1. Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases.
- Author
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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, Müschen M, Valent P, Wasik MA, Richardson C, Hantschel O, van der Kuip H, Stoklosa T, and Skorski T more...
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Blast Crisis drug therapy, Blast Crisis enzymology, Blast Crisis pathology, Cell Division drug effects, Cell Line, Tumor, Cytostatic Agents pharmacology, Gene Expression Regulation, Leukemic drug effects, Genomic Instability, Humans, Imatinib Mesylate pharmacology, Imatinib Mesylate therapeutic use, Imidazoles pharmacology, Imidazoles therapeutic use, Leukemia, Experimental drug therapy, Leukemia, Experimental enzymology, Leukemia, Experimental pathology, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase enzymology, Leukemia, Myeloid, Chronic-Phase pathology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins physiology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells enzymology, Oncogene Proteins v-abl antagonists & inhibitors, Oncogene Proteins v-abl genetics, Oncogene Proteins, Fusion antagonists & inhibitors, Oncogene Proteins, Fusion genetics, Oxidative Stress, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-abl genetics, Pyridazines pharmacology, Pyridazines therapeutic use, Tumor Suppressor Proteins antagonists & inhibitors, Tumor Suppressor Proteins genetics, Blast Crisis genetics, Genes, Tumor Suppressor, Genes, abl, Leukemia, Experimental genetics, Leukemia, Myeloid, Chronic-Phase genetics, Oncogene Proteins v-abl physiology, Oncogene Proteins, Fusion physiology, Proto-Oncogene Proteins c-abl physiology, Tumor Suppressor Proteins physiology
- 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., (© 2016 by The American Society of Hematology.) more...
- Published
- 2016
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