Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia.

Autor:	Laurent AP; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France.; Université Paris Diderot, Paris, France., Siret A; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Ignacimouttou C; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Panchal K; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia., Diop M; Gustave Roussy Institute Cancer Campus, Department of Pediatric and Adolescent Oncology, INSERM U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Villejuif, France., Jenni S; Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland., Tsai YC; Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland., Roos-Weil D; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Aid Z; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Prade N; Centre of Research on Cancer of Toulouse (CRCT), CHU Toulouse, Université Toulouse III, Toulouse, France., Lagarde S; Centre of Research on Cancer of Toulouse (CRCT), CHU Toulouse, Université Toulouse III, Toulouse, France., Plassard D; IGBMC, Plateforme GenomEast, UMR7104 CNRS, Ilkirch, France., Pierron G; Service de Génétique, Institut Curie, Paris, France., Daudigeos E; Gustave Roussy Institute Cancer Campus, Department of Pediatric and Adolescent Oncology, INSERM U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Villejuif, France., Lecluse Y; Gustave Roussy Institute Cancer Campus, Department of Pediatric and Adolescent Oncology, INSERM U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Villejuif, France., Droin N; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Bornhauser BC; Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland., Cheung LC; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia., Crispino JD; Division of Hematology/Oncology, Northwestern University, Chicago, Illinois., Gaudry M; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Bernard OA; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France., Macintyre E; Hematology, Université de Paris, Institut Necker-Enfants Malades and Assistance Publique-Hopitaux de Paris, Paris, France., Barin Bonnigal C; Centre Hospitalier Universitaire de Tours, Tours, France., Kotecha RS; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.; School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Australia.; Department of Clinical Haematology, Oncology and Bone Marrow Transplantation, Perth Children's Hospital, Perth, Australia., Geoerger B; Gustave Roussy Institute Cancer Campus, Department of Pediatric and Adolescent Oncology, INSERM U1015, Equipe Labellisée Ligue Nationale Contre le Cancer, Université Paris-Saclay, Villejuif, France., Ballerini P; Laboratoire d'Hématologie, Hôpital Trousseau, APHP, Paris-Sorbonne, Paris, France., Bourquin JP; Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland., Delabesse E; Centre of Research on Cancer of Toulouse (CRCT), CHU Toulouse, Université Toulouse III, Toulouse, France., Mercher T; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France.; Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France., Malinge S; INSERM U1170, Gustave Roussy Institute, Université Paris Saclay, Villejuif, France. sebastien.malinge@telethonkids.org.au.; Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Jul 01; Vol. 26 (13), pp. 3307-3318. Date of Electronic Publication: 2020 Mar 27.
DOI:	10.1158/1078-0432.CCR-19-3519
Abstrakt:	Purpose: Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL. Experimental Design: To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents. Results: Whole-exome and RNA-sequencing experiments revealed a high incidence of somatic alterations leading to RAS/MAPK pathway activation in our cohort of DS-ALL, as well as in other pediatric B-ALL presenting somatic gain of the chromosome 21 (B-ALL+21). In murine and human B-cell precursors, activated KRAS G12D functionally cooperates with trisomy 21 to deregulate transcriptional networks that promote increased proliferation and self renewal, as well as B-cell differentiation blockade. Moreover, we revealed that inhibition of RAS/MAPK pathway activation using the MEK1/2 inhibitor trametinib decreased leukemia burden in several PDX models of B-ALL+21, and enhanced survival of DS-ALL PDX in combination with conventional chemotherapy agents such as vincristine. Conclusions: Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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