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

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.

• Authors: 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
• Journal: Haematologica (Haematologica) Vol. 104 Issue 4 Pg. 738-748 (04 2019) ISSN: 1592-8721 [Electronic] Italy
• PMID: 30381299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2019 Ferrata Storti Foundation.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Oncogene Proteins, Fusion
• TEL-AML1 fusion protein
• Class III Phosphatidylinositol 3-Kinases
• Asparaginase

Topics

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