Vol 1, No 3 (2010)
Review paper
Published online: 2010-07-27
Pathogenesis of chronic myeloid leukemia - from gene to targeted therapy
Hematologia 2010;1(3):195-218.
Abstract
The occurrence of chronic myeloid leukemia (CML) is related to the appearance of reciprocal
chromosomal translocation (9;22)(q34;q11). As a result of translocation between chromosomes
9 and 22, shortened chromosome 22 - Philadelphia (Ph) chromosome arises, coding for
constitutively active protein tyrosine kinase, BCR-ABL1. The subsequent deregulation of the
ABL1 kinase activity in cells leads to enhanced proliferation, resistance to apoptosis and
altered adhesion. The discovery of imatinib, a relatively specific tyrosine kinase inhibitor,
including ABL1 and BCR-ABL1 kinases, was a breakthrough in CML treatment. Imatinib
functions by binding to the active site of ABL1 kinase in an inactive conformation, thus
blocking the ATP binding site crucial for enzyme activity. Although imatinib has revolutionized CML therapy, appearance of resistance to this inhibitor leads to CML progression. In case of
imatinib-resistance, several possible strategies exist for the management of the disease, which
include increasing the dose of imatinib, changing therapy to the 2nd generation tyrosine kinase
inhibitors or allogeneic hematopoietic stem cell transplantation. CML therapy, appearance of resistance to this inhibitor leads to CML progression. In case of
imatinib-resistance, several possible strategies exist for the management of the disease, which
include increasing the dose of imatinib, changing therapy to the 2nd generation tyrosine kinase
inhibitors or allogeneic hematopoietic stem cell transplantation.CML therapy, appearance of resistance to this inhibitor leads to CML progression. In case of
imatinib-resistance, several possible strategies exist for the management of the disease, which
include increasing the dose of imatinib, changing therapy to the 2nd generation tyrosine kinase
inhibitors or allogeneic hematopoietic stem cell transplantation.
Hematologia 2010; 1, 3: 195-218
Hematologia 2010; 1, 3: 195-218
Keywords: chronic myeloid leukemiaBCR-ABL1 kinasetargeted therapyimatinibdrug resistance