Bcl-XL and Akt cooperate to promote leukemogenesis in vivo
Bcl-XL and Akt cooperate to promote leukemogenesis in vivo
复制标题
DOI：
10.1038/sj.onc.1206159
复制
发表时间：
2003-02-06
期刊：
影响因子：
8
通讯作者：
Rudin, CM
中科院分区：
文献类型：
--
作者：
Karnauskas, R;Niu, Q;Rudin, CM
为了分析可能有助于白血病体内转化的个体因素，我们基于早期造血前体细胞FL5.12开发了白血病发生的小鼠模型。FL5.12细胞的生长、增殖和存活依赖于白细胞介素-3（IL-3）。在IL-3撤除后对细胞死亡的相对抗性可通过Bcl-x（L）凋亡抑制剂的过表达或丝氨酸/苏氨酸激酶Akt的组成性激活来赋予。在无胸腺nu（+）/nu（+）小鼠中比较Bcl-x（L）或组成型活性肉豆蔻酰化Akt促进FL 5.12细胞白血病转化的能力。单独的Bcl-x（L）不能促进白血病转化，但注射过表达Bcl-x（L）的FL5.12细胞和显性阴性p53构建体的小鼠出现了淋巴结、脾脏和肝脏的白细胞增多和母细胞浸润，具有高度淋巴恶性肿瘤的特征。与注射到这些动物中的细胞相反，来自小鼠的细胞系能够在不存在IL-3的情况下增殖，并且发现具有组成性激活的Akt。这种组成性激活与调节Akt活性的信号通路的多种改变相关，包括PTEN mRNA和蛋白表达的改变。此外，这些白血病克隆中的一些表现出ERK活性的同时组成性上调。将组成型活性Akt构建体引入到FL5.12细胞中促进了体内类似的克隆扩增，出现了不依赖于IL-3的克隆增殖。Bcl-x（L）和Akt在该模型中表现出协同作用，相对于单独的Akt，增强了体内快速克隆生长。这些结果暗示激活Akt和生长因子的白血病转化的独立性，并证明白血病发生的遗传决定因素的体内分析的潜力。
To analyse individual factors that may contribute to leukemic transformation in vivo, we have developed a murine model of leukemogenesis based on the early hematopoietic precursor cell FL5.12. FL5.12 cells are interleukin-3 (IL-3) dependent for growth, proliferation, and survival. Relative resistance to cell death following IL-3 withdrawal can be conferred by either overexpression of the Bcl-x(L) apoptotic inhibitor, or constitutive activation of the serine/threonine kinase Akt. The ability of Bcl-x(L) or a constitutively active myristylated Akt to promote leukemic transformation of FL5.12 cells was compared in athymic nu(+)/nu(+) mice. Bcl-x(L) alone could not promote leukemic transformation, but mice injected with FL5.12 cells overexpressing Bcl-x(L), and a dominant-negative p53 construct developed leukocytosis and blastic infiltration of lymph nodes, spleen, and liver with features of a high-grade lymphoid malignancy. In contrast to the cells injected into these animals, cell lines derived from the mice were able to proliferate in the absence of IL-3, and were found to have constitutively activated Akt. This constitutive activation was associated with a variety of alterations of the signaling pathway regulating Akt activity, including alterations of PTEN mRNA and protein expression. In addition, some of these leukemic clones demonstrated concurrent constitutive upregulation of ERK activity. A constitutively active Akt construct introduced into FL5.12 cells promoted similar clonal expansion in vivo, with emergence of clonal IL-3-independent proliferation. Bcl-x(L) and Akt appeared to function cooperatively in this model, enhancing rapid clonal outgrowth in vivo relative to Akt alone. These results implicate activated Akt and growth-factor independence in leukemogenic transformation, and demonstrate the potential for in vivo analysis of genetic determinants of leukemogenesis.