Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia

Roel Polak, Marc B Bierings, Cindy S van der Leije, Mathijs A Sanders, Onno Roovers, João R M Marchante, Judith M Boer, Jan J Cornelissen, Rob Pieters, Monique L den Boer, Miranda Buitenhuis

Research output: Contribution to journalArticlepeer-review

Abstract

Translocation t(12;21), resulting in the ETV6-RUNX1 (or TEL-AML1) fusion protein, is present in 25% of pediatric patients with B-cell precursor acute lymphoblastic leukemia and is considered a first hit in leukemogenesis. A targeted therapy approach is not available for children with this subtype of leukemia. To identify the molecular mechanisms underlying ETV6-RUNX1-driven leukemia, we performed gene expression profiling of healthy hematopoietic progenitors in which we ectopically expressed ETV6-RUNX1. We reveal an ETV6-RUNX1-driven transcriptional network that induces proliferation, survival and cellular homeostasis. In addition, Vps34, an important regulator of autophagy, was found to be induced by ETV6-RUNX1 and up-regulated in ETV6-RUNX1-positive leukemic patient cells. We show that induction of Vps34 was transcriptionally regulated by ETV6-RUNX1 and correlated with high levels of autophagy. Knockdown of Vps34 in ETV6-RUNX1-positive cell lines severely reduced proliferation and survival. Inhibition of autophagy by hydroxychloroquine, a well-tolerated autophagy inhibitor, reduced cell viability in both ETV6-RUNX1-positive cell lines and primary acute lymphoblastic leukemia samples, and selectively sensitized primary ETV6-RUNX1-positive leukemia samples to L asparaginase. These findings reveal a causal relationship between ETV6-RUNX1 and autophagy, and provide pre-clinical evidence for the efficacy of autophagy inhibitors in ETV6-RUNX1-driven leukemia.

Original languageEnglish
Pages (from-to)738-748
Number of pages11
JournalHaematologica
Volume104
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • Asparaginase/pharmacology
  • Autophagic Cell Death/drug effects
  • Child
  • Child, Preschool
  • Class III Phosphatidylinositol 3-Kinases/genetics
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Drug Delivery Systems
  • Female
  • Humans
  • Male
  • Oncogene Proteins, Fusion/genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

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