INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

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Ping Wang1,2,3, Dan Ma1,2,4, Jishi Wang5,6,7

  • 1Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.

Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
|June 26, 2016
PubMed

Insights

Inositol polyphosphate-4-phosphatase type II (INPP4B) promotes chemotherapy resistance in acute myeloid leukemia (AML) by enhancing DNA repair. Inhibiting INPP4B or DNA repair pathways may improve AML treatment outcomes.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Inositol polyphosphate-4-phosphatase type II (INPP4B) is linked to poor prognosis and treatment resistance in acute myeloid leukemia (AML).
  • The precise mechanisms by which INPP4B confers chemoresistance in AML remain largely undefined.
  • Understanding these mechanisms is crucial for developing effective therapeutic strategies against AML.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying INPP4B-mediated resistance to chemotherapy in AML.
  • To investigate the role of DNA damage repair pathways in INPP4B-driven chemoresistance.
  • To explore potential therapeutic targets for overcoming INPP4B-associated treatment resistance.

Main Methods:

  • Utilized KG-1 AML cell lines with INPP4B knockdown and control groups.
  • Assessed DNA damage accumulation (p-H2AX) and repair dynamics following cytarabine treatment.
  • Analyzed the expression and activation of key DNA repair proteins (ATM, p-ATM, p-BRCA1, p-ATR, p-RAD51).
  • Investigated the role of NF-κB (p65) signaling in INPP4B-mediated resistance.
  • Correlated INPP4B and ATM expression in AML cells and tested the efficacy of INPP4B knockdown and ATM inhibition (KU55933) in primary AML cells.

Main Results:

  • INPP4B knockdown sensitized AML cells to cytarabine, increasing p-H2AX accumulation and delaying its repair.
  • INPP4B downregulation significantly reduced ATM expression and inhibited the activation of its downstream DNA repair targets.
  • Nuclear translocation of p65 was inhibited by INPP4B knockdown, and its reactivation rescued the suppression of DNA repair pathways.
  • INPP4B expression positively correlated with ATM expression in AML cells.
  • Both INPP4B knockdown and ATM inhibition sensitized primary AML cells to cytarabine.

Conclusions:

  • Enhanced ATM-dependent DNA repair, potentially mediated by p65 nuclear translocation, contributes to cytarabine resistance in INPP4B-high AML.
  • Targeting INPP4B or inhibiting DNA repair pathways represents a promising therapeutic strategy for INPP4B-high AML.
  • Combination chemotherapy involving INPP4B inhibition could improve treatment efficacy in AML patients with high INPP4B expression.
Keywords:
CytarabineDNA repairINPP4BResistance

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