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.
Zhang
Weizhou
W
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.
Kater
Arnon P
AP
Widhopf
George F
GF
Chuang
Han-Yu
HY
Enzler
Thomas
T
James
Danelle F
DF
Poustovoitov
Maxim
M
Tseng
Ping-Hui
PH
Janz
Siegfried
S
Hoh
Carl
C
Herschman
Harvey
H
Karin
Michael
M
Kipps
Thomas J
TJ
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