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

Anouchka P. Laurent, Aurélie Siret, Cathy Ignacimouttou, Kunjal Panchal, M'Boyba Diop, Silvia Jenni, Yi Chien Tsai, Damien Roos-Weil, Zakia Aid, Nais Prade, Stephanie Lagarde, Damien Plassard, Gaelle Pierron, Estelle Daudigeos, Yann Lecluse, Nathalie Droin, Beat C. Bornhauser, Laurence C. Cheung, John D. Crispino, Muriel GaudryOlivier A. Bernard, Elizabeth Macintyre, Carole Barin Bonnigal, Rishi S. Kotecha, Birgit Geoerger, Paola Ballerini, Jean Pierre Bourquin, Eric Delabesse, Thomas Mercher, Sebastien Malinge

Research output: Contribution to journalArticle

Abstract

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 KRASG12D 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.

Original languageEnglish
Pages (from-to)3307-3318
Number of pages12
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume26
Issue number13
DOIs
Publication statusPublished - Jul 2020

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    Laurent, A. P., Siret, A., Ignacimouttou, C., Panchal, K., Diop, MB., Jenni, S., Tsai, Y. C., Roos-Weil, D., Aid, Z., Prade, N., Lagarde, S., Plassard, D., Pierron, G., Daudigeos, E., Lecluse, Y., Droin, N., Bornhauser, B. C., Cheung, L. C., Crispino, J. D., ... Malinge, S. (2020). Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research, 26(13), 3307-3318. https://doi.org/10.1158/1078-0432.CCR-19-3519