Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the BCR–ABL1 tyrosine kinase (TK). The development of TK inhibitors (TKIs) revolutionized the treatment of CML patients. However, TKIs are not effective to those at advanced phases when amplified BCR–ABL1 levels and increased genomic instability lead to secondary oncogenic modifications. Wiskott–Aldrich syndrome protein (WASP) is an important regulator of signaling transduction in hematopoietic cells and was shown to be an endogenous inhibitor of the c-ABL TK. Here, we show that the expression of WASP decreases with the progression of CML, inversely correlates with the expression of BCR–ABL1 and is particularly low in blast crisis. Enforced expression of BCR–ABL1 negatively regulates the expression of WASP. Decreased expression of WASP is partially due to DNA methylation of the proximal WASP promoter. Importantly, lower levels of WASP in CML advanced phase patients correlate with poorer overall survival (OS) and is associated with TKI response. Interestingly, enforced expression of WASP in BCR–ABL1-positive K562 cells increases the susceptibility to apoptosis induced by TRAIL or chemotherapeutic drugs and negatively modulates BCR–ABL1-induced tumorigenesis in vitro and in vivo. Taken together, our data reveal a novel molecular mechanism that operates in BCR–ABL1-induced tumorigenesis that can be used to develop new strategies to help TKI-resistant, CML patients in blast crisis (BC).
Highlights
Chronic myeloid leukemia (CML) is a hematological malignancy caused by the chromosome translocation t (9:22) (q34;q11), which originates the oncogene BCR– ABL1
Patients responsive to TK inhibitors (TKIs) were no different from either healthy individuals or CML patients at diagnosis (Figure 1b). These data indicate that WAS protein (WASP) expression is linked to CML patient’s response to TKIs therapy and to BCR–ABL1 levels
Twenty-one CML patients resistant to TKIs were tested for BCR–ABL mutation; 9 of them were positive for Y253H (2); M244V (2); T315I (2); F317L (1); H396R (1) e G250E/Y253H (1) mutations
Summary
Chronic myeloid leukemia (CML) is a hematological malignancy caused by the chromosome translocation t (9:22) (q34;q11), which originates the oncogene BCR– ABL1. In the accelerated phase (AP), differentiation becomes arrested, and the severe disease phenotype is caused by the proliferation of immature blasts, which increases in the BC.[3,10] Mechanisms of imatinib resistance are multifactorial and include point mutations within the BCR–ABL kinase domain,[11,12] BCR–ABL gene amplification,[11] decreased intracellular drug availability[13] and activation of alternative signaling oncogenic pathways.[14,15] In the advanced phases, patients present a stronger resistance to imatinib or other second- and thirdgeneration TK inhibitors (TKIs),[16] indicating an unmet need for improved therapeutic approaches in CML treatment. WASP was shown to act as an endogenous inhibitor of the TKs LCK, FYN and c-ABL.[30,31,32]
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