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In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.<\/jats:p>","DOI":"10.3390\/ijms242316899","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T03:48:24Z","timestamp":1701229704000},"page":"16899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-7539","authenticated-orcid":false,"given":"Keli","family":"Lima","sequence":"first","affiliation":[{"name":"Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), 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of Internal Medicine, Hematology Division, Faculdade de Medicina, University of S\u00e3o Paulo, S\u00e3o Paulo CEP 13566-590, Brazil"},{"name":"Department of Experimental Hematology, University of Groningen, 9718 BG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1337-7635","authenticated-orcid":false,"given":"Frederico Lisboa","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology Division, Faculdade de Medicina, University of S\u00e3o Paulo, S\u00e3o Paulo CEP 13566-590, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00edvia Bassani Lins","family":"de Miranda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo CEP 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Jacob","family":"Schuringa","sequence":"additional","affiliation":[{"name":"Department of Experimental Hematology, University of Groningen, 9718 BG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-8109","authenticated-orcid":false,"given":"Jo\u00e3o Agostinho","family":"Machado-Neto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo CEP 13566-590, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1567-4086","authenticated-orcid":false,"given":"Eduardo Magalh\u00e3es","family":"Rego","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology Division, Faculdade de Medicina, University of S\u00e3o Paulo, S\u00e3o 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