title: Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy.
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.
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Wei
authors: W
authors: An
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Scott A
authors: SA
authors: Nadeau
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Bhopal C
authors: BC
authors: Mohapatra
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Dan
authors: D
authors: Feng
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Neha
authors: N
authors: Zutshi
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Matthew D
authors: MD
authors: Storck
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Priyanka
authors: P
authors: Arya
authors: Departments of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: James E
authors: JE
authors: Talmadge
authors: College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Jane L
authors: JL
authors: Meza
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Vimla
authors: V
authors: Band
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Hamid
authors: H
authors: Band
mesh_terms: D000818:Animals; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human; C493849:Cbl protein, mouse; D005472:Fluorouracil
keywords: Cbl; HSC; quiescence; tyrosine kinase; ubiquitin ligase