896–1904.
    CrossRefPubMed
  247. Takahashi K, Inukai T, Imamura T, et al. Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL cell lines. PLoS One. 2017; 12(12): e0188680.
    CrossRefPubMed
  248. Swift L, Jayanthan A, Ruan Y, et al. Targeting the Proteasome in Refractory Pediatric Leukemia Cells: Characterization of Effective Cytotoxicity of Carfilzomib. Target Oncol. 2018; 13(6): 779–793.
    CrossRefPubMed
  249. Cheung LC, de Kraa R, Oommen J, et al. Preclinical Evaluation of Carfilzomib for Infant -Rearranged Acute Lymphoblastic Leukemia. Front Oncol. 2021; 11: 631594.
    CrossRefPubMed
  250. Messinger YH, Bostrom BC. Bortezomib-based four-drug induction does induce a response in advanced relapsed ALL but cure remains elusive. Pediatr Blood Cancer. 2020; 67(3): e28115.
    CrossRefPubMed
  251. Messinger YH, Gaynon PS, Sposto R, et al. Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood. 2012; 120(2): 285–290.
    CrossRefPubMed
  252. Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol. 2019; 186(2): 274–285.
    CrossRefPubMed
  253. Teachey DT, Devidas M, Wood BL, et al. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol. 2022; 40(19): 2106–2118.
    CrossRefPubMed
  254. Kamens JL, Nance S, Koss C, et al. Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia. Nat Commun. 2023; 14(1): 809.
    CrossRefPubMed
  255. Roeten MSF, van Meerloo J, Kwidama ZJ, et al. Pre-Clinical Evaluation of the Proteasome Inhibitor Ixazomib against Bortezomib-Resistant Leukemia Cells and Primary Acute Leukemia Cells. Cells. 2021; 10(3).
    CrossRefPubMed
  256. Placke T, Faber K, Nonami A, et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood. 2014; 124(1): 13–23.
    CrossRefPubMed
  257. van der Linden MH, Willekes M, van Roon E, et al. MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL. Cell Cycle. 2014; 13(5): 834–844.
    CrossRefPubMed
  258. Antony-Debré I, Steidl U. CDK6, a new target in MLL-driven leukemia. Blood. 2014; 124(1): 5–6.
    CrossRefPubMed
  259. Sorf A, Sucha S, Morell A, et al. Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors. Cancers (Basel). 2020; 12(6).
    CrossRefPubMed
  260. Lee DJ, Zeidner JF. Cyclin-dependent kinase (CDK) 9 and 4/6 inhibitors in acute myeloid leukemia (AML): a promising therapeutic approach. Expert Opin Investig Drugs. 2019; 28(11): 989–1001.
    CrossRefPubMed
  261. Sawai CM, Freund J, Oh P, et al. Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. Cancer Cell. 2012; 22(4): 452–465.
    CrossRefPubMed
  262. Bortolozzi R, Mattiuzzo E, Trentin L, et al. Ribociclib, a Cdk4/Cdk6 kinase inhibitor, enhances glucocorticoid sensitivity in B-acute lymphoblastic leukemia (B-All). Biochem Pharmacol. 2018; 153: 230–241.
    CrossRefPubMed
  263. Pikman Y, Alexe G, Roti G, et al. Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia. Clin Cancer Res. 2017; 23(4): 1012–1024.
    CrossRefPubMed
  264. Xie X, Zhang W, Zhou X, et al. Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells. Br J Haematol. 2023; 201(5): 940–953.
    CrossRefPubMed
  265. Gelbert LM, Cai S, Lin Xi, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014; 32(5): 825–837.
    CrossRefPubMed
  266. Tao YF, Wang NN, Xu LX, et al. Molecular mechanism of G arrest and cellular senescence induced by LEE011, a novel CDK4/CDK6 inhibitor, in leukemia cells. Cancer Cell Int. 2017; 17: 35.
    CrossRefPubMed
  267. Matsuo H, Yoshida K, Fukumura K, et al. Recurrent mutations in -rearranged acute myeloid leukemia. Blood Adv. 2018; 2(21): 2879–2889.
    CrossRefPubMed
  268. Kurtz S, Eide C, Kaempf A, et al. Patterns of Sensitivity Exhibited By Venetoclax-Inclusive Drug Combinations in Acute Myeloid Leukemia. Blood. 2019; 134(Supplement_1): 878–878.
    CrossRef
  269. Wang A, Fang M, Jiang H, et al. Palbociclib promotes the antitumor activity of Venetoclax plus Azacitidine against acute myeloid leukemia. Biomed Pharmacother. 2022; 153: 113527.
    CrossRefPubMed
  270. Nazha A, Mukherjee S, Siebenaller C, et al. A Phase I/II Trial of CPX-351 + Palbociclib in Patients with Acute Myeloid Leukemia. Blood. 2020; 136(Supplement 1): 13–14.
    CrossRef
  271. Raetz EA, Teachey DT, Minard C, et al. Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1). Pediatr Blood Cancer. 2023; 70(11): e30609.
    CrossRefPubMed
  272. Fröhling S, Agrawal M, Jahn N, et al. CDK4/6 Inhibitor Palbociclib for Treatment of KMT2A-Rearranged Acute Myeloid Leukemia: Interim Analysis of the AMLSG 23-14 Trial. Blood. 2016; 128(22): 1608–1608.
    CrossRef
  273. Gaidzik VI, Paschka P, Schlenk RF, et al. Palbociclib in Acute Leukemias With -rearrangement: Results of AMLSG 23-14 Trial. Hemasphere. 2023; 7(5): e877.
    CrossRefPubMed
  274. Pizzolo G, Trentin L, Vinante F, et al. Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission. Br J Cancer. 1988; 58(3): 368–372.
    CrossRefPubMed
  275. La P, Schnepp RW, D Petersen C, et al. Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. Endocrinology. 2004; 145(7): 3443–3450.
    CrossRefPubMed
  276. Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013; 38(8): 394–402.
    CrossRefPubMed
  277. Yokoyama A, Cleary ML. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell. 2008; 14(1): 36–46.
    CrossRefPubMed
  278. Murai MJ, Chruszcz M, Reddy G, et al. Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein. J Biol Chem. 2011; 286(36): 31742–31748.
    CrossRefPubMed
  279. Shi Q, Xu M, Kang Z, et al. Menin-MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers. Molecules. 2023; 28(7).
    CrossRefPubMed
  280. Borkin D, He S, Miao H, et al. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell. 2015; 27(4): 589–602.
    CrossRefPubMed
  281. Fiskus W, Daver N, Boettcher S, et al. Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1. Leukemia. 2022; 36(11): 2729–2733.
    CrossRefPubMed
  282. Wang ES, Issa GC, Erba HP, et al. Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia. Blood 140 (Supplement 1). 2022; 31(4): 153–156.
    CrossRef
  283. https://classic.clinicaltrials.gov/ct2/show/NCT04067336. Accessed on September. ; 4: 2023.
  284. Issa G, Aldoss I, DiPersio J, et al. The Menin Inhibitor SNDX-5613 (revumenib) Leads to Durable Responses in Patients (Pts) with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase (Ph) 1 Study. Blood. 2022; 140(Supplement 1): 150–152.
    CrossRef
  285. Issa GC, Aldoss I, Thirman MJ, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023; 615(7954): 920–924.
    CrossRefPubMed
  286. https://www.onclive.com/view/fda-grants-breakthrough-therapy-designation-to-revumenib-in-relapsed-refractory-kmt2a--rearranged-acute-leukemia.
  287. Syndax announces pivotal AUGMENT-101 trial of revumenib in relapsed/refractory KMT2Ar acute leukemia meets primary endpoint and stopped early for efficacy following protocol-defined interim analysis. News release. Syndax Pharmaceuticals. https://www.prnewswire.com/news-releases/syndax-announces-pivotal-augment-101-trial-of-revumenib-in-relapsedrefractory-kmt2ar-acute-leukemia-meets-primary-endpoint-and-stopped-early-for-efficacy-following-protocol-defined-interim-analysis-301943954.html.
  288. Heikamp EB, Henrich JA, Perner F, et al. The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. Blood. 2022; 139(6): 894–906.
    CrossRefPubMed
  289. Rasouli M, Blair H, Troester S, et al. The MLL-Menin Interaction is a Therapeutic Vulnerability in -rearranged AML. Hemasphere. 2023; 7(8): e935.
    CrossRefPubMed
  290. Dafflon C, Craig VJ, Méreau H, et al. Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia. Leukemia. 2017; 31(6): 1269–1277.
    CrossRefPubMed
  291. Fiskus W, Boettcher S, Daver N, et al. Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c). Blood Cancer J. 2022; 12(1): 5.
    CrossRefPubMed
  292. Miao H, Kim E, Chen D, et al. Combinatorial treatment with menin and FLT3 inhibitors induces complete remission in AML models with activating FLT3 mutations. Blood. 2020; 136(25): 2958–2963.
    CrossRefPubMed
  293. Swaminathan M, Bourgeois W, Armstrong SA, et al. Menin Inhibitors in Acute Myeloid Leukemia-What Does the Future Hold? Cancer J. 2022; 28(1): 62–66.
    CrossRefPubMed
  294. Min J, Feng Q, Li Z, et al. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell. 2003; 112(5): 711–723.
    CrossRefPubMed
  295. Chen CW, Koche RP, Sinha AU, et al. DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat Med. 2015; 21(4): 335–343.
    CrossRefPubMed
  296. Daigle SR, Olhava EJ, Therkelsen CA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013; 122(6): 1017–1025.
    CrossRefPubMed
  297. Klaus CR, Iwanowicz D, Johnston D, et al. DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells. J Pharmacol Exp Ther. 2014; 350(3): 646–656.
    CrossRefPubMed
  298. Li LH, Wang J, Ke XY. [Effects of DOT1L Inhibitor EPZ-5676 Combined with Chemotherapeutic Drugs on Prolifiration and Apoptosis of RS 4;11 Cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017; 25(5): 1334–1341.
    CrossRefPubMed
  299. Stein EM, Garcia-Manero G, Rizzieri DA, et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018; 131(24): 2661–2669.
    CrossRefPubMed
  300. Shukla N, Wetmore C, O'Brien M, et al. Final Report of Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood. 2016; 128(22): 2780–2780.
    CrossRef
  301. https://clinicaltrials.gov/study/NCT03724084. Accessed September. ; 4: 2023.
  302. Perner F, Gadrey JY, Xiong Y, et al. Novel inhibitors of the histone methyltransferase DOT1L show potent antileukemic activity in patient-derived xenografts. Blood. 2020; 136(17): 1983–1988.
    CrossRefPubMed
  303. Cao M, Li T, Chen Y, et al. Nucleoside and Non-Nucleoside DOT1L Inhibitors: Dawn of MLLrearranged Leukemia. Mini Rev Med Chem. 2021; 21(11): 1337–1350.
    CrossRefPubMed
  304. Yi Y, Ge S. Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias. J Hematol Oncol. 2022; 15(1): 35.
    CrossRefPubMed
  305. Biswas S, Rao CM. Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy. Eur J Pharmacol. 2018; 837: 8–24.
    CrossRefPubMed
  306. Rahman S, Sowa ME, Ottinger M, et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol. 2011; 31(13): 2641–2652.
    CrossRefPubMed
  307. Lamonica JM, Deng W, Kadauke S, et al. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. Proc Natl Acad Sci U S A. 2011; 108(22): E159–E168.
    CrossRefPubMed
  308. White ME, Fenger JM, Carson WE. Emerging roles of and therapeutic strategies targeting BRD4 in cancer. Cell Immunol. 2019; 337: 48–53.
    CrossRefPubMed
  309. Devaiah BN, Mu J, Akman B, et al. MYC protein stability is negatively regulated by BRD4. Proc Natl Acad Sci U S A. 2020; 117(24): 13457–13467.
    CrossRefPubMed
  310. Kotekar A, Singh AK, Devaiah BN. BRD4 and MYC: power couple in transcription and disease. FEBS J. 2023; 290(20): 4820–4842.
    CrossRefPubMed
  311. Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011; 478(7370): 524–528.
    CrossRefPubMed
  312. Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011; 478(7370): 529–533.
    CrossRefPubMed
  313. Ott CJ, Kopp N, Bird L, et al. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012; 120(14): 2843–2852.
    CrossRefPubMed
  314. Bardini M, Trentin L, Rizzo F, et al. Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4 Infant ALL. Mol Cancer Ther. 2018; 17(8): 1705–1716.
    CrossRefPubMed
  315. Wellbrock J, Behrmann L, Muschhammer J, et al. The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia. Ann Hematol. 2021; 100(12): 2933–2941.
    CrossRefPubMed
  316. Qin C, Hu Y, Zhou B, et al. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression. J Med Chem. 2018; 61(15): 6685–6704.
    CrossRefPubMed
  317. Imayoshi N, Yoshioka M, Tanaka K, et al. CN470 is a BET/CBP/p300 multi-bromodomain inhibitor and has an anti-tumor activity against MLL-rearranged acute lymphoblastic leukemia. Biochem Biophys Res Commun. 2022; 590: 49–54.
    CrossRefPubMed
  318. Basheer F, Huntly BJP. BET bromodomain inhibitors in leukemia. Exp Hematol. 2015; 43(8): 718–731.
    CrossRefPubMed
  319. Braun T, Gardin C. Investigational BET bromodomain protein inhibitors in early stage clinical trials for acute myelogenous leukemia (AML). Expert Opin Investig Drugs. 2017; 26(7): 803–811.
    CrossRefPubMed
  320. Roboz GJ, Desai P, Lee S, et al. A dose escalation study of RO6870810/TEN-10 in patients with acute myeloid leukemia and myelodysplastic syndrome. Leuk Lymphoma. 2021; 62(7): 1740–1748.
    CrossRefPubMed

About cookies

Necessary cookies

Allways active

These cookies are necessary for the proper display and operation of the website. Blocking them may cause the website to malfunction.

Analytical cookies

As part of our website, we use analytical tools, such as Google Analytics, that allow us to verify website traffic. These tools may require the use of cookies.

Community cookies

These are cookies associated with the social networks we use. Accepting them will allow us to associate your visit to the site with our social media profiles.

Marketing cookies

These are cookies responsible for carrying out advertising and marketing activities - consenting to their use will allow us to target you with advertisements based on your previous activities within our website.

Copyright © 2023-2025 Via Medica Regulations Cookie policy Privacy Statement Legal Note