DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.
DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.
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DOI：
10.1158/2159-8290.cd-16-0008
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发表时间：
2016-05
期刊：
影响因子：
28.2
通讯作者：
Grimes HL
中科院分区：
文献类型：
--
作者：
Meyer SE;Qin T;Muench DE;Masuda K;Venkatasubramanian M;Orr E;Suarez L;Gore SD;Delwel R;Paietta E;Tallman MS;Fernandez H;Melnick A;Le Beau MM;Kogan S;Salomonis N;Figueroa ME;Grimes HL
细胞遗传学正常的急性髓性白血病（CN-AML）占人类AML的近50%。新生DNA甲基转移酶DNMT 3A和FMS相关酪氨酸激酶3 FLT 3中的共同发生突变在CN-AML中很常见，并导致预后较差。我们证明了Flt 3-内部串联重复（Flt 3 ITD）和Dnmt 3a的诱导性缺失的小鼠自发地发展为具有正常核型的快速致死、完全渗透和可移植的AML。AML细胞保留单个Dnmt 3a floxed等位基因，揭示了Dnmt 3a单倍不足的致癌潜力。FLT 3-ITD/DNMT 3A突变型原发性人和鼠AML表现出与附近基因表达变化相关的相似的整体DNA甲基化模式。在小鼠模型中，拯救DNMT 3A表达伴随着DNA再甲基化和克隆形成潜力的丧失，这表明Dnmt 3a突变体致癌作用是可逆的。使用单细胞测定法对AML模型的细胞结构进行解剖，鉴定了表达对附近基因组基因座的甲基化敏感的基因并且响应于Dnmt 3a水平的克隆形成亚群。因此，Dnmt 3a单倍不足通过调节克隆性AML亚群中甲基化敏感基因的表达来转化Flt 3 ITD骨髓增生性疾病。
Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 FLT3 are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal-tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly-lethal, completely-penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3-ITD/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing DNMT3A expression was accompanied by DNA re-methylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci, and responsive to Dnmt3a levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.