{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:35:30Z","timestamp":1790760930517,"version":"4.1.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002923","name":"CONICET, Argentina","doi-asserted-by":"crossref","award":["PIP 11220170100146CO01"],"award-info":[{"award-number":["PIP 11220170100146CO01"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002923","name":"CONICET, Argentina","doi-asserted-by":"crossref","award":["PIP 11220170100146CO01"],"award-info":[{"award-number":["PIP 11220170100146CO01"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002923","name":"CONICET, Argentina","doi-asserted-by":"crossref","award":["PIP 11220170100146CO01"],"award-info":[{"award-number":["PIP 11220170100146CO01"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002923","name":"CONICET, Argentina","doi-asserted-by":"crossref","award":["PIP 11220170100146CO01"],"award-info":[{"award-number":["PIP 11220170100146CO01"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002923","name":"CONICET, Argentina","doi-asserted-by":"crossref","award":["PIP 11220170100146CO01"],"award-info":[{"award-number":["PIP 11220170100146CO01"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Universidad de Buenos Aires, Argentina","award":["20720170100021BA"],"award-info":[{"award-number":["20720170100021BA"]}]},{"name":"Universidad de Buenos Aires, Argentina","award":["20720170100021BA"],"award-info":[{"award-number":["20720170100021BA"]}]},{"name":"Universidad de Buenos Aires, Argentina","award":["20720170100021BA"],"award-info":[{"award-number":["20720170100021BA"]}]},{"name":"Universidad de Buenos Aires, Argentina","award":["20720170100021BA"],"award-info":[{"award-number":["20720170100021BA"]}]},{"name":"Universidad de Buenos Aires, Argentina","award":["20720170100021BA"],"award-info":[{"award-number":["20720170100021BA"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Metabolic reprogramming (MR) influences progression of chronic myeloid leukaemia (CML) to blast crisis (BC), but metabolic programs may change transiently in a second dimension (metabolic plasticity, MP), driven by environments as hypoxia, affecting cytotoxic potency (CPot) of drugs targeting mitochondria or mitochondria-related cell stress responses (MRCSR) such as mitophagy and mitochondrial biogenesis. We assessed mitochondrial membrane potential (MMP), mitochondrial mass (MM), apoptosis, glucose uptake (GU), and CPot of arsenic trioxide (ATO), CCCP, valproic acid (VPA), vincristine (VCR), Mdivi1, and dichloroacetic acid (DCA) in CML BC cells K562 (BC-K562) under hypoxia through flow cytometry, and gene expression from GEO database. About 60% of untreated cells were killed after 72\u00a0h under hypoxia, but paradoxically, all drugs but ATO rescued cells and increased survival rates to almost 90%. Blocking mitophagy either with VCR or Mdivi1, or increasing mitochondrial biogenesis with VPA enhanced cell-survival with increased MM. DCA increased MM and rescued cells in spite of its role in activating pyruvate dehydrogenase and Krebs cycle. Cells rescued by DCA, VPA and CCCP showed decreased GU. ATO showed equal CPot in hypoxia and normoxia. MP was evidenced by differential expression of genes (DEG) under hypoxia related to Krebs cycle, lipid synthesis, cholesterol homeostasis, mitophagy, and mitochondrial biogenesis (GSE144527). A 25-gene MP-signature of BC-K562 cells under hypoxia identified BC cases among 113 transcriptomes from CML patients (GSE4170). We concluded that hypoxic environment drove a MP change evidenced by DEG that was reflected in a paradoxical pro-survival, instead of cytotoxic, effect of drugs targeting mitochondria and MRCSR.<\/jats:p>","DOI":"10.1007\/s12672-022-00524-y","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T07:03:03Z","timestamp":1657263783000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabolic plasticity in blast crisis-chronic myeloid leukaemia cells under hypoxia reduces the cytotoxic potency of drugs targeting mitochondria"],"prefix":"10.1007","volume":"13","author":[{"given":"Luciana S.","family":"Salaverry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Lombardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda C.","family":"Cabral-Lorenzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin L.","family":"Gil-Folgar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela B.","family":"Rey-Rold\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura I.","family":"Kornblihtt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2375-0077","authenticated-orcid":false,"given":"Guillermo A.","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"issue":"6","key":"524_CR1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ajh.25792","volume":"95","author":"E Jabbour","year":"2020","unstructured":"Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. Am J Hematol. 2020;95(6):691\u2013709. https:\/\/doi.org\/10.1002\/ajh.25792.","journal-title":"Am J Hematol"},{"key":"524_CR2","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2007.1.384","author":"JP Radich","year":"2007","unstructured":"Radich JP. The biology of CML blast crisis. Hematology. 2007. https:\/\/doi.org\/10.1182\/asheducation-2007.1.384.","journal-title":"Hematology"},{"issue":"5","key":"524_CR3","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600200","volume":"2","author":"RJ DeBerardinis","year":"2016","unstructured":"DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5): e1600200. https:\/\/doi.org\/10.1126\/sciadv.1600200.","journal-title":"Sci Adv"},{"issue":"4","key":"524_CR4","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1021\/acs.jproteome.9b00028","volume":"18","author":"BM Noel","year":"2019","unstructured":"Noel BM, Ouellette SB, Marholz L, Dickey D, Navis C, Yang TY, et al. Multiomic profiling of tyrosine kinase inhibitor-resistant K562 cells suggests metabolic reprogramming to promote cell survival. J Proteome Res. 2019;18(4):1842\u201356. https:\/\/doi.org\/10.1021\/acs.jproteome.9b00028.","journal-title":"J Proteome Res"},{"issue":"1","key":"524_CR5","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/leu.2015.187","volume":"30","author":"KM Koczula","year":"2016","unstructured":"Koczula KM, Ludwig C, Hayden R, Cronin L, Pratt G, Parry H, et al. Metabolic plasticity in CLL: adaptation to the hypoxic niche. Leukemia. 2016;30(1):65\u201373. https:\/\/doi.org\/10.1038\/leu.2015.187.","journal-title":"Leukemia"},{"issue":"3","key":"524_CR6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/cr.2017.155","volume":"28","author":"PE Porporato","year":"2018","unstructured":"Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28(3):265\u201380. https:\/\/doi.org\/10.1038\/cr.2017.155.","journal-title":"Cell Res"},{"issue":"2","key":"524_CR7","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41580-019-0173-8","volume":"21","author":"FJ Bock","year":"2020","unstructured":"Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21(2):85\u2013100. https:\/\/doi.org\/10.1038\/s41580-019-0173-8.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"524_CR8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11081144","author":"A Sharma","year":"2019","unstructured":"Sharma A, Boise LH, Shanmugam M. Cancer metabolism and the evasion of apoptotic cell death. Cancers (Basel). 2019. https:\/\/doi.org\/10.3390\/cancers11081144.","journal-title":"Cancers (Basel)"},{"key":"524_CR9","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3389\/fonc.2018.00090","volume":"8","author":"RS Vidal","year":"2018","unstructured":"Vidal RS, Quarti J, Rodrigues MF, Rumjanek FD, Rumjanek VM. Metabolic reprogramming during multidrug resistance in leukemias. Front Oncol. 2018;8:90. https:\/\/doi.org\/10.3389\/fonc.2018.00090.","journal-title":"Front Oncol"},{"key":"524_CR10","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1152\/physiol.00045.2008","volume":"24","author":"GL Semenza","year":"2009","unstructured":"Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009;24:97\u2013106. https:\/\/doi.org\/10.1152\/physiol.00045.2008.","journal-title":"Physiology (Bethesda)"},{"issue":"16","key":"524_CR11","doi-asserted-by":"publisher","first-page":"10892","DOI":"10.1074\/jbc.M800102200","volume":"283","author":"H Zhang","year":"2008","unstructured":"Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892\u2013903. https:\/\/doi.org\/10.1074\/jbc.M800102200.","journal-title":"J Biol Chem"},{"issue":"18","key":"524_CR12","doi-asserted-by":"publisher","first-page":"3243","DOI":"10.1016\/j.ejca.2014.09.012","volume":"50","author":"V Cavaliere","year":"2014","unstructured":"Cavaliere V, Lombardo T, Costantino SN, Kornblihtt L, Alvarez EM, Blanco GA. Synergism of arsenic trioxide and MG132 in Raji cells attained by targeting BNIP3, autophagy, and mitochondria with low doses of valproic acid and vincristine. Eur J Cancer. 2014;50(18):3243\u201361. https:\/\/doi.org\/10.1016\/j.ejca.2014.09.012.","journal-title":"Eur J Cancer"},{"key":"524_CR13","doi-asserted-by":"publisher","first-page":"393","DOI":"10.5772\/63306","volume-title":"Autophagy","author":"L Kornblihtt","year":"2016","unstructured":"Kornblihtt L, Carreras M, Blanco G. Targeting mitophagy in combined therapies of haematological malignancies. In: Gorbunov N, editor. Autophagy. Rijeka: Intech Open Publisher; 2016. p. 393\u2013418. https:\/\/doi.org\/10.5772\/63306."},{"issue":"2","key":"524_CR14","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.yexcr.2004.06.024","volume":"299","author":"AO de Graaf","year":"2004","unstructured":"de Graaf AO, van den Heuvel LP, Dijkman HB, de Abreu RA, Birkenkamp KU, de Witte T, et al. Bcl-2 prevents loss of mitochondria in CCCP-induced apoptosis. Exp Cell Res. 2004;299(2):533\u201340. https:\/\/doi.org\/10.1016\/j.yexcr.2004.06.024.","journal-title":"Exp Cell Res"},{"issue":"5","key":"524_CR15","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1111\/bcpt.12945","volume":"122","author":"T Lombardo","year":"2018","unstructured":"Lombardo T, Folgar MG, Salaverry L, Rey-Roldan E, Alvarez EM, Carreras MC, et al. Regulated cell death of lymphoma cells after graded mitochondrial damage is differentially affected by drugs targeting cell stress responses. Basic Clin Pharmacol Toxicol. 2018;122(5):489\u2013500. https:\/\/doi.org\/10.1111\/bcpt.12945.","journal-title":"Basic Clin Pharmacol Toxicol"},{"issue":"14","key":"524_CR16","first-page":"3893","volume":"62","author":"WH Miller Jr","year":"2002","unstructured":"Miller WH Jr, Schipper HM, Lee JS, Singer J, Waxman S. Mechanisms of action of arsenic trioxide. Cancer Res. 2002;62(14):3893\u2013903.","journal-title":"Cancer Res"},{"issue":"6","key":"524_CR17","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.jorganchem.2008.12.028","volume":"694","author":"ER Bergquist","year":"2009","unstructured":"Bergquist ER, Fischer RJ, Sugden KD, Martin BD. Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases. J Organomet Chem. 2009;694(6):973\u201380. https:\/\/doi.org\/10.1016\/j.jorganchem.2008.12.028.","journal-title":"J Organomet Chem"},{"key":"524_CR18","doi-asserted-by":"publisher","first-page":"2193706","DOI":"10.1155\/2019\/2193706","volume":"2019","author":"X Luo","year":"2019","unstructured":"Luo X, Liu R, Zhang Z, Chen Z, He J, Liu Y. Mitochondrial division inhibitor 1 attenuates mitophagy in a rat model of acute lung injury. Biomed Res Int. 2019;2019:2193706. https:\/\/doi.org\/10.1155\/2019\/2193706.","journal-title":"Biomed Res Int"},{"issue":"2","key":"524_CR19","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/sj.emboj.7601963","volume":"27","author":"G Twig","year":"2008","unstructured":"Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433\u201346. https:\/\/doi.org\/10.1038\/sj.emboj.7601963.","journal-title":"EMBO J"},{"issue":"Pt 5","key":"524_CR20","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1242\/jcs.115626","volume":"126","author":"R Mackeh","year":"2013","unstructured":"Mackeh R, Perdiz D, Lorin S, Codogno P, Pous C. Autophagy and microtubules\u2014new story, old players. J Cell Sci. 2013;126(Pt 5):1071\u201380. https:\/\/doi.org\/10.1242\/jcs.115626.","journal-title":"J Cell Sci"},{"issue":"1","key":"524_CR21","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ymgme.2014.03.006","volume":"112","author":"KS Sitarz","year":"2014","unstructured":"Sitarz KS, Elliott HR, Karaman BS, Relton C, Chinnery PF, Horvath R. Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts. Mol Genet Metab. 2014;112(1):57\u201363. https:\/\/doi.org\/10.1016\/j.ymgme.2014.03.006.","journal-title":"Mol Genet Metab"},{"key":"524_CR22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147265","author":"KM Cook","year":"2021","unstructured":"Cook KM, Shen H, McKelvey KJ, Gee HE, Hau E. Targeting glucose metabolism of cancer cells with dichloroacetate to radiosensitize high-grade gliomas. Int J Mol Sci. 2021. https:\/\/doi.org\/10.3390\/ijms22147265.","journal-title":"Int J Mol Sci"},{"issue":"3","key":"524_CR23","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1182\/blood.V45.3.321.321","volume":"45","author":"CB Lozzio","year":"1975","unstructured":"Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood. 1975;45(3):321\u201334.","journal-title":"Blood"},{"issue":"10\u201311","key":"524_CR24","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.crvi.2003.08.005","volume":"326","author":"JN Weinstein","year":"2003","unstructured":"Weinstein JN, Pommier Y. Transcriptomic analysis of the NCI-60 cancer cell lines. C R Biol. 2003;326(10\u201311):909\u201320. https:\/\/doi.org\/10.1016\/j.crvi.2003.08.005.","journal-title":"C R Biol"},{"key":"524_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2020.115016","volume":"398","author":"LI Kornblihtt","year":"2020","unstructured":"Kornblihtt LI, Cabral Lorenzo MC, Gil Folgar ML, Minissale CJ, Malusardi C, Rojas F, et al. A drug potency signature links progression of chronic lymphocytic leukemia to mitochondria-related stress responses and metabolic reprogramming under hypoxia. Toxicol Appl Pharmacol. 2020;398: 115016. https:\/\/doi.org\/10.1016\/j.taap.2020.115016.","journal-title":"Toxicol Appl Pharmacol"},{"key":"524_CR26","doi-asserted-by":"publisher","DOI":"10.3791\/2899","author":"D Wu","year":"2011","unstructured":"Wu D, Yotnda P. Induction and testing of hypoxia in cell culture. J Vis Exp. 2011. https:\/\/doi.org\/10.3791\/2899.","journal-title":"J Vis Exp"},{"issue":"2","key":"524_CR27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148923","volume":"11","author":"SP Mathupala","year":"2016","unstructured":"Mathupala SP, Kiousis S, Szerlip NJ. A lab assembled microcontroller-based sensor module for continuous oxygen measurement in portable hypoxia chambers. PLoS ONE. 2016;11(2): e0148923. https:\/\/doi.org\/10.1371\/journal.pone.0148923.","journal-title":"PLoS ONE"},{"issue":"5","key":"524_CR28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1369\/0022155415574818","volume":"63","author":"XX Li","year":"2015","unstructured":"Li XX, Tsoi B, Li YF, Kurihara H, He RR. Cardiolipin and its different properties in mitophagy and apoptosis. J Histochem Cytochem. 2015;63(5):301\u201311. https:\/\/doi.org\/10.1369\/0022155415574818.","journal-title":"J Histochem Cytochem"},{"issue":"7","key":"524_CR29","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/cyto.a.22625","volume":"87","author":"S Van Gassen","year":"2015","unstructured":"Van Gassen S, Callebaut B, Van Helden MJ, Lambrecht BN, Demeester P, Dhaene T, et al. FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A. 2015;87(7):636\u201345. https:\/\/doi.org\/10.1002\/cyto.a.22625.","journal-title":"Cytometry A"},{"issue":"1","key":"524_CR30","doi-asserted-by":"publisher","first-page":"5415","DOI":"10.1038\/s41467-019-13055-y","volume":"10","author":"AC Belkina","year":"2019","unstructured":"Belkina AC, Ciccolella CO, Anno R, Halpert R, Spidlen J, Snyder-Cappione JE. Automated optimized parameters for T-distributed stochastic neighbor embedding improve visualization and analysis of large datasets. Nat Commun. 2019;10(1):5415. https:\/\/doi.org\/10.1038\/s41467-019-13055-y.","journal-title":"Nat Commun"},{"issue":"2","key":"524_CR31","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","volume":"70","author":"TC Chou","year":"2010","unstructured":"Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440\u20136. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-1947.","journal-title":"Cancer Res"},{"issue":"3","key":"524_CR32","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.cell.2020.03.029","volume":"181","author":"IH Jain","year":"2020","unstructured":"Jain IH, Calvo SE, Markhard AL, Skinner OS, To TL, Ast T, et al. Genetic screen for cell fitness in high or low oxygen highlights mitochondrial and lipid metabolism. Cell. 2020;181(3):716-727 e11. https:\/\/doi.org\/10.1016\/j.cell.2020.03.029.","journal-title":"Cell"},{"issue":"8","key":"524_CR33","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1073\/pnas.0510423103","volume":"103","author":"JP Radich","year":"2006","unstructured":"Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103(8):2794\u20139. https:\/\/doi.org\/10.1073\/pnas.0510423103.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"7","key":"524_CR34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7): e47. https:\/\/doi.org\/10.1093\/nar\/gkv007.","journal-title":"Nucleic Acids Res"},{"issue":"43","key":"524_CR35","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545\u201350. https:\/\/doi.org\/10.1073\/pnas.0506580102.","journal-title":"Proc Natl Acad Sci USA"},{"key":"524_CR36","volume-title":"Practical Guide to Cluster Analysis in R: Unsupervised Machine Learning","author":"AU Kassambara","year":"2017","unstructured":"Kassambara AU. Practical Guide to Cluster Analysis in R: Unsupervised Machine Learning. STHDA: New york; 2017."},{"issue":"2","key":"524_CR37","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3324\/haematol.2010.029082","volume":"96","author":"S Giuntoli","year":"2011","unstructured":"Giuntoli S, Tanturli M, Di Gesualdo F, Barbetti V, Rovida E, Dello Sbarba P. Glucose availability in hypoxia regulates the selection of chronic myeloid leukemia progenitor subsets with different resistance to imatinib-mesylate. Haematologica. 2011;96(2):204\u201312. https:\/\/doi.org\/10.3324\/haematol.2010.029082.","journal-title":"Haematologica"},{"issue":"2","key":"524_CR38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017008","volume":"6","author":"M Tanturli","year":"2011","unstructured":"Tanturli M, Giuntoli S, Barbetti V, Rovida E, Dello Sbarba P. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia. PLoS ONE. 2011;6(2): e17008. https:\/\/doi.org\/10.1371\/journal.pone.0017008.","journal-title":"PLoS ONE"},{"issue":"2","key":"524_CR39","doi-asserted-by":"publisher","first-page":"166016","DOI":"10.1016\/j.bbadis.2020.166016","volume":"1867","author":"GL Oliveira","year":"2021","unstructured":"Oliveira GL, Coelho AR, Marques R, Oliveira PJ. Cancer cell metabolism: rewiring the mitochondrial hub. Biochim Biophys Acta Mol Basis Dis. 2021;1867(2):166016. https:\/\/doi.org\/10.1016\/j.bbadis.2020.166016.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"7","key":"524_CR40","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1016\/j.biocel.2010.05.003","volume":"43","author":"K Smolkova","year":"2011","unstructured":"Smolkova K, Plecita-Hlavata L, Bellance N, Benard G, Rossignol R, Jezek P. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol. 2011;43(7):950\u201368. https:\/\/doi.org\/10.1016\/j.biocel.2010.05.003.","journal-title":"Int J Biochem Cell Biol"},{"key":"524_CR41","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040762","author":"O Shuvalov","year":"2021","unstructured":"Shuvalov O, Daks A, Fedorova O, Petukhov A, Barlev N. Linking metabolic reprogramming, plasticity and tumor progression. Cancers (Basel). 2021. https:\/\/doi.org\/10.3390\/cancers13040762.","journal-title":"Cancers (Basel)."},{"issue":"1","key":"524_CR42","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.trecan.2019.11.009","volume":"6","author":"S McGuirk","year":"2020","unstructured":"McGuirk S, Audet-Delage Y, St-Pierre J. Metabolic fitness and plasticity in cancer progression. Trends Cancer. 2020;6(1):49\u201361. https:\/\/doi.org\/10.1016\/j.trecan.2019.11.009.","journal-title":"Trends Cancer"},{"issue":"5","key":"524_CR43","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1083\/jcb.200809125","volume":"183","author":"D Narendra","year":"2008","unstructured":"Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183(5):795\u2013803. https:\/\/doi.org\/10.1083\/jcb.200809125.","journal-title":"J Cell Biol"},{"issue":"1","key":"524_CR44","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.cmet.2011.12.009","volume":"15","author":"A Le","year":"2012","unstructured":"Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15(1):110\u201321. https:\/\/doi.org\/10.1016\/j.cmet.2011.12.009.","journal-title":"Cell Metab"},{"key":"524_CR45","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/273947","volume":"2012","author":"K Smolkova","year":"2012","unstructured":"Smolkova K, Jezek P. The role of mitochondrial NADPH-dependent isocitrate dehydrogenase in cancer cells. Int J Cell Biol. 2012;2012: 273947. https:\/\/doi.org\/10.1155\/2012\/273947.","journal-title":"Int J Cell Biol"},{"issue":"11","key":"524_CR46","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.trecan.2017.09.007","volume":"3","author":"RG Shulman","year":"2017","unstructured":"Shulman RG, Rothman DL. The glycogen shunt maintains glycolytic homeostasis and the warburg effect in cancer. Trends Cancer. 2017;3(11):761\u20137. https:\/\/doi.org\/10.1016\/j.trecan.2017.09.007.","journal-title":"Trends Cancer"},{"issue":"Pt B","key":"524_CR47","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1016\/j.ijbiomac.2021.10.213","volume":"193","author":"GJ Yang","year":"2021","unstructured":"Yang GJ, Wu J, Leung CH, Ma DL, Chen J. A review on the emerging roles of pyruvate kinase M2 in anti-leukemia therapy. Int J Biol Macromol. 2021;193(Pt B):1499\u2013506. https:\/\/doi.org\/10.1016\/j.ijbiomac.2021.10.213.","journal-title":"Int J Biol Macromol"},{"key":"524_CR48","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13578-019-0317-8","volume":"9","author":"Z Zhang","year":"2019","unstructured":"Zhang Z, Deng X, Liu Y, Liu Y, Sun L, Chen F. PKM2, function and expression and regulation. Cell Biosci. 2019;9:52. https:\/\/doi.org\/10.1186\/s13578-019-0317-8.","journal-title":"Cell Biosci"},{"issue":"1","key":"524_CR49","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s40164-021-00221-6","volume":"10","author":"H Cho","year":"2021","unstructured":"Cho H, Jang JE, Eom JI, Jeung HK, Chung H, Kim JS, et al. Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukaemia cells. Exp Hematol Oncol. 2021;10(1):28. https:\/\/doi.org\/10.1186\/s40164-021-00221-6.","journal-title":"Exp Hematol Oncol"},{"issue":"12","key":"524_CR50","doi-asserted-by":"publisher","first-page":"e115250","DOI":"10.1371\/journal.pone.0115250","volume":"9","author":"MC Estan","year":"2014","unstructured":"Estan MC, Calvino E, Calvo S, Guillen-Guio B, Boyano-Adanez Mdel C, de Blas E, et al. Apoptotic efficacy of etomoxir in human acute myeloid leukemia cells. Cooperation with arsenic trioxide and glycolytic inhibitors, and regulation by oxidative stress and protein kinase activities. PLoS ONE. 2014;9(12):e115250. https:\/\/doi.org\/10.1371\/journal.pone.0115250.","journal-title":"PLoS ONE"},{"issue":"11","key":"524_CR51","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1182\/blood-2015-01-621870","volume":"126","author":"N Jacque","year":"2015","unstructured":"Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015;126(11):1346\u201356. https:\/\/doi.org\/10.1182\/blood-2015-01-621870.","journal-title":"Blood"},{"issue":"3","key":"524_CR52","doi-asserted-by":"publisher","first-page":"E55","DOI":"10.1002\/ajh.25719","volume":"95","author":"HH Zhu","year":"2020","unstructured":"Zhu HH, Qian JJ, Sun WJ, You LS, Wang QQ, Naranmandura H, et al. Venetoclax and arsenic showed synergistic anti-leukemia activity in vitro and in vivo for acute myeloid leukemia with the NPM1 mutation. Am J Hematol. 2020;95(3):E55\u20137. https:\/\/doi.org\/10.1002\/ajh.25719.","journal-title":"Am J Hematol"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-022-00524-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-022-00524-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-022-00524-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T07:48:00Z","timestamp":1657266480000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-022-00524-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["524"],"URL":"https:\/\/doi.org\/10.1007\/s12672-022-00524-y","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"assertion":[{"value":"7 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}],"article-number":"60"}}