title: ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1.
abstract: ABL gene translocations create constitutively active tyrosine kinases that are causative in chronic myeloid leukemia, acute lymphocytic leukemia and other hematopoietic malignancies. Consistent retention of ABL SH3/SH2 autoinhibitory domains, however, suggests that these leukemogenic tyrosine kinase fusion proteins remain subject to regulation. We resolve this paradox, demonstrating that BCR-ABL1 kinase activity is regulated by RIN1, an ABL SH3/SH2 binding protein. BCR-ABL1 activity was increased by RIN1 overexpression and decreased by RIN1 silencing. Moreover, Rin1(-/-) bone marrow cells were not transformed by BCR-ABL1, ETV6-ABL1 or BCR-ABL1(T315I), a patient-derived drug-resistant mutant, as judged by growth factor independence. Rescue by ectopic RIN1 verified a cell autonomous mechanism of collaboration with BCR-ABL1 during transformation. Sensitivity to the ABL kinase inhibitor imatinib was increased by RIN1 silencing, consistent with RIN1 stabilization of an activated BCR-ABL1 conformation having reduced drug affinity. The dependence on activation by RIN1 to unleash full catalytic and cell transformation potential reveals a previously unknown vulnerability that could be exploited for treatment of leukemic cases driven by ABL translocations. The findings suggest that RIN1 targeting could be efficacious for imatinib-resistant disease and might complement ABL kinase inhibitors in first-line therapy.
authors.affiliation: Department of Biological Chemistry, Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thai
authors.forename: P Y
authors.initials: PY
authors.lastname: Ting
authors.forename: J
authors.initials: J
authors.lastname: McLaughlin
authors.forename: D
authors.initials: D
authors.lastname: Cheng
authors.forename: M
authors.initials: M
authors.lastname: Müschen
authors.forename: O N
authors.initials: ON
authors.lastname: Witte
authors.forename: J
authors.initials: J
authors.lastname: Colicelli
mesh_terms: D000818:Animals; D001549:Benzamides; D002471:Cell Transformation, Neoplastic; D016044:Fusion Proteins, bcr-abl; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020014:K562 Cells; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D014178:Translocation, Genetic; D018909:src Homology Domains
chemical_list: D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C092117:RIN1 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl