{"id":"https://openalex.org/W4310107077","doi":"https://doi.org/10.1182/blood-2022-167220","title":"Idasanutlin and Navitoclax Induce Synergistic Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia","display_name":"Idasanutlin and Navitoclax Induce Synergistic Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia","publication_year":2022,"publication_date":"2022-11-15","ids":{"openalex":"https://openalex.org/W4310107077","doi":"https://doi.org/10.1182/blood-2022-167220"},"language":"en","primary_location":{"id":"doi:10.1182/blood-2022-167220","doi":"https://doi.org/10.1182/blood-2022-167220","is_oa":false,"landing_page_url":"https://doi.org/10.1182/blood-2022-167220","pdf_url":null,"source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"},"volume":null,"type":"article","indexed_in":["crossref"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5048719435","display_name":"Kimberly B. Johansson","orcid":"https://orcid.org/0000-0002-7096-8602","observed_orcids":["https://orcid.org/0000-0002-7096-8602"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Kimberly B. Johansson","raw_affiliation_strings":["1Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO","2Medical Scientist Training Program, Washington University in St. Louis, Saint Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"1Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO","institution_ids":["https://openalex.org/I204465549"]},{"raw_affiliation_string":"2Medical Scientist Training Program, Washington University in St. Louis, Saint Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5073595009","display_name":"Megan Gauthier","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Megan Gauthier","raw_affiliation_strings":["1Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"1Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5101452556","display_name":"Feng Gao","orcid":"https://orcid.org/0009-0007-8910-4760","observed_orcids":["https://orcid.org/0009-0007-8910-4760"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Feng Gao","raw_affiliation_strings":["3Public Health Sciences Division, Washington University School of Medicine, St. Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"3Public Health Sciences Division, Washington University School of Medicine, St. Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5049284725","display_name":"Daniel C. Link","orcid":"https://orcid.org/0000-0002-3170-7581","observed_orcids":["https://orcid.org/0000-0002-3170-7581"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Daniel C. Link","raw_affiliation_strings":["1Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"1Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":[],"corresponding_institution_ids":["https://openalex.org/I204465549"],"apc_list":{"value":2500,"currency":"USD","value_usd":2500},"apc_paid":null,"fwci":0.2103,"has_fulltext":false,"cited_by_count":2,"citation_normalized_percentile":{"value":0.50629786,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":{"min":94,"max":96},"biblio":{"volume":"140","issue":"Supplement 1","first_page":"3262","last_page":"3263"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10583","display_name":"Cancer-related Molecular Pathways","score":0.5889000296592712,"subfield":{"id":"https://openalex.org/subfields/2730","display_name":"Oncology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T10583","display_name":"Cancer-related Molecular Pathways","score":0.5889000296592712,"subfield":{"id":"https://openalex.org/subfields/2730","display_name":"Oncology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10950","display_name":"Acute Lymphoblastic Leukemia research","score":0.3953000009059906,"subfield":{"id":"https://openalex.org/subfields/2739","display_name":"Public Health, Environmental and Occupational Health"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10294","display_name":"Cell death mechanisms and regulation","score":0.003800000064074993,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/navitoclax","display_name":"navitoclax","score":1.0},{"id":"https://openalex.org/keywords/t-cell-acute-lymphoblastic-leukemia","display_name":"T-cell acute lymphoblastic leukemia","score":0.9860000014305115},{"id":"https://openalex.org/keywords/mdm2-inhibition","display_name":"MDM2 inhibition","score":0.8240000009536743},{"id":"https://openalex.org/keywords/p53","display_name":"p53","score":0.6029999852180481},{"id":"https://openalex.org/keywords/bcl-2","display_name":"Bcl-2","score":0.5230000019073486},{"id":"https://openalex.org/keywords/apoptosis","display_name":"apoptosis","score":0.48500001430511475},{"id":"https://openalex.org/keywords/synergistic-drug-combination","display_name":"synergistic drug combination","score":0.6859999895095825},{"id":"https://openalex.org/keywords/notch-signaling","display_name":"Notch signaling","score":0.699999988079071},{"id":"https://openalex.org/keywords/c-myc","display_name":"c-Myc","score":0.9470000267028809},{"id":"https://openalex.org/keywords/p19arf","display_name":"p19ARF","score":0.7070000171661377},{"id":"https://openalex.org/keywords/cdkn2a","display_name":"CDKN2A","score":0.7879999876022339},{"id":"https://openalex.org/keywords/patient-derived-xenografts","display_name":"patient-derived xenografts","score":0.843999981880188}],"concepts":[{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.7164124250411987},{"id":"https://openalex.org/C2780265364","wikidata":"https://www.wikidata.org/wiki/Q5009957","display_name":"CDKN2A","level":3,"score":0.6969075202941895},{"id":"https://openalex.org/C190283241","wikidata":"https://www.wikidata.org/wiki/Q14599311","display_name":"Apoptosis","level":2,"score":0.692570686340332},{"id":"https://openalex.org/C2778461978","wikidata":"https://www.wikidata.org/wiki/Q29496","display_name":"Leukemia","level":2,"score":0.5642649531364441},{"id":"https://openalex.org/C2779343474","wikidata":"https://www.wikidata.org/wiki/Q3109175","display_name":"Context (archaeology)","level":2,"score":0.5346293449401855},{"id":"https://openalex.org/C2776192174","wikidata":"https://www.wikidata.org/wiki/Q18028978","display_name":"Mdm2","level":3,"score":0.47716110944747925},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.4081461429595947},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.39380544424057007},{"id":"https://openalex.org/C121608353","wikidata":"https://www.wikidata.org/wiki/Q12078","display_name":"Cancer","level":2,"score":0.3183022141456604},{"id":"https://openalex.org/C203014093","wikidata":"https://www.wikidata.org/wiki/Q101929","display_name":"Immunology","level":1,"score":0.3099479675292969},{"id":"https://openalex.org/C126322002","wikidata":"https://www.wikidata.org/wiki/Q11180","display_name":"Internal medicine","level":1,"score":0.22182312607765198},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.1415940523147583},{"id":"https://openalex.org/C151730666","wikidata":"https://www.wikidata.org/wiki/Q7205","display_name":"Paleontology","level":1,"score":0.0}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1182/blood-2022-167220","doi":"https://doi.org/10.1182/blood-2022-167220","is_oa":false,"landing_page_url":"https://doi.org/10.1182/blood-2022-167220","pdf_url":null,"source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"}],"best_oa_location":null,"sustainable_development_goals":[{"score":0.98580002784729,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"pdf":false,"grobid_xml":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W4389247667","https://openalex.org/W3096406577","https://openalex.org/W4394646536","https://openalex.org/W3095845450","https://openalex.org/W2475371777","https://openalex.org/W4310096167","https://openalex.org/W4361220721","https://openalex.org/W7133285066","https://openalex.org/W3089021149","https://openalex.org/W4213431353"],"abstract_inverted_index":{"We":[0],"report":[1],"here":[2],"investigation":[3],"of":[4,7,14,67,81,93,98,111,129,135,158,196,225,233,265,294,297,324,332,338,370,378,419,434,480,553,562],"the":[5,12,65,79,103,156,223,366,376,403,430,478,508,542,550],"combination":[6,395,494,509,543,552],"idasanutlin":[8,187,283,310,461,488,497,554],"and":[9,24,83,121,133,164,193,202,268,275,305,311,393,425,454,498,555],"navitoclax":[10,261,312,394,463,499,556],"in":[11,25,78,89,117,183,212,318,368,375,413,431,465,471,474,502,515,529,541,567],"context":[13],"T-cell":[15],"acute":[16],"lymphoblastic":[17],"leukemia":[18],"(T-ALL),":[19],"including":[20,423],"detailed":[21],"mechanistic":[22],"characterization":[23],"vivo":[26,432],"patient":[27,178],"derived":[28,179,302],"xenograft":[29,180],"results.":[30],"T-ALL":[31,82,112,131,167,177,207,245,255,307,326,437,446,472,505],"is":[32,389,557],"an":[33,263,481,563],"aggressive":[34],"hematologic":[35],"malignancy":[36],"with":[37,45,151,185,240,260,282,288,308,329,402,416,460,477,496,560],"a":[38,249,295,325,330,350,379,383,398,466,520],"five-year":[39],"event-free":[40],"survival":[41,537],"rate":[42],"that":[43,149,231,253,364,549],"declines":[44],"age,":[46],"ranging":[47],"from":[48,303],"70-75%":[49],"for":[50,55,64,70,532],"pediatric":[51,304],"patients":[52,56],"to":[53,86,123,166,214,243,258,314,439,487,493,512],"21.7%":[54],"aged":[57],"60-79.":[58],"An":[59],"unmet":[60],"clinical":[61],"need":[62],"remains":[63],"development":[66],"better":[68],"therapies":[69],"T-ALL.":[71,568],"Notch":[72],"pathway":[73],"activation":[74,92],"mutations":[75,116],"are":[76,84],"present":[77],"majority":[80],"thought":[85],"induce":[87],"transformation,":[88],"part,":[90],"through":[91,102],"c-Myc.":[94],"Typically,":[95],"increased":[96,540],"expression":[97,163],"c-Myc":[99],"induces":[100],"apoptosis":[101,209],"p19(ARF)-Mdm2-p53":[104],"tumor":[105,530],"suppressor":[106],"pathway.":[107],"Unsurprisingly,":[108],"over":[109],"70%":[110],"cases":[113,132,137],"have":[114],"inactivating":[115],"CDKN2A":[118],"(p19Arf).":[119],"However,":[120,204],"critical":[122],"our":[124],"approach,":[125],"greater":[126,386],"than":[127,387],"95%":[128],"primary":[130],"75%":[134],"relapsed":[136],"maintain":[138],"wild":[139],"type":[140],"p53.":[141],"Based":[142,218],"on":[143,219,519],"these":[144,220],"genetic":[145],"data,":[146],"we":[147,174,229,428],"hypothesized":[148,230],"treatment":[150,259,293,323,411,457,495,544],"MDM2":[152,191,215,241],"inhibitors,":[153],"by":[154,344,354],"bypassing":[155],"loss":[157],"ARF,":[159],"would":[160,238],"increase":[161],"p53":[162,198,227,421],"lead":[165],"cell":[168,208,316,565],"apoptosis.":[169],"To":[170],"test":[171],"this":[172],"hypothesis,":[173],"initially":[175],"treated":[176],"(PDX)":[181],"lines":[182,301],"vitro":[184,292],"single-agent":[186],"(a":[188],"second":[189,380],"generation":[190],"inhibitor)":[192],"observed":[194,211],"upregulation":[195],"pro-apoptotic":[197,226,420],"target":[199],"genes":[200],"Bax":[201],"Puma1.":[203],"only":[205],"modest":[206,467],"was":[210,278,342,485,500,510,538],"response":[213,373,433,492],"inhibition":[216,232,242,287],"alone.":[217],"observations,":[221],"particularly":[222],"induction":[224,418,561],"targets,":[228,422],"pro-survival":[234],"BH3":[235],"domain":[236],"proteins":[237],"synergize":[239],"kill":[244],"cells.":[246],"Of":[247],"note,":[248],"prior":[250],"study":[251],"showed":[252,335],"most":[254,271,404],"(~62%)":[256],"respond":[257],"(ABT-263),":[262],"inhibitor":[264],"BCL2,":[266],"BCLXL,":[267],"BCLW,":[269],"although":[270],"responses":[272],"were":[273,448],"transient":[274],"dose-limiting":[276],"thrombocytopenia":[277],"observed.":[279],"Combination":[280],"therapy":[281,396],"could":[284],"permit":[285],"on-target":[286],"tolerable":[289],"dosing.":[290],"In":[291,321,442],"panel":[296],"5":[298,388],"different":[299,436],"PDX":[300,327],"adult":[306],"dual":[309,440],"led":[313],"robust":[315],"death":[317,566],"all":[319,475,503],"lines.":[320],"addition,":[322],"line":[328],"matrix":[331],"dose":[333,372,406],"combinations":[334],"strong":[336,417],"evidence":[337],"synergic":[339,405],"activity.":[340],"Synergy":[341],"assessed":[343,429],"ZIP":[345,384,400,408],"(zero":[346],"interaction":[347],"potency)":[348],"score,":[349],"statistical":[351],"method":[352],"developed":[353],"B":[355],"Yadav":[356],"et":[357],"al.":[358],"(Comput.":[359],"Struct.":[360],"Biotechnol.":[361],"J.":[362],"2015)":[363],"compares":[365],"change":[367,528],"potency":[369],"individual":[371],"curves":[374],"presence":[377],"agent.":[381],"Generally,":[382],"score":[385],"considered":[390],"significant;":[391],"Idasanutlin":[392],"had":[397],"global":[399],"score=16-18,":[401],"area":[407],"score=40-52.":[409],"Combined":[410],"resulted":[412,464],"marked":[414,491],"apoptosis,":[415],"PUMA":[424],"BAX.":[426],"Finally,":[427],"four":[435,504],"xenografts":[438],"treatment.":[441],"each":[443,516],"case,":[444],"human":[445],"cells":[447],"injected":[449],"into":[450,456],"immunodeficient":[451],"NSG":[452],"mice":[453],"randomized":[455],"groups.":[458],"Monotherapy":[459],"or":[462],"but":[468],"significant":[469],"decrease":[470],"burden":[473,531],"cases,":[476],"exception":[479],"ETP":[482],"T-ALL,":[483],"which":[484],"resistant":[486],"monotherapy.":[489],"A":[490],"seen":[501],"xenografts.":[506],"Specifically,":[507],"found":[511],"be":[513],"synergistic":[514],"case":[517],"based":[518],"modified":[521],"Bliss":[522],"Independence":[523],"test,":[524],"analyzing":[525],"average":[526],"daily":[527],"synergy":[533],"interaction.":[534],"Furthermore,":[535],"overall":[536],"significantly":[539],"group.":[545],"These":[546],"data":[547],"suggest":[548],"rational":[551],"highly":[558],"active,":[559],"apoptotic":[564],"Figure":[569],"1View":[570,573],"largeDownload":[571,574],"PPTFigure":[572],"PPT":[575],"Close":[576],"modal":[577]},"counts_by_year":[{"year":2024,"cited_by_count":2}],"updated_date":"2026-08-28T12:50:07.497085","created_date":"2022-11-30T00:00:00"}
