TY - JOUR
T1 - Constitutive activation of RAS/MAPK pathway cooperates with trisomy 21 and is therapeutically exploitable in down syndrome b-cell leukemia
AU - Laurent, Anouchka P.
AU - Siret, Aurelie
AU - Ignacimouttou, Cathy
AU - Panchal, Kunjal
AU - Diop, M'Boyba
AU - Jenni, Silvia
AU - Tsai, Yi Chien
AU - Roos-Weil, Damien
AU - Aid, Zakia
AU - Prade, Nais
AU - Lagarde, Stephanie
AU - Plassard, Damien
AU - Pierron, Gaelle
AU - Daudigeos, Estelle
AU - Lecluse, Yann
AU - Droin, Nathalie
AU - Bornhauser, Beat C.
AU - Cheung, Laurence C.
AU - Crispino, John D.
AU - Gaudry, Muriel
AU - Bernard, Olivier A.
AU - Macintyre, Elizabeth
AU - Bonnigal, Carole Barin
AU - Kotecha, Rishi S.
AU - Geoerger, Birgit
AU - Ballerini, Paola
AU - Bourquin, Jean Pierre
AU - Delabesse, Eric
AU - Mercher, Thomas
AU - Malinge, Sebastien
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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-ALLþ21). 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-ALLþ21, 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.
AB - 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-ALLþ21). 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-ALLþ21, 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.
UR - http://www.scopus.com/inward/record.url?scp=85087470199&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-3519
DO - 10.1158/1078-0432.CCR-19-3519
M3 - Article
C2 - 32220889
AN - SCOPUS:85087470199
SN - 1078-0432
VL - 26
SP - 3307
EP - 3318
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -