Abstract
Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET. Treatment with a MET inhibitor resensitized K562/IR cells to BCR-ABL1 TKIs. Combined treatment of K562/IR cells with imatinib and a MET inhibitor suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Our findings implicate the MET/ERK and MET/JNK pathways in conferring resistance to imatinib, providing new insights into the mechanisms of BCR-ABL1 TKI resistance in CML.
Highlights
Leukemia is a cancer of the bone marrow or blood characterized by an excessive increase in immature white blood cells
We found that the resistant K562/IR cells displayed a significantly higher IC50 for viability compared to the parental K562 cells following exposure to all tyrosine kinase inhibitor (TKI) tested (Supplementary Figure 1)
We found that K562/IR and KU812/ IR cells exhibited strong resistance to many BCR-ABL1 TKIs
Summary
Leukemia is a cancer of the bone marrow or blood characterized by an excessive increase in immature white blood cells. The BCR-ABL1 oncogene is a fusion protein that results from transposition of a segment of the c-ABL1 gene from chromosome 9q34 onto the BCR gene on chromosome 22q11. It encodes a cytoplasmic protein tyrosine kinase with elevated and dysregulated enzymatic activity that plays a vital role in the pathogenesis and progression of CML [2]. This fusion protein is found in approximately 95% of patients with CML and 30% of adult patients with acute lymphoblastic leukemia (ALL) [3]. BCR-ABL1 constitutively activates mitogenic signaling pathways, such as the Janus kinase/signal transduction and transcription (JAK/STAT) pathway, phosphatidylinositide-3 kinase (PI3K) pathway, RAS/mitogen-activated protein kinase (MAPK) pathways, and the MYC pathway [4]
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