Mutation of inhibitory helix-loop-helix protein Id3 causes γδ T-cell lymphoma in mice.
Human γδ T-cell lymphoma is a rare clinicopathologic entity with aggressive course and poor prognosis. The etiology and pathogenesis of γδ T-cell lymphoma is unknown. We show here that mice with deficiency in inhibitory helix-loop-helix protein Id3 (Id3(-/-)) developed γδ T-cell lymphoma that resembled human γδ T-cell lymphoma. The Id3(-/-) mice with lymphoma showed splenomegaly, hepatomegaly, and lymphadenopathy with involvement of bone marrow, thymus, kidney, and lungs between 6 and 15 months of age. Phenotypic analysis revealed that lymphomatous cells were cluster of differentiation (CD)3(+), γδ T-cell receptor (TCR)(+), and αβ TCR(-), and expressed CD8(+)CD4(-), CD4(+)CD8(-), or a mixture of the two. Id3(-/-) γδ T-cell lymphoma used predominantly Vγ1.1, some Vγ3, yet no Vγ2 TCR, and some showed increased levels of the oncogene c-Myc. Strikingly, adoptive transfer of the γδ T-cell lymphoma into syngeneic Rag1(-/-) mice resulted in aggressive γδ T-cell lymphoma, identical to the Id3(-/-) donor. Thus, our data demonstrate that Id3 regulates the development of γδ T-cell lymphoma in mice, raising a possibility of Id3 gene mutation in human γδ T-cell lymphoma. Our model will provide a tool for studying the molecular mechanisms and development of human γδ T-cell lymphoma.
Li
Jun
J
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Maruyama
Takashi
T
Zhang
Pin
P
Konkel
Joanne E
JE
Hoffman
Victoria
V
Zamarron
Brian
B
Chen
Wanjun
W
D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018398:Homeodomain Proteins; D051796:Inhibitor of Differentiation Proteins; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; C064658:RAG-1 protein; C067679:Idb3 protein, mouse