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International Journal of Molecular Sciences

International Journal of Molecular Sciences

IF: 5.6
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Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia

Published:29 November 2023 DOI: 10.3390/ijms242316899 PMID: 38069220
Keli Lima,?Maria Fernanda Lopes Carvalho,?Diego Antonio Pereira-Martins,?Frederico Lisboa Nogueira,?Lívia Bassani Lins de Miranda,?Mariane Cristina do Nascimento,?Rita de Cássia Cavaglieri,?Jan Jacob Schuringa,?Jo?o Agostinho Machado-Neto,?Eduardo Magalh?es Rego

Abstract

Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. 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.

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ABT-199 1257044-40-8 C45H50ClN7O7S 534 suppliers $12.00-$4766.80
ABT-199 1257044-40-8 C45H50ClN7O7S 534 suppliers $12.00-$4766.80
ABT-199 1257044-40-8 C45H50ClN7O7S 534 suppliers $12.00-$4766.80
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