{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:08:01Z","timestamp":1791068881529,"version":"4.1.0"},"reference-count":58,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01CA173852,R01CA134777,R01HL146137,R01HL140961,R21CA263470,R21CA263239"],"award-info":[{"award-number":["R01CA173852,R01CA134777,R01HL146137,R01HL140961,R21CA263470,R21CA263239"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,8]]},"abstract":"<jats:p>\n                    Loss-of-function mutations in the\n                    <jats:italic>DNA methyltransferase 3A (DNMT3A<\/jats:italic>\n                    ) are seen in a large number of patients with acute myeloid leukemia (AML) with normal cytogenetics and are frequently associated with poor prognosis.\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    mutations are an early preleukemic event, which \u2014 when combined with other genetic lesions \u2014 result in full-blown leukemia. Here, we show that loss of\n                    <jats:italic>Dnmt3a<\/jats:italic>\n                    in hematopoietic stem and progenitor cells (HSC\/Ps) results in myeloproliferation, which is associated with hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway. PI3K\u03b1\/\u03b2 or the PI3K\u03b1\/\u03b4 inhibitor treatment partially corrects myeloproliferation, although the partial rescue is more efficient in response to the PI3K\u03b1\/\u03b2 inhibitor treatment. In vivo RNA-Seq analysis on drug-treated\n                    <jats:italic>\n                      Dnmt3a\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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\n                    <jats:italic>\n                      Dnmt3a\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    mutant AML, PI3K\u03b1\/\u03b2 inhibitor treatment prolonged their survival and rescued the leukemic burden. Our results identify a potentially new target for treating\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    mutation\u2013driven myeloid malignancies.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.163864","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T12:01:16Z","timestamp":1680004876000},"source":"Crossref","is-referenced-by-count":11,"title":["Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway"],"prefix":"10.1172","volume":"8","author":[{"given":"Lakshmi Reddy","family":"Palam","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baskar","family":"Ramdas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric 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