B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia.
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.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
Weizhou
W
Zhang
Arnon P
AP
Kater
George F
GF
Widhopf
Han-Yu
HY
Chuang
Thomas
T
Enzler
Danelle F
DF
James
Maxim
M
Poustovoitov
Ping-Hui
PH
Tseng
Siegfried
S
Janz
Carl
C
Hoh
Harvey
H
Herschman
Michael
M
Karin
Thomas J
TJ
Kipps
D000818:Animals; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics / Q000276:immunology; D016259:Genes, myc; D006801:Humans; D007156:Immunologic Memory; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D053264:B-Cell Activating Factor; C489427:MYC protein, human; C489428:Myc protein, mouse; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; C505720:Tnfsf13b protein, mouse