{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:51:24Z","timestamp":1774288284002,"version":"3.50.1"},"reference-count":79,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T00:00:00Z","timestamp":1598572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["19117 to riccardo Masetti"],"award-info":[{"award-number":["19117 to riccardo Masetti"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.<\/jats:p>","DOI":"10.3390\/ijms21176251","type":"journal-article","created":{"date-parts":[[2020,8,30]],"date-time":"2020-08-30T06:06:22Z","timestamp":1598767582000},"page":"6251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias"],"prefix":"10.3390","volume":"21","author":[{"given":"Laura","family":"Anselmi","sequence":"first","affiliation":[{"name":"Pediatric Hematology and Oncology Unit, S.Orsola-Malpighi Hospital, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore Nicola","family":"Bertuccio","sequence":"additional","affiliation":[{"name":"Pediatric Hematology-Oncology Unit, Department of Medical and Surgical Sciences DIMEC, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-3090","authenticated-orcid":false,"given":"Annalisa","family":"Lonetti","sequence":"additional","affiliation":[{"name":"Giorgio Prodi Interdepartmental Cancer Research Centre, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arcangelo","family":"Prete","sequence":"additional","affiliation":[{"name":"Pediatric Hematology-Oncology Unit, Department of Medical and Surgical Sciences DIMEC, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1264-057X","authenticated-orcid":false,"given":"Riccardo","family":"Masetti","sequence":"additional","affiliation":[{"name":"Pediatric Hematology-Oncology Unit, Department of Medical and Surgical Sciences DIMEC, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0379-9562","authenticated-orcid":false,"given":"Andrea","family":"Pession","sequence":"additional","affiliation":[{"name":"Pediatric Hematology-Oncology Unit, Department of Medical and Surgical Sciences DIMEC, University of Bologna, 40126 Bologna, Italy"},{"name":"Giorgio Prodi Interdepartmental Cancer Research Centre, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1200\/JCO.2014.59.1636","article-title":"Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration","volume":"33","author":"Pui","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1038\/s41375-018-0071-7","article-title":"Successes and challenges in the treatment of pediatric acute myeloid leukemia: A retrospective analysis of the AML-BFM trials from 1987 to 2012","volume":"32","author":"Rasche","year":"2018","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e127","DOI":"10.3324\/haematol.2014.106526","article-title":"Infants with acute myeloid leukemia treated according to the Associazione Italiana di Ematologia e Oncologia Pediatrica 2002\/01 protocol have an outcome comparable to that of older children","volume":"99","author":"Masetti","year":"2014","journal-title":"Haematologica"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.critrevonc.2019.04.011","article-title":"The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children","volume":"138","author":"Masetti","year":"2019","journal-title":"Crit. Rev. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1586\/era.12.101","article-title":"All-transretinoic acid in the treatment of pediatric acute promyelocytic leukemia","volume":"12","author":"Masetti","year":"2012","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1182\/blood-2015-09-667808","article-title":"LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia","volume":"127","author":"Helsmoortel","year":"2016","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13045-017-0396-0","article-title":"Hh\/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene","volume":"10","author":"Masetti","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1158\/0008-5472.CAN-16-2074","article-title":"Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation","volume":"77","author":"Yu","year":"2017","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrc2981","article-title":"Regulation of cancer cell metabolism","volume":"11","author":"Cairns","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.3109\/10428194.2010.512966","article-title":"Energy metabolism of leukemia cells: Glycolysis versus oxidative phosphorylation","volume":"51","author":"Suganuma","year":"2010","journal-title":"Leuk. Lymphoma"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1182\/blood-2019-124475","article-title":"Mitochondrial Oxphos as Survival Mechanism of Minimal Residual AML Cells after Induction Chemotherapy: Survival Benefit by Complex I Inhibition with Iacs-010759","volume":"134","author":"Han","year":"2019","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tabe, Y., Konopleva, M., and Andreeff, M. (2020). Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00155"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1101\/gad.326470.119","article-title":"Metabolic dependencies and vulnerabilities in leukemia","volume":"33","author":"Rashkovan","year":"2019","journal-title":"Genes Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nrm3772","article-title":"Metabolic requirements for the maintenance of self-renewing stem cells","volume":"15","author":"Ito","year":"2014","journal-title":"Nat. Rev. Mol. Cell Boil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.cmet.2016.03.008","article-title":"AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival","volume":"23","author":"Kishton","year":"2016","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.18632\/oncoscience.394","article-title":"In quest for leukemia initiating cells in AML","volume":"5","author":"Mancini","year":"2018","journal-title":"Oncoscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.cmet.2018.11.013","article-title":"Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche","volume":"29","author":"Hao","year":"2019","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.cell.2014.07.048","article-title":"Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis","volume":"158","author":"Wang","year":"2014","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1158\/1078-0432.CCR-10-1613","article-title":"Molecular Pathways: BCR-ABL","volume":"18","author":"Cilloni","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1241854","DOI":"10.1080\/23723556.2016.1241854","article-title":"Aggressive leukemia driven by MLL-AF9","volume":"5","author":"Stavropoulou","year":"2017","journal-title":"Mol. Cell. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Winters, A.C., and Bernt, K.M. (2017). MLL-Rearranged Leukemias\u2014An Update on Science and Clinical Approaches. Front. Pediatr., 5.","DOI":"10.3389\/fped.2017.00004"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"36832","DOI":"10.18632\/oncotarget.15981","article-title":"The hypoxia signalling pathway in haematological malignancies","volume":"8","author":"Irigoyen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nepstad, I., Hatfield, K.J., Gr\u00f8nnings\u00e6ter, I.S., and Reikvam, H. (2020). The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082907"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"150155","DOI":"10.1098\/rsob.150155","article-title":"Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle","volume":"6","author":"Slaninova","year":"2016","journal-title":"Open Boil."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.stem.2012.12.013","article-title":"BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells","volume":"12","author":"Lagadinou","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1158\/2159-8290.CD-16-0441","article-title":"Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism","volume":"7","author":"Farge","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.tibs.2010.05.003","article-title":"Glutamine addiction: A new therapeutic target in cancer","volume":"35","author":"Wise","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1146\/annurev-bioeng-071516-044546","article-title":"Glutaminolysis: A Hallmark of Cancer Metabolism","volume":"19","author":"Yang","year":"2017","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1080\/14737140.2017.1347507","article-title":"New targeted therapies for relapsed pediatric acute lymphoblastic leukemia","volume":"17","author":"Pierro","year":"2017","journal-title":"Expert Rev. Anticancer. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1038\/sj.leu.2404365","article-title":"Altered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia","volume":"20","author":"Boag","year":"2006","journal-title":"Leukemia"},{"key":"ref_31","first-page":"275","article-title":"Novel non-neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia","volume":"93","author":"Soini","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/leu.2017.303","article-title":"RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia","volume":"32","author":"Jerchel","year":"2018","journal-title":"Leukemia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e28255","DOI":"10.1002\/pbc.28255","article-title":"Metabolic reprogramming in childhood acute lymphoblastic leukemia","volume":"67","author":"Sbirkov","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1182\/blood-2013-09-525741","article-title":"MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia","volume":"124","author":"Manara","year":"2014","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1158\/1078-0432.CCR-14-2425","article-title":"Metabolic Dependencies in RAS-Driven Cancers","volume":"21","author":"Kimmelman","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pajak, B., Siwiak, E., So\u0142tyka, M., Priebe, A., Zieli\u0144ski, R., Fokt, I., Ziemniak, M., Ja\u015bkiewicz, A., Borowski, R., and Domoradzki, T. (2019). 2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010234"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nature21076","article-title":"Metabolic gatekeeper function of B-lymphoid transcription factors","volume":"542","author":"Chan","year":"2017","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11864-016-0393-5","article-title":"Obesity and Metabolic Syndrome Among Adult Survivors of Childhood Leukemia","volume":"17","author":"Gibson","year":"2016","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41419-018-0625-7","article-title":"Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment","volume":"9","author":"Dyczynski","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/j.1365-2141.2008.06981.x","article-title":"Prediction of relapse in paediatric pre-B acute lymphoblastic leukaemia using a three-gene risk index","volume":"140","author":"Hoffmann","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/2487297","article-title":"2-Deoxy-d-glucose Restore Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia via Modification of N-Linked Glycosylation in an Oxygen Tension-Independent Manner","volume":"2017","author":"Leni","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.canlet.2013.04.015","article-title":"The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL\/T-LL cancer cells","volume":"336","author":"Rosilio","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Biondani, G., and Peyron, J.F. (2018). Metformin, an Anti-diabetic Drug to Target Leukemia. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00446"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.4161\/cc.20770","article-title":"Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells","volume":"11","author":"Pan","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e27224","DOI":"10.1002\/pbc.27224","article-title":"A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxo","volume":"65","author":"Trucco","year":"2018","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/1985750","article-title":"Synergistic Cytotoxic Effect of L-Asparaginase Combined with Decitabine as a Demethylating Agent in Pediatric T-ALL, with Specific Epigenetic Signature","volume":"2016","author":"Serravalle","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Chiu, M., Taurino, G., Bianchi, M.G., Kilberg, M.S., and Bussolati, O. (2020). Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01480"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.exphem.2012.04.005","article-title":"Low expression of asparagine synthetase in lymphoid blasts precludes its role in sensitivity to L-asparaginase","volume":"40","author":"Hermanova","year":"2012","journal-title":"Exp. Hematol."},{"key":"ref_49","first-page":"209","article-title":"Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of l-asparaginase in childhood ALL cells","volume":"30","author":"Valis","year":"2015","journal-title":"Leukemia"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1172\/JCI66203","article-title":"Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia","volume":"123","author":"Figueroa","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5201","DOI":"10.1182\/blood-2012-01-401687","article-title":"Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia","volume":"119","author":"Bhatla","year":"2012","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K Pathway in Human Disease","volume":"170","author":"Fruman","year":"2017","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3892","DOI":"10.1158\/0008-5472.CAN-03-2904","article-title":"Akt Stimulates Aerobic Glycolysis in Cancer Cells","volume":"64","author":"Elstrom","year":"2004","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1182\/blood.V108.11.1833.1833","article-title":"Relationship between mTOR-Mediated Upregulation of Glycolysis and Chemosensitivity of ALL Blasts","volume":"108","author":"Frolova","year":"2006","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1182\/blood-2019-130898","article-title":"Activation of AKT\/mTOR Pathway in Ph+ Acute Lymphoblastic Leukemia (ALL) Leads to Non-Mutational Resistance","volume":"134","author":"Mian","year":"2019","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3510","DOI":"10.1182\/blood-2012-03-415448","article-title":"Targeting JAK1\/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia","volume":"120","author":"Maude","year":"2012","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1158\/1535-7163.MCT-15-0163","article-title":"Anti-leukemic activity of 2-deoxy-d-glucose through inhibition of N-linked glycosylation in acute myeloid leukemia with FLT3-ITD or cKIT mutations","volume":"14","author":"Larrue","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"109915","DOI":"10.18632\/oncotarget.18565","article-title":"Identification of a cytogenetic and molecular subgroup of acute myeloid leukemias showing sensitivity to L-Asparaginase","volume":"8","author":"Bertuccio","year":"2017","journal-title":"Oncotarget"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1038\/nm.3955","article-title":"Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia","volume":"21","author":"Herranz","year":"2015","journal-title":"Nat. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1038\/s41591-018-0052-4","article-title":"An inhibitor of oxidative phosphorylation exploits cancer vulnerability","volume":"24","author":"Molina","year":"2018","journal-title":"Nat. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"52269","DOI":"10.18632\/oncotarget.13699","article-title":"The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed\/refractory acute myeloid leukemia: A phase Ib\/II study","volume":"8","author":"Tan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1182\/blood.V110.11.876.876","article-title":"PI-103, a Dual Inhibitor of Class I Phosphatidylinositide 3-Kinase and mTOR, Has Anti-Leukemic Activity in Acute Myeloid Leukemia","volume":"110","author":"Park","year":"2007","journal-title":"Blood"},{"key":"ref_63","first-page":"12","article-title":"Cell cycle-dependent activity of the novel dual PI3K-MTORC1\/2 inhibitor NVP-BGT226 in acute leukemia","volume":"1476\u20134598","author":"Heinrich","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/aps.2016.121","article-title":"The PI3K\/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia","volume":"38","author":"Deng","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1182\/blood-2009-02-206722","article-title":"High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia","volume":"114","author":"Sanda","year":"2009","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"56746","DOI":"10.18632\/oncotarget.10778","article-title":"Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing","volume":"7","author":"Masetti","year":"2016","journal-title":"Oncotarget"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5534","DOI":"10.1038\/s41598-018-23863-9","article-title":"Distinct Metabolic features differentiating FLT3-ITD AML from FLT3-WT childhood Acute Myeloid Leukemia","volume":"8","author":"Stockard","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s13361-016-1544-4","article-title":"Prognostic Metabolite Biomarkers for Soft Tissue Sarcomas Discovered by Mass Spectrometry Imaging","volume":"28","author":"Lou","year":"2016","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"510","DOI":"10.18632\/oncotarget.290","article-title":"Targeting mTOR for the treatment of AML. New agents and new directions","volume":"2","author":"Altman","year":"2011","journal-title":"Oncotarget"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/bjh.15920","article-title":"Acute myeloid leukaemia niche regulates response to L-asparaginase","volume":"186","author":"Michelozzi","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Mirabilii, S., Ricciardi, M.R., and Tafuri, A. (2020). mTOR Regulation of Metabolism in Hematologic Malignancies. Cells, 9.","DOI":"10.3390\/cells9020404"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Tasian, S.K., Teachey, D.T., and Rheingold, S. (2014). Targeting the PI3K\/mTOR Pathway in Pediatric Hematologic Malignancies. Front. Oncol., 4.","DOI":"10.3389\/fonc.2014.00108"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1038\/nm909","article-title":"Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia","volume":"9","author":"Matsunaga","year":"2003","journal-title":"Nat. Med."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Lonetti, A., Pession, A., and Masetti, R. (2019). Targeted Therapies for Pediatric AML: Gaps and Perspective. Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00463"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kuhlen, M., Klusmann, J.-H., and Hoell, J.I. (2019). Molecular Approaches to Treating Pediatric Leukemias. Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00368"},{"key":"ref_76","first-page":"299","article-title":"Targeting the PI3KAKTmTOR signaling axis in children with hematologic malignancies","volume":"14","author":"Barrett","year":"2012","journal-title":"Pediatric Drugs"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Khandia, R., Dadar, M., Munjhal, A., Dhama, K., Karthik, K., Tiwari, R., Yatoo, M.I., Iqbal, H.M., Singh, K.P., and Joshi, S.K. (2019). A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy. Cells, 8.","DOI":"10.3390\/cells8070674"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1158\/1078-0432.CCR-13-3218","article-title":"Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2\/mTORC1 targeting","volume":"20","author":"Altman","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.blre.2017.11.006","article-title":"Dueling for dual inhibition: Means to enhance effectiveness of PI3K\/Akt\/mTOR inhibitors in AML","volume":"32","author":"Herschbein","year":"2018","journal-title":"Blood Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:04:31Z","timestamp":1760177071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,28]]},"references-count":79,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21176251"],"URL":"https:\/\/doi.org\/10.3390\/ijms21176251","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,28]]}}}