Journal
CLINICAL CANCER RESEARCH
Volume 26, Issue 13, Pages 3307-3318Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-3519
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Funding
- Leukemia Research Foundation
- European Hematology Association
- Fondation ARC
- GEFLUC
- Fondation Lejeune [1485, 1806]
- Channel 7 Telethon 2017 Lexus Ball for Cancer
- Children's Leukaemia and Cancer Research Foundation (CLCRF, Australia)
- Genomic Core Facility of Gustave Roussy
- MAPPYACTS [INCa PHRC-K14-175]
- Fondation ARC [MAPY201501241]
- PDX development [Societe Francaise de Lutte contre les Cancers et les Leucemies de l'Enfant et l'Adolescent (SFCE)]
- Fondation Enfants et Sante
- Fondation AREMIG
- Association Thibault BRIET
- National Health and Medical Research Council of Australia (NHMRC) [APP1142627]
- NIH [CA101774]
- PAIR-Pediatrie/CONECT-AML [INCa-ARC-LIGUE_11905]
- Canceropole Ile-de-France
- Fondation pour la Recherche Medicale
- Swiss National Research Foundation
- Clinical Research Priority Program of the University of Zurich
- Cancer Council Western Australia (CCWA)
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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.
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