{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T22:51:14Z","timestamp":1740178274760,"version":"3.37.3"},"reference-count":34,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2013derived 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.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002700","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T12:36:43Z","timestamp":1612269403000},"page":"700-710","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":8,"title":["Adenylate kinase 2 expression and addiction in T-ALL"],"prefix":"10.1182","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5553-462X","authenticated-orcid":false,"given":"Nabih","family":"Maslah","sequence":"first","affiliation":[{"name":"Laboratory of Onco-Hematology, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Necker Enfants-Malades, Paris, France;"},{"name":"INSERM Unit\u00e9 Mixte de Recherche en Sant\u00e9 (UMRS) 1131, Institut Universitaire d\u2019H\u00e9matologie, H\u00f4pital Saint-Louis, Paris, France;"},{"name":"Universit\u00e9 Paris, Institut 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