Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.
Combined heterozygosity of FLT3 ITD, TET2, and DNMT3A results in aggressive leukemia.
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FLT3 ITD、TET2 和 DNMT3A 的组合杂合性导致侵袭性白血病。
DOI：
10.1172/jci.insight.162016
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发表时间：
2022-09-08
期刊：
影响因子：
8
通讯作者：
Kapur, Reuben
中科院分区：
文献类型：
--
作者：
Ramdas, Baskar;Reddy, Palam Lakshmi;Mali, Raghuveer Singh;Pasupuleti, Santhosh Kumar;Zhang, Ji;Kelley, Mark R.;Paczesny, Sophie;Zhang, Chi;Kapur, Reuben
FLT3ITD、TET2和DNMT3A的杂合突变与人类血液恶性肿瘤有关。在患者中，FLT3ITD与TET2 （TF）或FLT3ITD与DNMT3A （DF）共同发生突变的频率较高。然而，在一些罕见的复杂急性髓性白血病（AML）中，这3种突变同时发生，即FLT3ITD、TET2和DNMT3A （TFD）。这些突变的联合存在是否会导致疾病表现的数量或质量差异尚未研究。我们产生了表达杂合Flt3ITD和伴随Tet2 （TF）或Dnmt3a （DF）或杂合缺失（TFD）的小鼠。尽管基因表达发生了类似的变化，但TF和DF小鼠并未在早期诱发疾病；在同一时间段内，在TFD小鼠中观察到一种侵袭性可移植白血病，这主要与相对于TF或DF小鼠的基因表达的定量而非定性差异有关。在单细胞RNA水平上，TFD小鼠的基因表达特征与人类TFD基因表达特征具有显著的相似性。重要的是，在小鼠模型和携带3个突变的AML PDX模型中，tfd驱动的AML对靶向Flt3ITD、炎症和甲基化的药物组合有反应。
Heterozygous mutations in FLT3ITD, TET2, and DNMT3A are associated with hematologic malignancies in humans. In patients, cooccurrence of mutations in FLT3ITD combined with TET2 (TF) or FLT3ITD combined with DNMT3A (DF) are frequent. However, in some rare complex acute myeloid leukemia (AML), all 3 mutations cooccur — i.e., FLT3ITD, TET2, and DNMT3A (TFD). Whether the presence of these mutations in combination result in quantitative or qualitative differences in disease manifestation has not been investigated. We generated mice expressing heterozygous Flt3ITD and concomitant for either heterozygous loss of Tet2 (TF) or Dnmt3a (DF) or both (TFD). TF and DF mice did not induce disease early on, in spite of similar changes in gene expression; during the same time frame, an aggressive form of transplantable leukemia was observed in TFD mice, which was mostly associated with quantitative but not qualitative differences in gene expression relative to TF or DF mice. The gene expression signature of TFD mice showed remarkable similarity to the human TFD gene signature at the single-cell RNA level. Importantly, TFD-driven AML responded to a combination of drugs that target Flt3ITD, inflammation, and methylation in a mouse model, as well as in a PDX model of AML bearing 3 mutations.
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影响因子：
28.5
作者：
Loghavi S;Zuo Z;Ravandi F;Kantarjian HM;Bueso-Ramos C;Zhang L;Singh RR;Patel KP;Medeiros LJ;Stingo F;Routbort M;Cortes J;Luthra R;Khoury JD
通讯作者：
Khoury JD
影响因子：
12.8
作者：
Dunlap, Jennifer B.;Leonard, Jessica;Traer, Elie
通讯作者：
Traer, Elie
影响因子：
7.5
作者：
Juliusson, Gunnar;Jadersten, Martin;Hoglund, Martin
通讯作者：
Hoglund, Martin
影响因子：
4.6
作者：
Lauber, Chris;Correia, Nadia;Seifert, Michael
通讯作者：
Seifert, Michael
影响因子：
15.9
作者：
Ghosh, Joydeep;Kobayashi, Michihiro;Kapur, Reuben
通讯作者：
Kapur, Reuben