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Haematologica 2019 Volume 104(4):738-748
Acute Lymphoblastic Leukemia
Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia
Roel Polak,1 Marc B. Bierings,2,3 Cindy S. van der Leije,4 Mathijs A. Sanders,4 Onno Roovers,4 João R. M. Marchante,1 Judith M. Boer,1 Jan J. Cornelissen,4 Rob Pieters,3 Monique L. den Boer1,3* and Miranda Buitenhuis4*
*MdB and MB contributed equally to this work.
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 con- sidered 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 pro- genitors in which we ectopically expressed ETV6-RUNX1. We reveal an ETV6-RUNX1-driven transcriptional network that induces prolifer- ation, survival and cellular homeostasis. In addition, Vps34, an impor- tant 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 prolifera- tion 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 rela- tionship between ETV6-RUNX1 and autophagy, and provide pre-clini- cal evidence for the efficacy of autophagy inhibitors in ETV6-RUNX1- driven leukemia.
Introduction
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. During the last decades, the overall survival rates of pediatric ALL have improved significantly.1 This is primarily due to optimization of conventional chemothera- peutic drug regimens combined with risk-directed therapies.1 However, to date, still 20% of pediatric ALL cases relapse because of resistance to therapy.2 In addi- tion, long-term treatment-induced side effects remain considerable.3 New treat- ment regimens increasingly aim to target specific intrinsic characteristics of leukemia. This approach has, for example, led to the successful development of BCR-ABL1 inhibitors.4 Regrettably, such a targeted approach is not available for the majority of children suffering from leukemia.
Translocation t(12;21)(p13;q22), resulting in the ETV6-RUNX1 fusion protein (also known as TEL-AML1), is present in 25% of pediatric patients with B-cell pre- cursor acute lymphoblastic leukemia (BCP-ALL) and is therefore the most com- mon fusion protein in childhood cancer.5 The t(12;21)(p13;q22) rearrangement fuses the 5' non-DNA binding region of the ETS family transcription factor ETV6 (TEL) to almost the entire RUNX1 (AML1) locus.5,6 Despite the favorable prognosis
1Department of Pediatric Oncology, Erasmus MC - Sophia Children’s Hospital, Rotterdam; 2Department of Pediatric Oncology, University Medical Center Utrecht; 3Princess Máxima Center for Pediatric Oncology, Utrecht and 4Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
Correspondence:
MONIQUE L. DEN BOER
m.l.denboer@prinsesmaximacentrum.nl
Received: March 18, 2018. Accepted: October 30, 2018. Pre-published: October 31, 2018.
doi:10.3324/haematol.2018.193631
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/738
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