Loss of <i>Dnmt3a</i> impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

Lakshmi Reddy Palam; Baskar Ramdas; Katelyn M. Pickerell; Santhosh Kumar Pasupuleti; Rahul Kanumuri; Annamaria Cesarano; Megan Szymanski; Bryce M. Selman; Utpal P. Davé; George Sandusky; Fabiana Perna; Sophie Paczesny; Reuben Kapur

doi:10.1172/jci.insight.163864

Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

Lakshmi Reddy Palam,¹ Baskar Ramdas,¹ Katelyn M. Pickerell,² Santhosh Kumar Pasupuleti,² Rahul Kanumuri,¹ Annamaria Cesarano,³ Megan Szymanski,⁴ Bryce M. Selman,⁴ Utpal P. Davé,⁵ George Sandusky,⁴ Fabiana Perna,³ Sophie Paczesny,⁶ and Reuben Kapur¹

Published March 28, 2023 - More info

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Abstract

Loss of function mutations in the DNA methyltransferase 3A (DNMT3A) are seen in a large number of AML patients with normal cytogenetics and are frequently associated with poor prognosis. DNMT3A mutations are an early pre-leukemic event, which when combined with other genetic lesions result in full blown leukemia. Here, we show that loss of Dnmt3a in HSC/Ps results in myeloproliferation, which is associated with hyperactivation of the PI3Kinase 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 to 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 new target for treating DNMT3A mutation driven myeloid malignancies.

Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

Lakshmi Reddy Palam,¹ Baskar Ramdas,¹ Katelyn M. Pickerell,² Santhosh Kumar Pasupuleti,² Rahul Kanumuri,¹ Annamaria Cesarano,³ Megan Szymanski,⁴ Bryce M. Selman,⁴ Utpal P. Davé,⁵ George Sandusky,⁴ Fabiana Perna,³ Sophie Paczesny,⁶ and Reuben Kapur¹

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Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

Lakshmi Reddy Palam,1 Baskar Ramdas,1 Katelyn M. Pickerell,2 Santhosh Kumar Pasupuleti,2 Rahul Kanumuri,1 Annamaria Cesarano,3 Megan Szymanski,4 Bryce M. Selman,4 Utpal P. Davé,5 George Sandusky,4 Fabiana Perna,3 Sophie Paczesny,6 and Reuben Kapur1

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Lakshmi Reddy Palam,¹ Baskar Ramdas,¹ Katelyn M. Pickerell,² Santhosh Kumar Pasupuleti,² Rahul Kanumuri,¹ Annamaria Cesarano,³ Megan Szymanski,⁴ Bryce M. Selman,⁴ Utpal P. Davé,⁵ George Sandusky,⁴ Fabiana Perna,³ Sophie Paczesny,⁶ and Reuben Kapur¹