Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis
Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis
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DOI：
10.1182/blood-2006-08-041202
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Nakamura, Takuro
中科院分区：
文献类型：
--
作者：
Jin, Guang;Yamazaki, Yukari;Nakamura, Takuro
Meis1和Hoxa9的协同激活扰乱了髓系细胞的分化，最终导致髓系祖细胞向白血病发展，但尚不清楚显性白血病的发生需要哪些后续的分子过程。为了了解Hoxa9/Meis1诱发白血病的分子途径，采用逆转录病毒介导的基因转移技术进行逆转录病毒插入突变。获得Hoxa9/Meis1转基因骨髓细胞的小鼠发生了急性髓系白血病(AML)，Trib1、Evi1、Ahi1、RARα、Pitpnb和AK039950被鉴定为位于常见逆转录病毒整合位点附近的候选合作基因。由于逆转录病毒的插入，Trib1和Evil的表达上调，并且这两个基因的共同表达显著加速了Hoxa9/Meis1诱导的AML的发生，表明Trib1和Evil是关键的协作者。此外，Trib1本身是一种新的髓系癌基因，可促进ERK的磷酸化，从而抑制细胞凋亡。这些结果证明了特定的癌基因相互作用在髓系白血病发生中的重要性。
Cooperative activation of Meis1 and Hoxa9 perturbs myeloid differentiation and eventually leads myeloid progenitors to leukemia, yet it remains to be clarified what kinds of subsequent molecular processes are required for development of overt leukemia. To understand the molecular pathway in Hoxa9/Meis1-induced leukemogenesis, retroviral insertional mutagenesis was applied using retrovirus-mediated gene transfer. The mice that received Hoxa9/Meis1-transduced bone marrow cells developed acute myeloid leukemia (AML), and Trib1, Evi1, Ahi1, Rar alpha, Pitpnb, and AK039950 were identified as candidate cooperative genes located near common retroviral integration sites. Trib1 and Evil were up-regulated due to retroviral insertions, and coexpression of these genes significantly accelerated the onset of Hoxa9/Meis1-induced AML, suggesting that Trib1 and Evil are the key collaborators. Furthermore, Trib1 by itself is a novel myeloid oncogene, enhancing phosphorylation of ERK, resulting in inhibition of apoptosis. These results demonstrate the importance of specific oncogene interaction in myeloid leukemogenesis.