BCR-ABL1-induced downregulation of WASP in chronic myeloid leukemia involves epigenetic modification and contributes to malignancy.
Welbert O PereiraDaniel D De CarvalhoMaria Emilia ZentenoBeatriz F RibeiroJacqueline F JacysynLuiz R SardinhaMaria A ZanichelliNelson HammerschlakGareth E JonesKatia B PagnanoFabiola A CastroYolanda CalleGustavo P Amarante-MendesPublished in: Cell death & disease (2017)
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).
Keyphrases
- chronic myeloid leukemia
- tyrosine kinase
- poor prognosis
- dna methylation
- end stage renal disease
- ejection fraction
- cell cycle arrest
- gene expression
- chronic kidney disease
- newly diagnosed
- peritoneal dialysis
- induced apoptosis
- binding protein
- public health
- genome wide
- epidermal growth factor receptor
- cell death
- high glucose
- transcription factor
- copy number
- acute lymphoblastic leukemia
- big data
- pi k akt
- artificial intelligence
- amino acid