Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases

作者：Dasgupta Yashodhara; Koptyra Mateusz; Hoser Grazyna; Kantekure Kanchan; Roy Darshan; Gornicka Barbara; Nieborowska Skorska Margaret; Bolton Gillespie Elisabeth; Cerny Reiterer Sabine; Muschen Markus; Valent Peter; Wasik Mariusz A; Richardson Christine; Hantschel Oliver; van der Kuip Heiko; Stoklosa Tomasz; Skorski Tomasz

来源：Blood, 2016, 127(17): 2131-2143.

DOI：10.1182/blood-2015-11-681171

Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1. Therefore, we postulate that normal ABL1 kinase behaves like a tumor suppressor and therapeutic target in leukemias expressing oncogenic forms of the kinase.

• 出版日期2016-4-28
• 单位上海生物信息技术研究中心