Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas.
The requirement for receptor components and the signalling effector, signal transducer and activator of transcription (STAT) 5A/5B, was assessed genetically in a lymphoma development model induced by interleukin-7 (IL-7). This growth factor for T- and B-cell progenitors and mature lymphocytes activates survival and proliferative pathways including Bcl-2, phosphatidylinositol-3 kinase and STAT5. Overexpression of IL-7 in vivo causes early mortality from lymphoma development. Mice overexpressing IL-7 that were heterozygous for the IL-7Ralpha subunit showed improved survival compared to wild-type mice. In addition, STAT5A/5B+/- compound heterozygous mice with one targeted allele each of STAT5A and STAT5B showed striking amelioration of IL-7-induced mortality and disease development. STAT5A/5B+/- compound heterozygous mice were otherwise normal in stem cell and lymphocyte development and cellularity. Lower STAT5 protein levels accompanied the reduction in STAT5A/5B copy number, which suggests that STAT5 haploinsufficiency is a modifier of IL-7 signal strength.
Abraham
Ninan
N
Department of Microbiology and Immunology, The University of British Columbia, #300-6174, University Boulevard, BC, Canada. ninan@interchange.ubc.ca
Ma
Melissa C
MC
Snow
Jonathan W
JW
Miners
Melissa Jill
MJ
Herndier
Brian G
BG
Goldsmith
Mark A
MA
D000818:Animals; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics*; D004195:Disease Models, Animal; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006239:Haplotypes; D006801:Humans; D015851:Interleukin-7 / Q000235:genetics / Q000502:physiology*; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008894:Milk Proteins / Q000032:analysis* / Q000235:genetics*; D020395:Receptors, Interleukin-7 / Q000502:physiology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000032:analysis* / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D015851:Interleukin-7; D008894:Milk Proteins; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins