REGULAR ARTICLE Adenylate kinase 2 expression and addiction in T-ALL Nabih Maslah, 1-3, * Mehdi Latiri, 1,3, * Vahid Asnafi, 1,3 M´ elanie F ´ eroul, 1,3 Nawel Bedjaoui, 1,3 Thomas Steiml ´ e, 1,3 Emmanuelle Six, 4 Els Verhoyen, 5,6 Elizabeth Macintyre, 1,3 Chantal Lagresle-Peyrou, 4 Ludovic Lhermitte, 1,3 and Guillaume P. Andrieu 1,3 1 Laboratory of Onco-Hematology, Assistance Publique-H ˆ opitaux de Paris (AP-HP), H ˆ opital Necker Enfants-Malades, Paris, France; 2 INSERM Unit ´ e Mixte de Recherche en Sant ´ e (UMRS) 1131, Institut Universitaire d’H´ ematologie, H ˆ opital Saint-Louis, Paris, France; 3 Universit ´ e Paris, Institut Necker-Enfants Malades (INEM), INSERM Unit ´ e 1151, Paris, France; 4 Laboratory of Human Lympho Hematopoiesis, INSERM UMR 1163, Clinical Investigation Center (CIC) 1416–Institut Imagine Universit ´ e Paris, Paris, France; 5 Centre International de Recherche en Infectiologie, Universit ´ e Lyon, Universit ´ e Claude Bernard Lyon 1, INSERM, Unit ´ e 1111, Centre National de la Recherche Scientifique (CNRS), UMR 5308, Ecole Normale Sup ´ erieure de Lyon, Lyon, France; and 6 Universit ´ eC ˆ ote d’Azur, INSERM, Centre M ´ editerran ´ een de M ´ edecine Mol ´ eculaire, Nice, France Key Points • T-ALL presents an ad- diction to AK2. • AK2 targeting provokes mitochondrial dysfunc- tion in T-ALL leading to blast eradication. T-cell acute lymphoblastic leukemia (T-ALL) represents the malignant expansion of immature T cells blocked in their differentiation. T-ALL is still associated with a poor prognosis, mainly related to occurrence of relapse or refractory disease. A critical medical need therefore exists for new therapies to improve the disease prognosis. Adenylate kinase 2 (AK2) is a mitochondrial kinase involved in adenine nucleotide homeostasis recently reported as essential in normal T-cell development, as defective AK2 signaling pathway results in a severe combined immunodeficiency with a complete absence of T-cell differentiation. In this study, we show that AK2 is constitutively expressed in T-ALL to varying levels, irrespective of the stage of maturation arrest or the underlying oncogenetic features. T-ALL cell lines and patient T-ALL–derived xenografts present addiction to AK2, whereas B-cell precursor ALL cells do not. Indeed, AK2 knockdown leads to early and massive apoptosis of T-ALL cells that could not be rescued by the cytosolic isoform AK1. Mechanistically, AK2 depletion results in mitochondrial dysfunction marked by early mitochondrial depolarization and reactive oxygen species production, together with the depletion of antiapoptotic molecules (BCL-2 and BCL-XL). Finally, T-ALL exposure to a BCL-2 inhibitor (ABT-199 [venetoclax]) significantly enhances the cytotoxic effects of AK2 depletion. We also show that AK2 depletion disrupts the oxidative phosphorylation pathway. Combined with pharmaceutical inhibition of glycolysis, AK2 silencing prevents T-ALL metabolic adaptation, resulting in dramatic apoptosis. Altogether, we pinpoint AK2 as a genuine and promising therapeutic target in T-ALL. Introduction T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy resulting from the oncogenic transformation of T-cell progenitors blocked at various stages of T-cell development. T-ALL accounts for 10% to 15% of pediatric ALL cases and 25% of adult ALL cases. Although T-ALL outcomes have improved with current therapy, survival rates only remain around 50% and 70% after 5 years in adult and pediatric T-ALL, respectively, highlighting the urgent medical need for new therapeutics. 1-3 Cytogenetics and global transcriptomic analyses led to the classification of T-ALL into molecular groups characterized by the abnormal expression of specific transcription factors (TAL, LMO1/2, TLX1/3, LYL, HOXA, and MEF2c). 4,5 Additional recurrent genetic abnormalities are frequent, irrespective of the maturation stage of arrest, including the loss of key tumor suppressive–genes (eg, inactivating mutations of PTEN and of the CDKN2A tumor suppressor locus) and activation of Submitted 17 June 2020; accepted 16 November 2020; published online 1 February 2021. DOI 10.1182/bloodadvances.2020002700. *N.M. and M.L. contributed equally to this study. The full-text version of this article contains a data supplement. © 2021 by The American Society of Hematology 700 9 FEBRUARY 2021 x VOLUME 5, NUMBER 3 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/5/3/700/1798716/advancesadv2020002700.pdf by guest on 08 July 2021