Pereira, Welbert O.
De Carvalho, Daniel D.
Zenteno, Maria Emilia
Ribeiro, Beatriz F.
Jacysyn, Jacqueline F.
Sardinha, Luiz R.
Zanichelli, Maria A.
Jones, Gareth E.
Pagnano, Katia B.
Castro, Fabiola A.
Amarante-Mendes, Gustavo P.
 Univ Sao Paulo, Fac Med LIM62, Sao Paulo - Brazil
 Univ Sao Paulo, Hosp Clin, Inst Crianca, Inst Tratamento Canc Infantil, Sao Paulo - Brazil
 Hosp Israelita Albert Einstein, Dept Hematol & Hemoterapia, Sao Paulo - Brazil
 Kings Coll London, Randall Div Cell & Mol Biophys, London - England
 Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto - Brazil
 Kings Coll London, Dept Haematooncol, London - England
 Univ Roehampton, Dept Life Sci, London - England
 INCT, Inst Invest Imunol, Sao Paulo - Brazil
Total Affiliations: 13
CELL DEATH & DISEASE;
Web of Science Citations:
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). (AU)