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Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs.
Dobson, Stephanie M; García-Prat, Laura; Vanner, Robert J; Wintersinger, Jeffrey; Waanders, Esmé; Gu, Zhaohui; McLeod, Jessica; Gan, Olga I; Grandal, Ildiko; Payne-Turner, Debbie; Edmonson, Michael N; Ma, Xiaotu; Fan, Yiping; Voisin, Veronique; Chan-Seng-Yue, Michelle; Xie, Stephanie Z; Hosseini, Mohsen; Abelson, Sagi; Gupta, Pankaj; Rusch, Michael; Shao, Ying; Olsen, Scott R; Neale, Geoffrey; Chan, Steven M; Bader, Gary; Easton, John; Guidos, Cynthia J; Danska, Jayne S; Zhang, Jinghui; Minden, Mark D; Morris, Quaid; Mullighan, Charles G; Dick, John E.
Afiliação
  • Dobson SM; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • García-Prat L; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Vanner RJ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Wintersinger J; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Waanders E; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Gu Z; Department of Computer Science, University of Toronto. Toronto, Ontario, Canada.
  • McLeod J; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Gan OI; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Grandal I; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Payne-Turner D; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Edmonson MN; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Ma X; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Fan Y; Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
  • Voisin V; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Chan-Seng-Yue M; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Xie SZ; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Hosseini M; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Abelson S; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Gupta P; Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada.
  • Rusch M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Shao Y; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Olsen SR; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Neale G; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Chan SM; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Bader G; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Easton J; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Guidos CJ; Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Danska JS; Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Zhang J; Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Morris Q; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Mullighan CG; Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada.
  • Dick JE; Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
Cancer Discov ; 10(4): 568-587, 2020 04.
Article em En | MEDLINE | ID: mdl-32086311
ABSTRACT
Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant.

SIGNIFICANCE:

Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strategies to identify and target clinically relevant subclones before further evolution toward relapse.
Assuntos

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Leucemia Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda Tipo de estudo: Diagnostic_studies Limite: Female / Humans / Male Idioma: En Revista: Cancer Discov Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Temas: Geral / Tipos_de_cancer / Leucemia Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda Tipo de estudo: Diagnostic_studies Limite: Female / Humans / Male Idioma: En Revista: Cancer Discov Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Canadá