8 research outputs found
Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease
Gene Correction of Induced Pluripotent Stem Cells Derived from a Murine Model of X-Linked Chronic Granulomatous Disorder
Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency
Characterization of T cell activation and regulation in children with asymptomatic Plasmodium falciparum infection
Cyclophosphamide promotes engraftment of gene-modified cells in a mouse model of Fanconi anemia without causing cytogenetic abnormalities
ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1
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