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| Blood. 2016 Feb 10. pii: blood-2015-11-681171. doi: 10.1182/blood-2015-11-681171 |
| Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases. |
| Dasgupta Y1, Koptyra M2, Hoser G3, Kantekure K4, Roy D5, Gornicka B6, Nieborowska-Skorska M7, Bolton-Gillespie E8, Cerny-Reiterer S9, Müschen M10, Valent P11, Wasik MA12, Richardson C13, Hantschel O14, van der Kuip H15, Stoklosa T16, Skorski T17 |
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Abstract Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least one normal ABL1 allele. Since 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-blast phase (CML-BP)-like disease in mice compared to less malignant CML-chronic phase (CML-CP)-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 anti-leukemia 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. |
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Copyright © 2016 American Society of Hematology. |
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Publikations ID: 26864341 Quelle: öffnen |
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