| First Author | Thai M | Year | 2011 |
| Journal | Leukemia | Volume | 25 |
| Issue | 2 | Pages | 290-300 |
| PubMed ID | 21102429 | Mgi Jnum | J:168490 |
| Mgi Id | MGI:4888447 | Doi | 10.1038/leu.2010.268 |
| Citation | Thai M, et al. (2011) ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1. Leukemia 25(2):290-300 |
| abstractText | 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. |
