title: Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases.
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.
authors: Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, PA;
authors: Yashodhara
authors: Y
authors: Dasgupta
authors: Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, PA;
authors: Mateusz
authors: M
authors: Koptyra
authors: Department of Clinical Cytology, Medical Center for Postgraduate Education, Warsaw, Poland;
authors: Grazyna
authors: G
authors: Hoser
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA;
authors: Kanchan
authors: K
authors: Kantekure
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA;
authors: Darshan
authors: D
authors: Roy
authors: Department of Pathology, Medical University of Warsaw, Warsaw, Poland;
authors: Barbara
authors: B
authors: Gornicka
authors: Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, PA;
authors: Margaret
authors: M
authors: Nieborowska-Skorska
authors: Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, PA;
authors: Elisabeth
authors: E
authors: Bolton-Gillespie
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna and Ludwig-Boltzmann Cluster Oncology, Vienna, Austria;
authors: Sabine
authors: S
authors: Cerny-Reiterer
authors: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA;
authors: Markus
authors: M
authors: Müschen
authors: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna and Ludwig-Boltzmann Cluster Oncology, Vienna, Austria;
authors: Peter
authors: P
authors: Valent
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA;
authors: Mariusz A
authors: MA
authors: Wasik
authors: Department of Biological Sciences and Center of Bioinformatics, University of North Carolina at Charlotte, Charlotte, NC;
authors: Christine
authors: C
authors: Richardson
authors: Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
authors: Oliver
authors: O
authors: Hantschel
authors: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany; and.
authors: Heiko
authors: H
authors: van der Kuip
authors: Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
authors: Tomasz
authors: T
authors: Stoklosa
authors: Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, PA;
authors: Tomasz
authors: T
authors: Skorski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D016313:Genes, abl; D042822:Genomic Instability; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000502:physiology*; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D007093:Imidazoles; D009363:Neoplasm Proteins; D016374:Oncogene Proteins v-abl; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D025521:Tumor Suppressor Proteins; C545373:ponatinib; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl