Meyer Sara E, Qin Tingting, Muench David E, Masuda Kohei, Venkatasubramanian Meenakshi, Orr Emily, Suarez Lauren, Gore Steven D, Delwel Ruud, Paietta Elisabeth, Tallman Martin S, Fernandez Hugo, Melnick Ari, Le Beau Michelle M, Kogan Scott, Salomonis Nathan, Figueroa Maria E, Grimes H Leighton
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Cancer Discov. 2016 May;6(5):501-15. doi: 10.1158/2159-8290.CD-16-0008. Epub 2016 Mar 25.
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 (Flt3(ITD)) 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 remethylation 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, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.
DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
细胞遗传学正常的急性髓系白血病（CN-AML）占人类AML的近50%。从头DNA甲基转移酶DNMT3A和FMS相关酪氨酸激酶激酶3激酶3（FLT3）的共发突变在CN-AML中很常见，且预后较差。我们证明，具有Flt3内部串联重复（Flt3(ITD)）和可诱导缺失Dnmt3a的小鼠会自发发展出一种具有正常核型的快速致死、完全显性且可移植的AML。AML细胞保留一个Dnmt3a floxed等位基因，揭示了Dnmt3a单倍体不足的致癌潜力。FLT3(ITD)/DNMT3A突变的原发性人类和小鼠AML表现出与附近基因表达变化相关的类似全基因组DNA甲基化模式。在小鼠模型中，恢复Dnmt3a表达伴随着DNA重新甲基化和克隆形成潜力的丧失，这表明Dnmt3a突变的致癌作用是可逆的。使用单细胞分析，包括单细胞RNA测序，剖析AML模型的细胞结构，确定了表达对附近基因组位点甲基化敏感且对DNMT3A水平有反应的基因的克隆形成亚群。因此，Dnmt3a单倍体不足通过调节克隆形成性AML亚群内甲基化敏感基因的表达，将Flt3(ITD)骨髓增殖性疾病转化为AML。
DNMT3A单倍体不足导致可逆的表观遗传改变，将FLT3(ITD)突变的骨髓增殖性肿瘤转化为AML。癌症发现；6(5)；501 - 15。©2016 AACR。本文在本期特刊第461页重点介绍。
