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.

ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia

“…Some of these biological processes include genes whose deregulation has been described in ALL patients [21][22][23][24][25][26]. Among them we observed a downregulation of CXCR7, LCK, PTPRG, VPS34, PTPRK, ARHGEF12, RGM and HAP1 genes and an upregulation of RXRA, CXXC5, ARX, SORBS2, RGS16, TLR7, mir-146 and TP63 genes.…”

Single cell characterization of B-lymphoid differentiation and leukemic cell states during chemotherapy in ETV6-RUNX1-positive pediatric leukemia identifies drug-targetable transcription factor activities

“…Previous bulk cancer genomics studies have established that repeated gene expression patterns also characterize cancer samples [ 99 ], including ALL where such studies have established several transcriptome-based subtypes [ 67 , 100 – 103 ]. They have also shed light on pathway activity and TF expression in E/R+ cells that could be utilized to design targeted therapies [ 6 , 104 , 105 ]. However, the rarity of normal B-lymphoid pro-B cells in BM tissue has represented a challenge to perform direct comparison of E/R+ and healthy BM lymphoid cell states in vivo.…”

Current Outlook on Autophagy in Human Leukemia: Foe in Cancer Stem Cells and Drug Resistance, Friend in New Therapeutic Interventions

“…There are genetic connections between lymphoblastic leukemia driver mutations and autophagy. B-ALL patients with the ETV6-RUX1 translocation have significantly increased expression of the autophagy initiating lipidase VPS34 compared to normal hematopoietic stem/progenitor cells, and the presence of the ETV6-RUNX1 fusion protein was found to have a causal relationship to VPS34 overexpression through epigenetic regulation [131]. In CLL, a positive prognostic factor is the deletion of 13q14, containing microRNA-15 and -16, both of which target anti-apoptotic B-cell CLL/lymphoma 2 (BCL-2) leading to BCL-2 upregulation in CLL [132].…”