Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy.

摘要: Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human mutations associated with myeloproliferative disorders (MPD) reproduced in mice mutant knock-in or hematopoietic double knockout. However, the role of proteins stem cell (HSC) homeostasis, especially context MPD is unclear. Here we demonstrate HSC expansion development upon combined deletion dependent on HSCs. Cell cycle analysis demonstrated DKO HSCs exhibit reduced quiescence compromised reconstitution ability propensity to undergo exhaustion. We show sustained c-Kit FLT3 signaling promotes loss colony-forming potential, inhibition vitro protects from In vivo, treatment 5-fluorouracil hastens exhaustion death due MPD. Our data reveal a novel leukemia therapy-relevant maintenance protection against exhaustion, through negative regulation kinase-coupled receptor signaling.