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Genes Dev. 2014 Jun 1;28(11):1179-90. doi: 10.1101/gad.240820.114.

MuLV-related endogenous retroviral elements and Flt3 participate in aberrant end-joining events that promote B-cell leukemogenesis.

Author information

1
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Department of Immunology.
2
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
3
Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada;
4
The Centre for Applied Genomics, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada;
5
The Centre for Applied Genomics, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada; Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.
6
Department of Immunology, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada.

Abstract

During V(D)J recombination of immunoglobulin genes, p53 and nonhomologous end-joining (NHEJ) suppress aberrant rejoining of DNA double-strand breaks induced by recombinase-activating genes (Rags)-1/2, thus maintaining genomic stability and limiting malignant transformation during B-cell development. However, Rag deficiency does not prevent B-cell leukemogenesis in p53/NHEJ mutant mice, revealing that p53 and NHEJ also suppress Rag-independent mechanisms of B-cell leukemogenesis. Using several cytogenomic approaches, we identified a novel class of activating mutations in Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant Flt3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-Flt3 fusion genes encoding an N-terminally truncated mutant form of Flt3 (trFlt3) that was transcribed from ERV long terminal repeats. trFlt3 protein lacked most of the Flt3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trFlt3 in p53/NHEJ mutant hematopoietic progenitor cells promoted development of clinically aggressive B-cell leukemia. Thus, repetitive MuLV-related ERV sequences can participate in aberrant end-joining events that promote development of aggressive B-cell leukemia.

KEYWORDS:

B-cell development; Fms-like tyrosine kinase 3; endogenous retrovirus; lymphoblastic leukemia; nonhomologous end-joining; p53

PMID:
24888589
PMCID:
PMC4052764
DOI:
10.1101/gad.240820.114
[Indexed for MEDLINE]
Free PMC Article

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