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Multiomic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target.
Vanner, Robert J; Dobson, Stephanie M; Gan, Olga I; McLeod, Jessica; Schoof, Erwin M; Grandal, Ildiko; Wintersinger, Jeff A; Garcia-Prat, Laura; Hosseini, Mohsen; Xie, Stephanie Z; Jin, Liqing; Mbong, Nathan; Voisin, Veronique; Chan-Seng-Yue, Michelle; Kennedy, James A; Waanders, Esmé; Morris, Quaid; Porse, Bo; Chan, Steven M; Guidos, Cynthia J; Danska, Jayne S; Minden, Mark D; Mullighan, Charles G; Dick, John E.
Afiliação
  • Vanner RJ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Dobson SM; Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • Gan OI; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • McLeod J; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Schoof EM; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Grandal I; Technical University of Denmark (DTU), Lyngby, Denmark.
  • Wintersinger JA; Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
  • Garcia-Prat L; Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
  • Hosseini M; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Xie SZ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Jin L; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Mbong N; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Voisin V; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Chan-Seng-Yue M; Terrence Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Ontario, Canada.
  • Kennedy JA; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Waanders E; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Morris Q; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Porse B; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
  • Chan SM; Department of Genetics, University Medical Center, Utrecht, the Netherlands.
  • Guidos CJ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Danska JS; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Minden MD; Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
  • Mullighan CG; Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
  • Dick JE; Terrence Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Ontario, Canada.
Blood Cancer Discov ; 3(1): 16-31, 2022 01.
Article em En | MEDLINE | ID: mdl-35019858
Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing as well as transcriptional and proteomic profiling of paired leukemia-infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS-infiltrating cells, including complement component 3 (C3), and drug targeting of C3 influenced CNS disease in xenografts. CNS-infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. SIGNIFICANCE: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition.This article is highlighted in the In This Issue feature, p. 1.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças do Sistema Nervoso Central / Neoplasias do Sistema Nervoso Central / Leucemia-Linfoma Linfoblástico de Células Precursoras / Neoplasias Meníngeas Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças do Sistema Nervoso Central / Neoplasias do Sistema Nervoso Central / Leucemia-Linfoma Linfoblástico de Células Precursoras / Neoplasias Meníngeas Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article