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Dasgupta Y , Koptyra M , Hoser G , Kantekure K , Roy D , Gornicka B , Nieborowska-Skorska M , Bolton-Gillespie E , Cerny-Reiterer S , Muschen M , Valent P , Wasik MA , Richardson C , Hantschel O , van der Kuip H , Stoklosa T , Skorski T
Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases
Blood. 2016 Apr 28;127(17) :2131-43
PMID: 26864341    PMCID: PMC4850868   
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Abstract
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.
Notes
1528-0020 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 P30 CA006927/CA/NCI NIH HHS/United States R01 CA134458/CA/NCI NIH HHS/United States Journal Article United States Blood. 2016 Apr 28;127(17):2131-43. doi: 10.1182/blood-2015-11-681171. Epub 2016 Feb 10.