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

Abstract

Mice bearing a v-Myc myelocytomatosis viral oncogene homolog ( c-Myc ) transgene controlled by an Ig-alpha heavy-chain enhancer (i Myc 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 i Myc 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 i Myc 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.

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

“…For example, B-cell activating factor (BAFF) is made by supporting cells in the CLL microenvironment and promotes tumor progression. 23 BAFF activates the noncanonical NF-kB pathway, indicated by cleavage of p100 and the appearance of p52 in the p52/RelB active heterodimer. CLL cells treated with the stromal supernatant did not show increased expression levels of p52 ( Figure 2B), excluding a role for BAFF in this system.…”

Variable induction of PRDM1 and differentiation in chronic lymphocytic leukemia is associated with anergy

“…on May 10, 2018. by guest www.bloodjournal.org From expressed in circulating blood cells in U-CLL compared with M-CLL. [17][18][19][20] In normal B cells, anergy is associated with reduced differentiation in response to a range of stimuli.…”

Mouse Models of Chronic Lymphocytic Leukemia

“…Another interesting mouse model of CLL overexpressing both BAFF and c-Myc was recently described by Zhang and coworkers (Zhang et al, 2010). Transgenic mice with c-Myc under the control of the IgE enhancer (iMyc C  -tg) were initially generated to enforce c-Myc expression in plasma cells and memory cells (Cheung et al, 2004).…”

“…Transgenic mice with c-Myc under the control of the IgE enhancer (iMyc C  -tg) were initially generated to enforce c-Myc expression in plasma cells and memory cells (Cheung et al, 2004). Zhang and coworkers (Zhang et al, 2010) asked whether BAFF overexpression in these mice could induce development of CLL, since recent evidence indicates that CLL cells might arise from memory B cells (Klein et al, 2001). Interestingly, male c-Myc/Baff double transgenic mice did indeed developed lymphocytosis starting at 3 months of age because of increased blood Bcell number relative to that observed for single transgenic, wild type or female double transgenic mice.…”