Palam, Lakshmi ReddyRamdas, BaskarPickerell, KatelynPasupuleti, Santhosh KumarKanumuri, RahulCesarano, AnnamariaSzymanski, MeganSelman, BryceDave, Utpal P.Sandusky, GeorgePerna, FabianaPaczesny, SophieKapur, Reuben2024-01-122024-01-122023-05-08Palam LR, Ramdas B, Pickerell K, et al. Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway. JCI Insight. 2023;8(9):e163864. Published 2023 May 8. doi:10.1172/jci.insight.163864https://hdl.handle.net/1805/37998Loss-of-function mutations in the DNA methyltransferase 3A (DNMT3A) are seen in a large number of patients with acute myeloid leukemia (AML) with normal cytogenetics and are frequently associated with poor prognosis. DNMT3A mutations are an early preleukemic event, which - when combined with other genetic lesions - result in full-blown leukemia. Here, we show that loss of Dnmt3a in hematopoietic stem and progenitor cells (HSC/Ps) results in myeloproliferation, which is associated with hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway. PI3Kα/β or the PI3Kα/δ inhibitor treatment partially corrects myeloproliferation, although the partial rescue is more efficient in response to the PI3Kα/β inhibitor treatment. In vivo RNA-Seq analysis on drug-treated Dnmt3a-/- HSC/Ps showed a reduction in the expression of genes associated with chemokines, inflammation, cell attachment, and extracellular matrix compared with controls. Remarkably, drug-treated leukemic mice showed a reversal in the enhanced fetal liver HSC-like gene signature observed in vehicle-treated Dnmt3a-/- LSK cells as well as a reduction in the expression of genes involved in regulating actin cytoskeleton-based functions, including the RHO/RAC GTPases. In a human PDX model bearing DNMT3A mutant AML, PI3Kα/β inhibitor treatment prolonged their survival and rescued the leukemic burden. Our results identify a potentially new target for treating DNMT3A mutation-driven myeloid malignancies.en-USAttribution 4.0 InternationalHematopoietic stem cellsLeukemiasMyeloid cellsArticle