Deregulation of c-Myc Confers distinct survival requirements for memory B cells, plasma cells, and their progenitors.
Deregulation of c-Myc Confers distinct survival requirements for memory B cells, plasma cells, and their progenitors.
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DOI：
10.4049/jimmunol.181.11.7537
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Erickson LD
中科院分区：
文献类型：
--
作者：
Khuda SE;Loo WM;Janz S;Van Ness B;Erickson LD
c-Myc癌基因的失调与人类和小鼠浆细胞（PC）肿瘤密切相关。通过分析Myc靶向Igh Cα基因座的小鼠中Ag特异性B细胞应答，我们在此显示c-Myc显著损害初次和二次Ab应答。这种损伤是分化阶段特异性的，因为生发中心B细胞形成、亲和力成熟和类别转换重组是完整的。PC活力的检查显示，c-Myc仅在最终成熟时触发细胞凋亡，此时Ab被分泌并且对存活因子BAFF（属于TNF家族的B细胞活化因子）具有抗性。与此相反，PC前体（PCpre），最终产生成熟的PC正常存活，并大力扩大BAFF信号。我们进一步表明，c-Myc也促进记忆B细胞的凋亡。因此，Cα-Myc比以前预期的更能控制长寿B细胞免疫的两个细胞臂。只有当c-Myc的失调与强制Bcl-xL表达相结合时，成熟的PC才能在BAFF的作用下存活。这些数据表明，对肿瘤敏感的PCpre和PC的生存要求是不同的，当细胞凋亡途径如Bcl-2家族成员被禁用时，肿瘤进展可能随着PCpre向功能性PC的过渡而发展。
Deregulation of the c-Myc oncogene is tightly associated with human and murine plasma cell (PC) neoplasms. Through the analysis of Ag-specific B cell responses in mice where Myc is targeted to the Igh Cα locus, we show here that c-Myc dramatically impairs the primary and secondary Ab response. This impairment is differentiation stage specific, since germinal center B cell formation, affinity maturation, and class switch recombination were intact. Examination of PC viability revealed that c-Myc triggered apoptosis only upon final maturation when Ab is secreted and is resistant to the survival factor BAFF (B cell-activating factor belonging to the TNF family). In contrast, PC precursors (PCpre) that ultimately give rise to mature PCs survived normally and vigorously expanded with BAFF signaling. We further show that c-Myc also facilitates the apoptosis of memory B cells. Thus, Cα-Myc controls both cellular arms of long-lived B cell immunity than previously anticipated. Only when deregulation of c-Myc was combined with enforced Bcl-xL expression were mature PCs able to survive in response to BAFF. These data indicate that the survival requirements for tumor-susceptible PCpre and PCs are distinct and that tumor progression likely develops as PCpre transition to functional PCs when apoptotic pathways such as members of the Bcl-2 family are disabled.
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影响因子：
8
作者：
Butzler, C;Zou, XG;Bruggemann, M
通讯作者：
Bruggemann, M
DOI：
10.1073/pnas.93.24.13931
发表时间：
1996-11-26
影响因子：
11.1
作者：
Bergsagel, PL;Chesi, M;Kuehl, WM
通讯作者：
Kuehl, WM
影响因子：
20.3
作者：
Guzman, Monica L.;Li, Xiaojie;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
8
作者：
Bergsagel, PL;Kuehl, WM
通讯作者：
Kuehl, WM
影响因子：
3.7
作者：
George, TC;Basiji, DA;Morrissey, PJ
通讯作者：
Morrissey, PJ