RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia
RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia
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DOI：
10.1182/blood-2008-09-179812
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发表时间：
2009-09-24
期刊：
影响因子：
20.3
通讯作者：
Ge, Yubin
中科院分区：
文献类型：
--
作者：
Edwards, Holly;Xie, Chengzhi;Ge, Yubin
RUNX 1（AML 1）编码异二聚体转录因子复合物的核心结合因子α亚基，其在正常造血中起关键作用。RUNX 1的易位或下调与急性白血病的良好临床结局有关，表明RUNX 1也可能在急性白血病的化疗反应中发挥关键作用;然而，分子机制仍不清楚。患有唐氏综合征（DS）的急性巨核细胞白血病（AMkL）患儿的RUNX 1b转录水平中位数比非DS AMkL患儿低4.4倍（P <0.001）。在非DS AMkL细胞系Meg-01中，RUNX 1的短发夹RNA敲低导致对阿糖胞苷的敏感性显著增加，同时PIK 3CD的表达显著降低，PIK 3CD编码存活激酶磷酸肌醇3（PI 3）-激酶的δ催化亚基。通过染色质免疫沉淀和启动子报告基因测定进一步证实了RUNX 1对PIK 3 CD的转录调控。此外，PI 3-激酶抑制剂LY 294002和阿糖胞苷在对Meg-01和原代儿科AMkL细胞的抗白血病作用中协同作用。我们的研究结果表明，RUNX 1可能通过调节PI 3激酶/Akt通路在AMkL的化疗反应中发挥关键作用。因此，AMkL的治疗可以通过将PI 3-激酶或Akt抑制剂整合到这种疾病的化疗中来改善。（血。2009;114：2744-2752）
RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in acute leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in acute leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with acute megakaryocytic leukemia (AMkL) were 4.4-fold (P < .001) lower than that in non-DS AMkL cases. Short hairpin RNA knockdown of RUNX1 in a non-DS AMkL cell line, Meg-01, resulted in significantly increased sensitivity to cytosine arabinoside, accompanied by significantly decreased expression of PIK3CD, which encodes the delta catalytic subunit of the survival kinase, phosphoinositide 3 (PI3)-kinase. Transcriptional regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antileukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease. (Blood. 2009;114:2744-2752)