Research Papers:
Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy
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Abstract
Wei An1,2, Scott A. Nadeau1,2, Bhopal C. Mohapatra1,3, Dan Feng1, Neha Zutshi1,4, Matthew D. Storck1, Priyanka Arya1,2, James E. Talmadge4, Jane L. Meza5, Vimla Band1,2,6, Hamid Band1,2,3,4,6
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
2Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
3Departments of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
4Departments of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
5College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA
6Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Correspondence to:
Hamid Band, e-mail: [email protected]
Keywords: Cbl, ubiquitin ligase, HSC, quiescence, tyrosine kinase
Received: February 14, 2015 Accepted: February 16, 2015 Published: March 19, 2015
ABSTRACT
Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution ability and propensity to undergo exhaustion. We show that sustained c-Kit and FLT3 signaling in DKO HSCs promotes loss of colony-forming potential, and c-Kit or FLT3 inhibition in vitro protects HSCs from exhaustion. In vivo, treatment with 5-fluorouracil hastens DKO HSC exhaustion and protects mice from death due to MPD. Our data reveal a novel and leukemia therapy-relevant role of Cbl and Cbl-b in the maintenance of HSC quiescence and protection against exhaustion, through negative regulation of tyrosine kinase-coupled receptor signaling.
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