Pim1 and Myc reversibly transform murine precursor B lymphocytes but not mature B lymphocytes
Pim1 and Myc reversibly transform murine precursor B lymphocytes but not mature B lymphocytes
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DOI：
10.1002/eji.201141987
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发表时间：
2012-02-01
影响因子：
5.4
通讯作者：
Melchers, Fritz
中科院分区：
文献类型：
--
作者：
Bouquet, Corinne;Melchers, Fritz
已知在许多类型的癌症中失调的原癌基因Myc和Pim 1在B淋巴瘤的发展中协作。在这里，我们表明，在IL-7剥夺，生长停滞的前B细胞中，逆转录病毒转导的，强力霉素诱导的Myc单独过表达增强了细胞周期的进入，而不损害凋亡。Pim 1过表达减少细胞凋亡，但对细胞周期的进入没有影响。Pim 1和Myc的共表达抑制了细胞凋亡，并导致转导的前B细胞在体外的IL-7非依赖性增殖，同时阻断了它们向IgM+未成熟细胞的分化。将过表达Pim 1/Myc的前BI细胞移植到B细胞缺陷小鼠中，在48周内将前B细胞区室扩增至100倍。转化仍然依赖于这两种癌基因的表达，在体外和体内去除强力霉素终止增殖和诱导分化为IgM+ B细胞。相比之下，在体内不存在癌基因过表达的情况下，从癌基因转导的前BI细胞发育的Pim 1/Myc转导的成熟B细胞在体内或体外诱导Pim和Myc过表达后不能长期增殖，无论是否有多克隆激活剂的刺激。
The proto-oncogenes Myc and Pim1, which are deregulated in many types of cancers, are known to cooperate in B lymphoma development. Here we show that overexpression of retrovirally transduced, doxycycline-inducible Myc alone in IL-7-deprived, growth-arrested pre-B cells enhanced cell cycle entry without impairing apoptosis. Overexpression of Pim1 decreased apoptosis, but had no effect on cell cycle entry. Co-expression of Pim1 and Myc inhibited apoptosis and led to IL-7-independent proliferation of the transduced pre-B cells in vitro, while blocking their differentiation to IgM+ immature cells. Transplantation of Pim1/Myc overexpressing pre-BI cells into B-cell-deficient mice expanded the pre-B-cell compartments up to 100-fold within 48 weeks. Transformation remained dependent on the expression of both oncogenes, as removal of doxycycline in vitro and in vivo terminated proliferation and induced differentiation to IgM+ B cells. In contrast, Pim1/Myc-transduced mature B cells that developed from the oncogene-transduced pre-BI cells in the absence of oncogene overexpression in vivo were not capable of long-term proliferation after induction of Pim and Myc overexpression, neither in vivo nor in vitro, neither with nor without stimulation by polyclonal activators.