TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis

TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis

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Summary: 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 sophie allport zebra 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 read more TIFAB as an effector of USP15 activity and rheostat of p53 signaling in stressed and malignant HSPCs.

: Niederkorn et al.identify TIFAB as a critical node in hematopoietic cells under stressed and oncogenic cell states.Their studies indicate that deregulation of the TIFAB-USP15 complex, as observed in del(5q) myelodysplasia or MLL-rearranged leukemia, modulates p53 activity and has critical functional consequences for stressed and malignant hematopoietic cells.Keywords: TIFAB, TIFA, USP15, DUB, p53, hematopoiesis, AML, TRAF6.