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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD19 / metabolism
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Antigens, CD34 / metabolism
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Antigens, Ly / metabolism
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Apoptosis / physiology
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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B-Lymphocytes / physiology*
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Bone Marrow Cells / cytology
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Bone Marrow Cells / physiology
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p16 / genetics*
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Gene Expression Regulation, Leukemic / physiology
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology
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Hematopoietic Stem Cells / physiology*
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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Membrane Proteins / metabolism
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Mice
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Mice, Mutant Strains
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Neoplasm Transplantation
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Phenotype
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Receptor, Notch1 / genetics
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Signal Transduction / physiology
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Stromal Cells / cytology
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Stromal Cells / physiology
Substances
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Antigens, CD19
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Antigens, CD34
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Antigens, Ly
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Homeodomain Proteins
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Ly6a protein, mouse
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Membrane Proteins
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Notch1 protein, mouse
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Receptor, Notch1
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RAG-1 protein
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Proto-Oncogene Proteins c-kit