{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T14:24:43Z","timestamp":1793802283619,"version":"4.6.1"},"reference-count":95,"publisher":"American Society of Hematology","issue":"17","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex\u00a0vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT\/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and\u00a0primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.<\/jats:p>","DOI":"10.1182\/blood.2021015106","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T18:13:11Z","timestamp":1652292791000},"page":"1891-1906","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":46,"title":["Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6328-1741","authenticated-orcid":false,"given":"Saara","family":"Laukkanen","sequence":"first","affiliation":[{"name":"1Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-7578","authenticated-orcid":false,"given":"Alexandra","family":"Veloso","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Yan","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4468-9877","authenticated-orcid":false,"given":"Laura","family":"Oksa","sequence":"additional","affiliation":[{"name":"1Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4513-0066","authenticated-orcid":false,"given":"Eric J.","family":"Alpert","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Do","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noora","family":"Hyv\u00e4rinen","sequence":"additional","affiliation":[{"name":"1Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"McCarthy","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9228-480X","authenticated-orcid":false,"given":"Abhinav","family":"Adhikari","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1109-5044","authenticated-orcid":false,"given":"Qiqi","family":"Yang","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Iyer","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3312-6454","authenticated-orcid":false,"given":"Sara P.","family":"Garcia","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8313-8723","authenticated-orcid":false,"given":"Annukka","family":"Pello","sequence":"additional","affiliation":[{"name":"5Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Ruokoranta","sequence":"additional","affiliation":[{"name":"6Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanni","family":"Moisio","sequence":"additional","affiliation":[{"name":"7The Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7471-014X","authenticated-orcid":false,"given":"Sadiksha","family":"Adhikari","sequence":"additional","affiliation":[{"name":"5Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6083-1311","authenticated-orcid":false,"given":"Jeffrey A.","family":"Yoder","sequence":"additional","affiliation":[{"name":"8Department of Molecular Biomedical Sciences, Comparative Medicine Institute, and Center for Human Health and the Environment, North Carolina State University, Raleigh, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayleigh","family":"Gallagher","sequence":"additional","affiliation":[{"name":"9Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Whelton","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1314-9122","authenticated-orcid":false,"given":"James R.","family":"Allen","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7431-1456","authenticated-orcid":false,"given":"Alex H.","family":"Jin","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4602-4580","authenticated-orcid":false,"given":"Siebe","family":"Loontiens","sequence":"additional","affiliation":[{"name":"10Cancer Research Institute Ghent and Center for Medical Genetics, Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-3439","authenticated-orcid":false,"given":"Merja","family":"Hein\u00e4niemi","sequence":"additional","affiliation":[{"name":"7The Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kelliher","sequence":"additional","affiliation":[{"name":"9Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4324-8706","authenticated-orcid":false,"given":"Caroline A.","family":"Heckman","sequence":"additional","affiliation":[{"name":"5Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9195-0797","authenticated-orcid":false,"given":"Olli","family":"Lohi","sequence":"additional","affiliation":[{"name":"1Tampere Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland"},{"name":"11Tampere University Hospital, Tays Cancer Center, Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6664-8318","authenticated-orcid":false,"given":"David M.","family":"Langenau","sequence":"additional","affiliation":[{"name":"2Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA"},{"name":"3Harvard Stem Cell Institute, Boston, MA"},{"name":"4Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2022102715264367400_bib1","doi-asserted-by":"crossref","first-page":"12070","DOI":"10.1038\/s41598-019-48445-1","article-title":"An emerging trend of rapid increase of leukemia but not all cancers in the aging population in the United States","volume":"9","author":"Hao","year":"2019","journal-title":"Sci Rep"},{"issue":"10","key":"2022102715264367400_bib2","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1172\/JCI61269","article-title":"The molecular basis of T cell acute lymphoblastic leukemia","volume":"122","author":"Van Vlierberghe","year":"2012","journal-title":"J\u00a0Clin Invest"},{"issue":"9","key":"2022102715264367400_bib3","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1182\/blood-2016-10-706465","article-title":"The genetics and molecular biology of T-ALL","volume":"129","author":"Girardi","year":"2017","journal-title":"Blood"},{"issue":"C","key":"2022102715264367400_bib4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S1877-1173(10)92006-1","article-title":"Early T cell differentiation lessons from T-cell acute lymphoblastic leukemia","volume":"92","author":"Tremblay","year":"2010","journal-title":"Prog Mol Biol Transl Sci"},{"issue":"3","key":"2022102715264367400_bib5","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":"Gutierrez","year":"2009","journal-title":"Blood"},{"issue":"1","key":"2022102715264367400_bib6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13045-016-0344-4","article-title":"Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K\/AKT\/mTOR signaling pathway","volume":"9","author":"Lonetti","year":"2016","journal-title":"J\u00a0Hematol Oncol"},{"issue":"16","key":"2022102715264367400_bib7","doi-asserted-by":"crossref","first-page":"22128","DOI":"10.18632\/oncotarget.8031","article-title":"Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen","volume":"7","author":"Lynch","year":"2016","journal-title":"Oncotarget"},{"issue":"3","key":"2022102715264367400_bib8","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ccr.2014.01.032","article-title":"Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt\/mTORC1 pathway activation","volume":"25","author":"Blackburn","year":"2014","journal-title":"Cancer Cell"},{"issue":"8","key":"2022102715264367400_bib9","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/ng.3909","article-title":"The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia","volume":"49","author":"Liu","year":"2017","journal-title":"Nat Genet"},{"key":"2022102715264367400_bib10","doi-asserted-by":"crossref","first-page":"100591","DOI":"10.1016\/j.blre.2019.100591","article-title":"Targeting steroid resistance in T-cell acute lymphoblastic leukemia","volume":"38","author":"De Smedt","year":"2019","journal-title":"Blood Rev"},{"issue":"4","key":"2022102715264367400_bib11","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1084\/jem.20110105","article-title":"Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse","volume":"208","author":"Clappier","year":"2011","journal-title":"J\u00a0Exp Med"},{"issue":"7","key":"2022102715264367400_bib12","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1021\/ml500044g","article-title":"Small molecule that reverses dexamethasone resistance in T-cell acute lymphoblastic leukemia (T-ALL)","volume":"5","author":"Cantley","year":"2014","journal-title":"ACS Med Chem Lett"},{"issue":"6","key":"2022102715264367400_bib13","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.ccr.2013.10.022","article-title":"Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia","volume":"24","author":"Piovan","year":"2013","journal-title":"Cancer Cell"},{"issue":"10","key":"2022102715264367400_bib14","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1002\/eji.201646440","article-title":"T-cell development is regulated by the coordinated function of proximal and distal Lck promoters active at different developmental stages","volume":"46","author":"Chiang","year":"2016","journal-title":"Eur J Immunol"},{"issue":"48","key":"2022102715264367400_bib15","doi-asserted-by":"crossref","first-page":"7990","DOI":"10.1038\/sj.onc.1208074","article-title":"Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation","volume":"23","author":"Palacios","year":"2004","journal-title":"Oncogene"},{"issue":"5","key":"2022102715264367400_bib16","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S1074-7613(00)80499-9","article-title":"Alpha beta T cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases","volume":"5","author":"van Oers","year":"1996","journal-title":"Immunity"},{"key":"2022102715264367400_bib17","doi-asserted-by":"crossref","first-page":"72","DOI":"10.3389\/fimmu.2011.00072","article-title":"Initiation of TCR phosphorylation and signal transduction","volume":"2","author":"Gascoigne","year":"2011","journal-title":"Front Immunol"},{"issue":"6","key":"2022102715264367400_bib18","doi-asserted-by":"crossref","first-page":"a002485","DOI":"10.1101\/cshperspect.a002485","article-title":"ITAM-mediated signaling by the T-cell antigen receptor","volume":"2","author":"Love","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"1","key":"2022102715264367400_bib19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1158\/2643-3230.BCD-20-0093","article-title":"T-cell acute lymphoblastic leukemia: a roadmap to targeted therapies","volume":"2","author":"Cordo\u2019","year":"2020","journal-title":"Blood Cancer Discov"},{"issue":"3","key":"2022102715264367400_bib20","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1182\/blood.V71.3.603.603","article-title":"Cytoplasmic expression of the CD3 antigen as a diagnostic marker for immature T-cell malignancies","volume":"71","author":"van Dongen","year":"1988","journal-title":"Blood"},{"issue":"10","key":"2022102715264367400_bib21","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1182\/blood.2018852400","article-title":"Genetic defects in hematopoietic transcription factors and predisposition to acute lymphoblastic leukemia","volume":"134","author":"Gocho","year":"2019","journal-title":"Blood"},{"issue":"1","key":"2022102715264367400_bib22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-022-28682-1","article-title":"Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies","volume":"13","author":"Cordo\u2019","year":"2022","journal-title":"Nat. Commun"},{"issue":"19","key":"2022102715264367400_bib23","doi-asserted-by":"crossref","first-page":"6879","DOI":"10.1073\/pnas.84.19.6879","article-title":"Isolation and characterization of a T-lymphocyte somatic mutant with altered signal transduction by the antigen receptor","volume":"84","author":"Goldsmith","year":"1987","journal-title":"Proc Natl Acad Sci USA"},{"issue":"4","key":"2022102715264367400_bib24","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0092-8674(92)90428-F","article-title":"Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor","volume":"70","author":"Straus","year":"1992","journal-title":"Cell"},{"issue":"2","key":"2022102715264367400_bib25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/cells10020343","article-title":"A\u00a0novel, LAT\/Lck double deficient T cell subline J.CaM1.7 for combined analysis of early TCR signaling","volume":"10","author":"Vico-Barranco","year":"2021","journal-title":"Cells"},{"issue":"25","key":"2022102715264367400_bib26","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1182\/blood-2017-05-784603","article-title":"Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia","volume":"130","author":"Serafin","year":"2017","journal-title":"Blood"},{"issue":"3","key":"2022102715264367400_bib27","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41375-020-0937-3","article-title":"PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis","volume":"35","author":"Garcia","year":"2020","journal-title":"Leukemia"},{"issue":"9","key":"2022102715264367400_bib28","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1158\/2159-8290.CD-15-0675","article-title":"Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia","volume":"6","author":"Trinquand","year":"2016","journal-title":"Cancer Discov"},{"issue":"7","key":"2022102715264367400_bib29","doi-asserted-by":"crossref","first-page":"E1878","DOI":"10.3390\/ijms19071878","article-title":"Therapeutic targeting of mTOR in T-cell acute lymphoblastic leukemia: an update","volume":"19","author":"Evangelisti","year":"2018","journal-title":"Int J Mol Sci"},{"issue":"3","key":"2022102715264367400_bib30","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1111\/bjh.14569","article-title":"A\u00a0phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children\u2019s Oncology Group study (ADVL1114)","volume":"177","author":"Rheingold","year":"2017","journal-title":"Br J Haematol"},{"key":"2022102715264367400_bib31","first-page":"e2790","article-title":"Quantifying the frequency of tumor-propagating cells using limiting dilution cell transplantation in syngeneic zebrafish","volume":"53","author":"Blackburn","year":"2011","journal-title":"J\u00a0Vis Exp"},{"issue":"13","key":"2022102715264367400_bib32","doi-asserted-by":"crossref","first-page":"3585","DOI":"10.1182\/blood-2010-08-301267","article-title":"Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia","volume":"117","author":"Boulos","year":"2011","journal-title":"Blood"},{"issue":"3","key":"2022102715264367400_bib33","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1182\/blood-2005-05-1935","article-title":"The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL","volume":"107","author":"Teachey","year":"2006","journal-title":"Blood"},{"issue":"7","key":"2022102715264367400_bib34","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"issue":"6","key":"2022102715264367400_bib35","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1182\/blood-2016-02-699363","article-title":"JAK1\/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML","volume":"130","author":"Karjalainen","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2022102715264367400_bib36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep05193","article-title":"Quantitative scoring of differential drug sensitivity for individually optimized anticancer therapies","volume":"4","author":"Yadav","year":"2014","journal-title":"Sci Rep"},{"issue":"W1","key":"2022102715264367400_bib37","doi-asserted-by":"crossref","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","article-title":"SynergyFinder 2.0: visual analytics of multi-drug combination synergies","volume":"48","author":"Ianevski","year":"2020","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"2022102715264367400_bib38","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.leukres.2009.06.020","article-title":"Multiple mechanisms induce ectopic expression of LYL1 in subsets of T-ALL cell lines","volume":"34","author":"Nagel","year":"2010","journal-title":"Leuk Res"},{"issue":"6","key":"2022102715264367400_bib39","doi-asserted-by":"crossref","first-page":"e38463","DOI":"10.1371\/journal.pone.0038463","article-title":"High accuracy mutation detection in leukemia on a selected panel of cancer genes","volume":"7","author":"Kalender Atak","year":"2012","journal-title":"PLoS One"},{"issue":"1","key":"2022102715264367400_bib40","first-page":"106","article-title":"The SCL protein displays cell-specific heterogeneity in size","volume":"8","author":"Elwood","year":"1994","journal-title":"Leukemia"},{"key":"2022102715264367400_bib41","author":"Drexler","year":"2000"},{"issue":"6215","key":"2022102715264367400_bib42","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1126\/science.1259037","article-title":"Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element","volume":"346","author":"Mansour","year":"2014","journal-title":"Science"},{"issue":"10","key":"2022102715264367400_bib43","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1038\/s41375-018-0110-4","article-title":"Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic leukemia","volume":"32","author":"Ngoc","year":"2018","journal-title":"Leukemia"},{"issue":"1","key":"2022102715264367400_bib44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-84647-2","article-title":"Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)","volume":"11","author":"Shaw","year":"2021","journal-title":"Sci Rep"},{"issue":"7757","key":"2022102715264367400_bib45","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41586-019-1186-3","article-title":"Next-generation characterization of the Cancer Cell Line Encyclopedia","volume":"569","author":"Ghandi","year":"2019","journal-title":"Nature"},{"issue":"20","key":"2022102715264367400_bib46","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1056\/NEJMoa1114885","article-title":"Somatic STAT3 mutations in large granular lymphocytic leukemia","volume":"366","author":"Koskela","year":"2012","journal-title":"N\u00a0Engl J Med"},{"issue":"3","key":"2022102715264367400_bib47","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ccell.2020.08.019","article-title":"Immunogenomic landscape of hematological malignancies","volume":"38","author":"Dufva","year":"2020","journal-title":"Cancer Cell"},{"issue":"13","key":"2022102715264367400_bib48","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1080\/10428194.2020.1804560","article-title":"SIX6 is a TAL1-regulated transcription factor in T-ALL and associated with inferior outcome","volume":"61","author":"Laukkanen","year":"2020","journal-title":"Leuk Lymphoma"},{"issue":"9","key":"2022102715264367400_bib49","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1038\/leu.2012.116","article-title":"Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency","volume":"26","author":"Blackburn","year":"2012","journal-title":"Leukemia"},{"issue":"11","key":"2022102715264367400_bib50","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1158\/2159-8290.CD-17-0267","article-title":"TOX regulates growth, DNA repair, and genomic instability in T-cell acute lymphoblastic leukemia","volume":"7","author":"Lobbardi","year":"2017","journal-title":"Cancer Discov"},{"issue":"4","key":"2022102715264367400_bib51","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.ccr.2010.09.009","article-title":"T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation","volume":"18","author":"Feng","year":"2010","journal-title":"Cancer Cell"},{"issue":"7","key":"2022102715264367400_bib52","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1084\/jem.20170484","article-title":"JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia","volume":"215","author":"Mansour","year":"2018","journal-title":"J\u00a0Exp Med"},{"issue":"24","key":"2022102715264367400_bib53","doi-asserted-by":"crossref","first-page":"5621","DOI":"10.1182\/blood-2011-12-398818","article-title":"Zebrafish screen identifies novel compound with selective toxicity against leukemia","volume":"119","author":"Ridges","year":"2012","journal-title":"Blood"},{"issue":"1","key":"2022102715264367400_bib54","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/s41375-018-0201-2","article-title":"The MCL1-specific inhibitor S63845 acts synergistically with venetoclax\/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells","volume":"33","author":"Li","year":"2019","journal-title":"Leukemia"},{"issue":"2","key":"2022102715264367400_bib55","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1172\/JCI65093","article-title":"Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia","volume":"124","author":"Gutierrez","year":"2014","journal-title":"J\u00a0Clin Invest"},{"issue":"8","key":"2022102715264367400_bib56","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1038\/s41375-018-0130-0","article-title":"Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia","volume":"32","author":"Garcia","year":"2018","journal-title":"Leukemia"},{"issue":"2","key":"2022102715264367400_bib57","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41375-018-0328-1","article-title":"Molecularly distinct models of zebrafish Myc-induced B cell leukemia","volume":"33","author":"Borga","year":"2019","journal-title":"Leukemia"},{"issue":"5608","key":"2022102715264367400_bib58","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1126\/science.1080280","article-title":"Myc-induced T cell leukemia in transgenic zebrafish","volume":"299","author":"Langenau","year":"2003","journal-title":"Science"},{"issue":"2","key":"2022102715264367400_bib59","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41375-018-0226-6","article-title":"Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis","volume":"33","author":"Borga","year":"2019","journal-title":"Leukemia"},{"issue":"3","key":"2022102715264367400_bib60","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/s43018-020-00167-4","article-title":"Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia","volume":"2","author":"Gocho","year":"2021","journal-title":"Nat Cancer"},{"issue":"3","key":"2022102715264367400_bib61","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1182\/blood-2007-04-084814","article-title":"Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation","volume":"111","author":"Schade","year":"2008","journal-title":"Blood"},{"issue":"4","key":"2022102715264367400_bib62","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/leu.2010.11","article-title":"Lck is a key target of imatinib and dasatinib in T-cell activation","volume":"24","author":"Lee","year":"2010","journal-title":"Leukemia"},{"issue":"1","key":"2022102715264367400_bib63","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1158\/1078-0432.CCR-18-1211","article-title":"Preventing Lck activation in CAR T cells confers Treg resistance but requires 4-1BB signaling for them to persist and treat solid tumors in nonlymphodepleted hosts","volume":"25","author":"Suryadevara","year":"2019","journal-title":"Clin Cancer Res"},{"key":"2022102715264367400_bib64","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3389\/fimmu.2012.00167","article-title":"How does the kinase Lck phosphorylate the T cell receptor? Spatial organization as a regulatory mechanism","volume":"3","author":"Rossy","year":"2012","journal-title":"Front Immunol"},{"issue":"5","key":"2022102715264367400_bib65","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/s12276-020-0435-8","article-title":"Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development","volume":"52","author":"Hwang","year":"2020","journal-title":"Exp Mol Med"},{"issue":"9","key":"2022102715264367400_bib66","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1038\/sj.leu.2401866","article-title":"Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax\/Bcl-2 ratio and loss of spontaneous caspase-3 processing in\u00a0vivo","volume":"14","author":"Prokop","year":"2000","journal-title":"Leukemia"},{"issue":"16","key":"2022102715264367400_bib67","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.1073\/pnas.0401471101","article-title":"Bim is a suppressor of Myc-induced mouse B cell leukemia","volume":"101","author":"Egle","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"issue":"16","key":"2022102715264367400_bib68","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1182\/blood-2010-05-284968","article-title":"Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition","volume":"116","author":"Bachmann","year":"2010","journal-title":"Blood"},{"issue":"22","key":"2022102715264367400_bib69","doi-asserted-by":"crossref","first-page":"10685","DOI":"10.1073\/pnas.91.22.10685","article-title":"Bcl-2 expression during T-cell development: early loss and late return occur at specific stages of commitment to differentiation and survival","volume":"91","author":"Gratiot-Deans","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"issue":"25","key":"2022102715264367400_bib70","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1182\/blood-2014-05-574566","article-title":"ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia","volume":"124","author":"Peirs","year":"2014","journal-title":"Blood"},{"issue":"4","key":"2022102715264367400_bib71","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/sj.leu.2402090","article-title":"Phosphorylation of Bcl2 and regulation of apoptosis","volume":"15","author":"Ruvolo","year":"2001","journal-title":"Leukemia"},{"issue":"7336","key":"2022102715264367400_bib72","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature09732","article-title":"SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction","volume":"471","author":"Inuzuka","year":"2011","journal-title":"Nature"},{"issue":"1","key":"2022102715264367400_bib73","doi-asserted-by":"crossref","first-page":"e1593","DOI":"10.1038\/cddis.2014.525","article-title":"MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K\/AKT\/mTOR activation in lymphoid malignancies","volume":"6","author":"Choudhary","year":"2015","journal-title":"Cell Death Dis"},{"issue":"17","key":"2022102715264367400_bib74","doi-asserted-by":"crossref","first-page":"4520","DOI":"10.1158\/1078-0432.CCR-14-0259","article-title":"Cell and molecular determinants of in\u00a0vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts","volume":"20","author":"Suryani","year":"2014","journal-title":"Clin Cancer Res"},{"issue":"4","key":"2022102715264367400_bib75","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1172\/JCI113453","article-title":"Comparison of T cell receptor alpha, beta, and gamma gene rearrangement and expression in T cell acute lymphoblastic leukemia","volume":"81","author":"Hara","year":"1988","journal-title":"J\u00a0Clin Invest"},{"issue":"9","key":"2022102715264367400_bib76","doi-asserted-by":"crossref","first-page":"e604","DOI":"10.1038\/bcj.2017.87","article-title":"In silico and preclinical drug screening identifies dasatinib as a targeted therapy for T-ALL","volume":"7","author":"Laukkanen","year":"2017","journal-title":"Blood Cancer J"},{"issue":"2","key":"2022102715264367400_bib77","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/sj.leu.2404486","article-title":"Human T-cell lines with well-defined T-cell receptor gene rearrangements as controls for the BIOMED-2 multiplex polymerase chain reaction tubes","volume":"21","author":"Sandberg","year":"2007","journal-title":"Leukemia"},{"issue":"2","key":"2022102715264367400_bib78","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/pbc.23327","article-title":"Complete morphologic and molecular remission after introduction of dasatinib in the treatment of a pediatric patient with t-cell acute lymphoblastic leukemia and ABL1 amplification","volume":"59","author":"Crombet","year":"2012","journal-title":"Pediatr Blood Cancer"},{"issue":"3","key":"2022102715264367400_bib79","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3324\/haematol.10822","article-title":"Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain","volume":"92","author":"Soverini","year":"2007","journal-title":"Haematologica"},{"issue":"1","key":"2022102715264367400_bib80","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/leu.2012.222","article-title":"Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors","volume":"27","author":"W\u00f6hrle","year":"2013","journal-title":"Leukemia"},{"issue":"4","key":"2022102715264367400_bib81","first-page":"1056","article-title":"Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia","volume":"106","author":"Shi","year":"2021","journal-title":"Haematologica"},{"issue":"11","key":"2022102715264367400_bib82","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1182\/blood-2016-09-738070","article-title":"Ex\u00a0vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia","volume":"129","author":"Frismantas","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2022102715264367400_bib83","doi-asserted-by":"crossref","first-page":"521","DOI":"10.4049\/jimmunol.181.1.521","article-title":"The anti-apoptotic Bcl-2 family member Mcl-1 promotes T lymphocyte survival at multiple stages","volume":"181","author":"Dzhagalov","year":"2008","journal-title":"J\u00a0Immunol"},{"issue":"6","key":"2022102715264367400_bib84","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.immuni.2010.06.005","article-title":"Apoptosis threshold set by Noxa and Mcl-1 after T cell activation regulates competitive selection of high-affinity clones","volume":"32","author":"Wensveen","year":"2010","journal-title":"Immunity"},{"issue":"14","key":"2022102715264367400_bib85","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1016\/j.febslet.2010.05.061","article-title":"Mcl-1; the molecular regulation of protein function","volume":"584","author":"Thomas","year":"2010","journal-title":"FEBS Lett"},{"issue":"6","key":"2022102715264367400_bib86","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.molcel.2006.02.009","article-title":"Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1","volume":"21","author":"Maurer","year":"2006","journal-title":"Mol Cell"},{"issue":"10","key":"2022102715264367400_bib87","doi-asserted-by":"crossref","first-page":"5313","DOI":"10.1172\/JCI133310","article-title":"Everolimus improves the efficacy of dasatinib in PDGFR\u03b1-driven glioma","volume":"130","author":"Miklja","year":"2020","journal-title":"J\u00a0Clin Invest"},{"issue":"31","key":"2022102715264367400_bib88","doi-asserted-by":"crossref","first-page":"10853","DOI":"10.1073\/pnas.0804821105","article-title":"mTORC1 promotes survival through translational control of Mcl-1","volume":"105","author":"Mills","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"issue":"9","key":"2022102715264367400_bib89","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1038\/s41418-021-00773-4","article-title":"Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function","volume":"28","author":"Campbell","year":"2021","journal-title":"Cell Death Differ"},{"issue":"12","key":"2022102715264367400_bib90","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1158\/2159-8290.CD-18-0277","article-title":"Exploiting MCL1 dependency with combination MEK\u00a0+ MCL1 inhibitors leads to induction of apoptosis and tumor regression in KRAS-mutant non-small cell lung cancer","volume":"8","author":"Nangia","year":"2018","journal-title":"Cancer Discov"},{"issue":"13","key":"2022102715264367400_bib91","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1182\/blood.2020006785","article-title":"BCL2 and MCL1 inhibitors for hematologic malignancies","volume":"138","author":"Roberts","year":"2021","journal-title":"Blood"},{"issue":"6967","key":"2022102715264367400_bib92","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nature02067","article-title":"Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1","volume":"426","author":"Opferman","year":"2003","journal-title":"Nature"},{"issue":"5712","key":"2022102715264367400_bib93","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1126\/science.1106114","article-title":"Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells","volume":"307","author":"Opferman","year":"2005","journal-title":"Science"},{"issue":"24","key":"2022102715264367400_bib94","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.1523\/JNEUROSCI.4940-07.2008","article-title":"Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage","volume":"28","author":"Arbour","year":"2008","journal-title":"J\u00a0Neurosci"},{"issue":"12","key":"2022102715264367400_bib95","doi-asserted-by":"crossref","first-page":"8337","DOI":"10.4049\/jimmunol.175.12.8337","article-title":"Mcl-1 is essential for the survival of synovial fibroblasts in rheumatoid arthritis","volume":"175","author":"Liu","year":"2005","journal-title":"J\u00a0Immunol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/17\/1891\/1927401\/blood_bld-2021-015106-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/17\/1891\/1927401\/blood_bld-2021-015106-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T23:04:28Z","timestamp":1675551868000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/140\/17\/1891\/485213\/Therapeutic-targeting-of-LCK-tyrosine-kinase-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,27]]},"references-count":95,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2022,10,27]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2021015106","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,27]]}}}