B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2010 Nov 02;107(44):18956-60
Date
10/20/2010Pubmed ID
20956327Pubmed Central ID
PMC2973856DOI
10.1073/pnas.1013420107Scopus ID
2-s2.0-78650481186 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
Mice bearing a v-Myc myelocytomatosis viral oncogene homolog (c-Myc) transgene controlled by an Ig-alpha heavy-chain enhancer (iMyc(Cα) 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(Cα) 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(Cα) 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 IκB kinase (IKK)/NF-κB pathway. Inhibition of the IKK/NF-κB 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-κB pathway may be effective in treatment of patients with this disease.
Author List
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 TJAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsB-Cell Activating Factor
B-Lymphocytes
Female
Gene Expression Regulation, Leukemic
Genes, myc
Humans
Immunologic Memory
Leukemia, Lymphocytic, Chronic, B-Cell
Male
Mice
Mice, Transgenic
NF-kappa B
Proto-Oncogene Proteins c-myc
