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

• Published in: Cell death & disease Vol. 8; no. 10; p. e3114
• Main Authors: Pereira, Welbert O, De Carvalho, Daniel D, Zenteno, Maria Emilia, Ribeiro, Beatriz F, Jacysyn, Jacqueline F, Sardinha, Luiz R, Zanichelli, Maria A, Hamerschlak, Nelson, Jones, Gareth E, Pagnano, Katia B, Castro, Fabiola A, Calle, Yolanda, Amarante-Mendes, Gustavo P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/208/2489/2487/2486; 631/337/176/1988; 631/67/1990/283/1896; 631/80/82/23; Antibodies; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Azacitidine - therapeutic use; Biochemistry; Blast crisis; Carcinogenesis - genetics; Cell Biology; Cell Culture; Chronic myeloid leukemia; DNA methylation; DNA Methylation - drug effects; DNA Methylation - genetics; Drug Resistance, Neoplasm; Epigenesis, Genetic; Epigenetics; Fusion Proteins, bcr-abl - biosynthesis; Fusion Proteins, bcr-abl - metabolism; Genomic instability; Humans; Imatinib Mesylate - therapeutic use; Immunology; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - mortality; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Life Sciences; Malignancy; Myeloid leukemia; Original; original-article; Promoter Regions, Genetic - genetics; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Signal transduction; Signal Transduction - physiology; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL protein; Tumorigenesis; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome Protein - biosynthesis; Wiskott-Aldrich Syndrome Protein - genetics; Wiskott-Aldrich Syndrome Protein - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.458

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).