BCR-ABL1-induced downregulation of WASP in chronic myeloid leukemia involves epigenetic modification and contributes to malignancy

Autor(es):Mostrar menos -

Pereira, Welbert O. ^{[1, 2]} ; De Carvalho, Daniel D. ^{[3, 4]} ; Zenteno, Maria Emilia ^[2] ; Ribeiro, Beatriz F. ^[5] ; Jacysyn, Jacqueline F. ^{[6, 2]} ; Sardinha, Luiz R. ^[1] ; Zanichelli, Maria A. ^[7] ; Hamerschlak, Nelson ^[8] ; Jones, Gareth E. ^[9] ; Pagnano, Katia B. ; Castro, Fabiola A. ^[10] ; Calle, Yolanda ^{[11, 12]} ; Amarante-Mendes, Gustavo P. ^{[13, 2]}

Afiliação do(s) autor(es):Mostrar menos -

^[1] Hosp Israelita Albert Einstein, Inst Israelita Ensino & Pesquisa, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Av Prof Lineu Prestes 1730, Cidade Univ, BR-05508900 Sao Paulo - Brazil

^[3] Univ Toronto, Dept Med Biophys, Toronto, ON - Canada

^[4] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON - Canada

^[5] Univ Estadual Campinas, Ctr Hematol & Hemoterapia, Campinas, SP - Brazil

^[6] Univ Sao Paulo, Fac Med LIM62, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Hosp Clin, Inst Crianca, Inst Tratamento Canc Infantil, Sao Paulo - Brazil

^[8] Hosp Israelita Albert Einstein, Dept Hematol & Hemoterapia, Sao Paulo - Brazil

^[9] Kings Coll London, Randall Div Cell & Mol Biophys, London - England

^[10] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto - Brazil

^[11] Kings Coll London, Dept Haematooncol, London - England

^[12] Univ Roehampton, Dept Life Sci, London - England

^[13] INCT, Inst Invest Imunol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CELL DEATH & DISEASE; v. 8, OCT 2017.
• Citações Web of Science: 4

Resumo

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)

• Processo FAPESP: 15/21237-4 - Determinação do perfil de metilação de células-tronco hematopoéticas pré-leucêmicas e leucêmicas de leucemia mielóide aguda pelo ensaio "single cell dna methylation"
• Beneficiário: Fabíola Attié de Castro
• Modalidade de apoio: Bolsas no Exterior - Pesquisa