MuLV-related endogenous retroviral elements and F1t3 participate in aberrant end-joining events that promote B-cell leukemogenesis

作者：Johnson Radia M; Papp Eniko; Grandal Ildiko; Kowalski Paul E; Nutter Lauryl; Wong Raymond C C; Joseph George Ann M; Danska Jayne S; Guidos Cynthia J^*

来源：Genes & Development, 2014, 28(11): 1179-1190.

DOI：10.1101/gad.240820.114

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

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 Ens-like tyrosine kinase 3 (F1t3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant F1t3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-F1t3 fusion genes encoding an N-terminally truncated mutant form of F1t3 (trF1t3) that was transcribed from ERV long terminal repeats. trElt3 protein lacked most of the F1t3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trElt3 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.

• 出版日期2014-6-1