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

Keli Lima1,2, Maria Fernanda Lopes Carvalho2, Diego Antonio Pereira-Martins1,3

  • 1Laboratory 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 São Paulo, São Paulo CEP 13566-590, Brazil.

International Journal of Molecular Sciences
|December 9, 2023
PubMed

Insights

High expression of Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) in acute myeloid leukemia (AML) correlates with drug resistance. Combining a PIP4K2 inhibitor with venetoclax shows promise for improved AML treatment.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) proteins (PIP4K2A, PIP4K2B, PIP4K2C) generate PIP2, crucial for cell signaling, metabolism, and structure.
  • Elevated PIP4K2A and PIP4K2C levels are linked to poor prognosis in acute myeloid leukemia (AML).
  • Previous research indicated that the PIP4K2 pan-inhibitor THZ-P1-2 has anti-leukemic effects in AML models.

Purpose of the Study:

  • To investigate PIP4K2 expression in myeloid cells and AML samples.
  • To determine the relationship between PIP4K2 levels and sensitivity to antileukemia drugs.
  • To evaluate the efficacy of combining THZ-P1-2 with venetoclax in AML.

Main Methods:

  • Characterization of PIP4K2 expression in hematopoietic cells, AML cell lines, and clinical samples.
  • Ex vivo drug sensitivity assays.
  • Assessment of combined THZ-P1-2 and venetoclax treatment on AML cell viability and apoptosis.
  • Gene expression analysis of key apoptosis-related genes.

Main Results:

  • PIP4K2 expression levels correlated with sensitivity and resistance to various antileukemia drugs.
  • High PIP4K2A levels were associated with resistance to venetoclax.
  • The combination of THZ-P1-2 and venetoclax demonstrated synergistic effects, reducing AML cell viability and inducing apoptosis.
  • Combined treatment modulated the expression of genes including TAp73, BCL2, MCL1, and BCL2A1.

Conclusions:

  • PIP4K2 expression is a potential biomarker for predicting responses to antineoplastic agents in AML.
  • Targeting PIP4K2 in combination with venetoclax may offer a novel therapeutic strategy for AML.
  • This combination therapy could lead to improved treatment outcomes in AML patients.
Keywords:
THZ-P1-2acute myeloid leukemiaphosphatidylinositol-5-phosphate 4-kinase type 2venetoclax

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