JCI：CDK1或成为急性髓细胞性白血病治疗新靶标

急性髓细胞性白血病(acute myeloid leukemia, AML, 也译作急性髓系白血病或急性髓性白血病)是成年人身上常见的一种白血病，其特征在于癌性骨髓细胞(cancerous bone marrow cell)异常增殖。在急性髓细胞性白血病中，人们观察到的的最为流行的突变之一就是一种被称作FLT3受体的蛋白受体存在激活突变。FLT3突变体被认为能够激活促进癌症生长的信号途径。

来自美国波士顿市哈佛大学的Daniel Tenen博士和同事们发现FLT3突变激活的一种新途径。他们的研究结果表明一种细胞分裂的关键性调节分子，细胞周期蛋白依赖性激酶1(cyclin dependent kinase 1, CDK1)，在FLT3发生突变的白血病中被激活，从而导致下游的基因转录激活。

更为重要的是，他们证实抑制CDK1活性促进来自病人外周血样品的细胞分化。

鉴于利用CDK1抑制剂进行的临床试验正在进行中，他们的研究结果强烈地提示着靶向CDK1途径的治疗方法可能非常有效地治疗携带FLT3突变的急性髓细胞性白血病，特别是对那些对FLT3抑制剂疗法产生耐药性的病人而言，更是如此。

相关研究结果于2012年7月16日发表在Journal of Clinical Investigation期刊上。

本文编译自A new target in acute myeloid leukemia

doi:10.1172/JCI43354
PMC:
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Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα

Hanna S. Radomska1, Meritxell Alberich-Jordà1,2, Britta Will1, David Gonzalez1, Ruud Delwel3 and Daniel G. Tenen

Mutations that activate the fms-like tyrosine kinase 3 (FLT3) receptor are among the most prevalent mutations in acute myeloid leukemias. The oncogenic role of FLT3 mutants has been attributed to the abnormal activation of several downstream signaling pathways, such as STAT3, STAT5, ERK1/2, and AKT. Here, we discovered that the cyclin-dependent kinase 1 (CDK1) pathway is also affected by internal tandem duplication mutations in FLT3. Moreover, we also identified C/EBPα, a granulopoiesis-promoting transcription factor, as a substrate for CDK1. We further demonstrated that CDK1 phosphorylates C/EBPα on serine 21, which inhibits its differentiation-inducing function. Importantly, we found that inhibition of CDK1 activity relieves the differentiation block in cell lines with mutated FLT3 as well as in primary patient–derived peripheral blood samples. Clinical trials with CDK1 inhibitors are currently under way for various malignancies. Our data strongly suggest that targeting the CDK1 pathway might be applied in the treatment of FLT3ITD mutant leukemias, especially those resistant to FLT3 inhibitor therapies.