期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 44, 页码 18956-18960出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1013420107
关键词
nurselike cells; nuclear factor kappa-light-chain enhancer of activated B cells; I kappa B kinase inhibitor; prognostic factors; leukemia-cell survival
资金
- National Institutes of Health [R01 AI043477]
- Leukemia and Lymphoma Society Specialized Center
- Netherlands Organization for Health Research and Development
- Susan G. Komen for the Cure
Mice bearing a v-Myc myelocytomatosis viral oncogene homolog (c-Myc) transgene controlled by an Ig-alpha heavy-chain enhancer (iMyc(C alpha) 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(C alpha) 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(C alpha) 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 highlevels of BAFF. We find that BAFF could enhance CLL-cell expression of c-MYC via activation the canonical I kappa B kinase (IKK)/NF-kappa B pathway. Inhibition of the IKK/NF-kappa B 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-kappa B pathway may be effective in treatment of patients with this disease.
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