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B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia.

Authors: Zhang, W  Kater, AP  Widhopf GF, 2ND  Chuang, HY  Enzler, T  James, DF  Poustovoitov, M  Tseng, PH  Janz, S  Hoh, C  Herschman, H  Karin, M  Kipps, TJ 
Citation: Zhang W, etal., Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18956-60. doi: 10.1073/pnas.1013420107. Epub 2010 Oct 18.
Pubmed: (View Article at PubMed) PMID:20956327
DOI: Full-text: DOI:10.1073/pnas.1013420107

Mice bearing a v-Myc myelocytomatosis viral oncogene homolog (c-Myc) transgene controlled by an Ig-alpha heavy-chain enhancer (iMyc(Calpha) mice) rarely develop lymphomas but instead have increased rates of memory B-cell turnover and impaired antibody responses to antigen. We found that male progeny of iMyc(Calpha) mice mated with mice transgenic (Tg) for CD257 (B-cell activating factor, BAFF) developed CD5(+) B-cell leukemia resembling human chronic lymphocytic leukemia (CLL), which also displays a male gender bias. Surprisingly, leukemic cells of Myc/Baff Tg mice expressed higher levels of c-Myc than did B cells of iMyc(Calpha) mice. We found that CLL cells of many patients with progressive disease also expressed high amounts of c-MYC, particularly CLL cells whose survival depends on nurse-like cells (NLC), which express high-levels of BAFF. We find that BAFF could enhance CLL-cell expression of c-MYC via activation the canonical IkappaB kinase (IKK)/NF-kappaB pathway. Inhibition of the IKK/NF-kappaB pathway in mouse or human leukemia cells blocked the capacity of BAFF to induce c-MYC or promote leukemia-cell survival and significantly impaired disease progression in Myc/Baff Tg mice. This study reveals an important relationship between BAFF and c-MYC in CLL which may affect disease development and progression, and suggests that inhibitors of the canonical NF-kappaB pathway may be effective in treatment of patients with this disease.


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RGD Object Information
RGD ID: 11340590
Created: 2016-06-29
Species: All species
Last Modified: 2016-06-29
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.