title: VAV1-Cre mediated hematopoietic deletion of CBL and CBL-B leads to JMML-like aggressive early-neonatal myeloproliferative disease.
abstract: CBL and CBL-B ubiquitin ligases play key roles in hematopoietic stem cell homeostasis and their aberrations are linked to leukemogenesis. Mutations of CBL, often genetically-inherited, are particularly common in Juvenile Myelomonocytic Leukemia (JMML), a disease that manifests early in children. JMML is fatal unless corrected by bone marrow transplant, which is effective in only half of the recipients, stressing the need for animal models that recapitulate the key clinical features of this disease. However, mouse models established so far only develop hematological malignancy in adult animals. Here, using VAV1-Cre-induced conditional CBL/CBL-B double knockout (DKO) in mice, we established an animal model that exhibits a neonatal myeloproliferative disease (MPD). VAV1-Cre induced DKO mice developed a strong hematological phenotype at postnatal day 10, including severe leukocytosis and hepatomegaly, bone marrow cell hypersensitivity to cytokines including GM-CSF, and rapidly-progressive disease and invariable lethality. Interestingly, leukemic stem cells were most highly enriched in neonatal liver rather than bone marrow, which, along with the spleen and thymus, were hypo-cellular. Nonetheless, transplantation assays showed that both DKO bone marrow and liver cells can initiate leukemic disease in the recipient mice with seeding of both spleen and bone marrow. Together, our results support the usefulness of the new hematopoietic-specific CBL/CBL-B double KO animal model to study JMML-related pathogenesis and to further understand the function of CBL family proteins in regulating fetal and neonatal hematopoiesis. To our knowledge, this is the first mouse model that exhibits neonatal MPD in infancy, by day 10 of postnatal life.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: An
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Bhopal C
authors.initials: BC
authors.lastname: Mohapatra
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Zutshi
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Bielecki
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Goez
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Luan
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Fany
authors.initials: F
authors.lastname: Iseka
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Insha
authors.initials: I
authors.lastname: Mushtaq
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Storck
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.|Departments of Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D006410:Hematopoiesis; D019426:Integrases / Q000235:genetics; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; C045073:Cre recombinase; D019426:Integrases; C493849:Cbl protein, mouse
keywords: CBL; HSC; JMML; neonatal hematopoiesis; ubiquitin ligase