Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia
Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia
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DOI：
10.1182/blood-2017-01-760595
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发表时间：
2017-10-26
期刊：
影响因子：
20.3
通讯作者：
Vassiliou, George S.
中科院分区：
文献类型：
--
作者：
Dovey, Oliver M.;Cooper, Jonathan L.;Vassiliou, George S.
NPM1突变定义了急性髓性白血病（AML）最常见的亚群，并且经常与FLT3内部串联重复（ITD）或不太常见的NRAS或KRAS突变共同发生。突变体NPM1与FLT3-ITD共存的预后明显差于NPM1- ras组合。为了了解这些观察结果的分子基础，我们比较了两种组合对敲入小鼠造血和白血病发生的影响。这些突变对造血的早期影响表明复合Npm1(cA/+)；Nras（G12D/+）或Npm1(cA)；Flt3（ITD）有许多共同的特征：Hox基因过表达、自我更新增强、造血祖细胞扩张和骨髓分化偏向。然而,Npm1 (cA);与Npm1（cA/+）的粒细胞偏倚相比，Flt3（ITD）突变体表现出明显更高的外周白细胞计数、常见淋巴祖细胞的早期耗损和单核细胞偏倚；国家管制当局方面(G12D /(1 +)突变体。这背后是一种惊人的分子协同作用，表现为Npm1（cA）中基因表达谱的显著改变；Flt3(ITD)，但不含Npm1(cA/+)；Nras(G12D/+)，祖细胞与野生型比较。两种双突变模型都发展为高外显性AML，尽管Npm1（cA/+）的潜伏期明显更长；国家管制当局方面(G12D / +)。在AML进化过程中，两种模型都获得了突变Flt3或Nras等位基因的额外拷贝，但只有Npm1(cA/+)；Nras（G12D/+）小鼠显示获得其他人类AML突变，包括IDH1 R132Q。我们还发现，使用原代表达cas9的AML， Hoxa基因和选择的相互作用物或下游靶点是两种类型的双突变AML存活所必需的。我们的研究结果表明，分子互补性是NPM1c/FLT3-ITD与NPM1/ nrasg12d突变AML相关的更高频率和更差预后的基础，并在功能上证实了HOXA基因在NPM1c驱动的AML中的作用。
NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound Npm1(cA/+); Nras(G12D/+) or Npm1(cA); Flt3(ITD) share a number of features: Hox gene overexpression, enhanced self-renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias. However, Npm1(cA); Flt3(ITD) mutants displayed significantly higher peripheral leukocyte counts, early depletion of common lymphoid progenitors, and a monocytic bias in comparison with the granulocytic bias in Npm1(cA/+); Nras(G12D/1+) mutants. Underlying this was a striking molecular synergy manifested as a dramatically altered gene expression profile in Npm1(cA); Flt3(ITD), but not Npm1(cA/+); Nras(G12D/+), progenitors compared with wild-type. Both double-mutant models developed high-penetrance AML, although latency was significantly longer with Npm1(cA/+); Nras(G12D/+). During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1(cA/+); Nras(G12D/+) mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that Hoxa genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRASG12D-mutant AML and functionally confirm the role of HOXA genes in NPM1c-driven AML.