| First Author | Niederkorn M | Year | 2020 |
| Journal | Cell Rep | Volume | 30 |
| Issue | 8 | Pages | 2776-2790.e6 |
| PubMed ID | 32101751 | Mgi Jnum | J:287555 |
| Mgi Id | MGI:6415433 | Doi | 10.1016/j.celrep.2020.01.093 |
| Citation | Niederkorn M, et al. (2020) TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis. Cell Rep 30(8):2776-2790.e6 |
| abstractText | TRAF-interacting protein with a forkhead-associated domain B (TIFAB) is implicated in myeloid malignancies with deletion of chromosome 5q. Employing a combination of proteomic and genetic approaches, we find that TIFAB regulates ubiquitin-specific peptidase 15 (USP15) ubiquitin hydrolase activity. Expression of TIFAB in hematopoietic stem/progenitor cells (HSPCs) permits USP15 signaling to substrates, including MDM2 and KEAP1, and mitigates p53 expression. Consequently, TIFAB-deficient HSPCs exhibit compromised USP15 signaling and are sensitized to hematopoietic stress by derepression of p53. In MLL-AF9 leukemia, deletion of TIFAB increases p53 signaling and correspondingly decreases leukemic cell function and development of leukemia. Restoring USP15 expression partially rescues the function of TIFAB-deficient MLL-AF9 cells. Conversely, elevated TIFAB represses p53, increases leukemic progenitor function, and correlates with MLL gene expression programs in leukemia patients. Our studies uncover a function of TIFAB as an effector of USP15 activity and rheostat of p53 signaling in stressed and malignant HSPCs. |
