title: Loss of p19Arf in a Rag1(-/-) B-cell precursor population initiates acute B-lymphoblastic leukemia.
abstract: In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf(-/-)Rag1(-/-) mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemia-initiating mechanism originating from a Sca1(+)CD19(+) precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34(+)CD19(+) population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans.
authors.affiliation: Inserm U768, René Descartes University of Paris, and Necker Children's Hospital, Paris, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Hauer
authors.forename: Charles
authors.initials: C
authors.lastname: Mullighan
authors.forename: Estelle
authors.initials: E
authors.lastname: Morillon
authors.forename: Gary
authors.initials: G
authors.lastname: Wang
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: Marc
authors.initials: M
authors.lastname: Lelorc'h
authors.forename: Serge
authors.initials: S
authors.lastname: Romana
authors.forename: Amine
authors.initials: A
authors.lastname: Boudil
authors.forename: Daniela
authors.initials: D
authors.lastname: Tiedau
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushmann
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology
chemical_list: D018941:Antigens, CD19; D018952:Antigens, CD34; D000950:Antigens, Ly; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C064658:RAG-1 protein; D019009:Proto-Oncogene Proteins c-kit