Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.
Animals
Biomarkers, Tumor
/ genetics
Cell Transformation, Neoplastic
/ genetics
Chromosomes, Human, Pair 21
Cytokine Receptor Common beta Subunit
/ genetics
Disease Models, Animal
Disease Progression
Down Syndrome
/ diagnosis
GATA1 Transcription Factor
/ genetics
Gene Expression Regulation, Leukemic
Genetic Predisposition to Disease
HEK293 Cells
Humans
Leukemia, Myeloid
/ diagnosis
Leukemoid Reaction
/ diagnosis
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Mutation
Phenotype
Transcription, Genetic
Acute myeloid leukemia
CRISPR screen
Down syndrome
GATA1
cancer transformation
preleukemia
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
12 08 2019
12 08 2019
Historique:
received:
14
12
2018
revised:
07
04
2019
accepted:
11
06
2019
pubmed:
16
7
2019
medline:
21
4
2020
entrez:
16
7
2019
Statut:
ppublish
Résumé
Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.
Identifiants
pubmed: 31303423
pii: S1535-6108(19)30298-3
doi: 10.1016/j.ccell.2019.06.007
pmc: PMC6863161
mid: NIHMS1058372
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
CSF2RB protein, human
0
Cytokine Receptor Common beta Subunit
0
GATA1 Transcription Factor
0
GATA1 protein, human
0
Gata1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
123-138.e10Subventions
Organisme : Medical Research Council
ID : MC_UU_00016/11
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U137961146
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : Medical Research Council
ID : G1000729
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA022453
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12009/11
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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