Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model.
Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model.
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DOI：
10.18632/oncotarget.11986
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Small D
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作者：
Poitras JL;Heiser D;Li L;Nguyen B;Nagai K;Duffield AS;Gamper C;Small D
FLT 3跨膜结构域的内部串联重复（FLT 3/ITD）是急性髓性白血病（AML）中最常见的突变之一。FLT 3/ITD导致激酶的组成性激活，预示着特别差的预后，总生存率降低，复发率增加。我们先前产生了一个敲入小鼠，在内源性Flt 3基因座处具有内部串联重复，其发展为致命的骨髓增生性肿瘤（MPN），但未能发展为急性白血病，这表明额外的突变是转化所必需的。为了研究FLT 3/ITD和突变体DNMT 3A的潜在协同性，我们将条件性Dnmt 3a敲除培育到我们的Flt 3/ITD敲入小鼠的亚系中，并且发现Dnmt 3a的缺失以剂量依赖性方式显著降低Flt 3 ITD/+小鼠的中位存活率。正如预期的，pIpC处理的Flt 3 ITD/+小鼠仅发展了MPN，而Flt 3 ITD/+; Dnmt 3af/f和Flt 3 ITD/+; Dnmt 3af/+发展了一系列肿瘤，包括MPN、T-ALL和AML。在功能上，FLT 3/ITD和DNMT 3A缺失协同扩增LT-HSC，其在系列再铺板测定中表现出增强的自我更新。这些结果说明DNMT 3A缺失与FLT 3/ITD协同产生造血肿瘤，包括AML。与FLT 3/ITD组合，与仅丢失一个等位基因相比，纯合子Dnmt 3a敲除导致疾病发作时间缩短、LT-HSC扩增和T-ALL发生率升高。FLT 3和DNMT 3A突变在AML以及T-ALL亚群中的共同出现表明Flt 3 ITD/+; Dnmt 3af/f模型可以作为在两种临床相关背景下描绘有效治疗策略的有价值的资源。
Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3/ITD) are among the most common mutations in Acute Myeloid Leukemia (AML). Resulting in constitutive activation of the kinase, FLT3/ITD portends a particularly poor prognosis, with reduced overall survival and increased rates of relapse. We previously generated a knock-in mouse, harboring an internal tandem duplication at the endogenous Flt3 locus, which develops a fatal myeloproliferative neoplasm (MPN), but fails to develop acute leukemia, suggesting additional mutations are necessary for transformation. To investigate the potential cooperativity of FLT3/ITD and mutant DNMT3A, we bred a conditional Dnmt3a knockout to a substrain of our Flt3/ITD knock-in mice, and found deletion of Dnmt3a significantly reduced median survival of Flt3ITD/+ mice in a dose dependent manner. As expected, pIpC treated Flt3ITD/+ mice solely developed MPN, while Flt3ITD/+;Dnmt3af/f and Flt3ITD/+;Dnmt3af/+ developed a spectrum of neoplasms, including MPN, T-ALL, and AML. Functionally, FLT3/ITD and DNMT3A deletion cooperate to expand LT-HSCs, which exhibit enhanced self-renewal in serial re-plating assays. These results illustrate that DNMT3A loss cooperates with FLT3/ITD to generate hematopoietic neoplasms, including AML. In combination with FLT3/ITD, homozygous Dnmt3a knock-out results in reduced time to disease onset, LT-HSC expansion, and a higher incidence of T-ALL compared with loss of just one allele. The co-occurrence of FLT3 and DNMT3A mutations in AML, as well as subsets of T-ALL, suggests the Flt3ITD/+;Dnmt3af/f model may serve as a valuable resource for delineating effective therapeutic strategies in two clinically relevant contexts.