Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia.
Animals
Computational Biology
/ methods
Disease Models, Animal
Disease Susceptibility
Down Syndrome
/ complications
Gene Expression Profiling
Humans
Immunophenotyping
Leukemia, B-Cell
/ diagnosis
Mice
Mice, Transgenic
Mitogen-Activated Protein Kinases
/ metabolism
Oncogenes
Protein Kinase Inhibitors
/ pharmacology
Pyridones
/ pharmacology
Pyrimidinones
/ pharmacology
Signal Transduction
/ drug effects
ras Proteins
/ metabolism
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
26
10
2019
revised:
20
02
2020
accepted:
23
03
2020
pubmed:
30
3
2020
medline:
15
9
2021
entrez:
30
3
2020
Statut:
ppublish
Résumé
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. 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. 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 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.
Identifiants
pubmed: 32220889
pii: 1078-0432.CCR-19-3519
doi: 10.1158/1078-0432.CCR-19-3519
pmc: PMC7334063
mid: NIHMS1580360
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Pyridones
0
Pyrimidinones
0
trametinib
33E86K87QN
Mitogen-Activated Protein Kinases
EC 2.7.11.24
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3307-3318Subventions
Organisme : NCI NIH HHS
ID : R01 CA101774
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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