Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model.
Cell Cycle Proteins
/ genetics
Child
Chondroitin Sulfate Proteoglycans
/ genetics
Chromosomal Proteins, Non-Histone
/ genetics
Down Syndrome
/ genetics
GATA1 Transcription Factor
/ genetics
Hematopoiesis
Humans
Leukemia, Megakaryoblastic, Acute
/ complications
Megakaryocytes
/ metabolism
Mutation
Trisomy
Hematology
Leukemias
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
15 07 2022
15 07 2022
Historique:
received:
01
11
2021
accepted:
13
05
2022
pubmed:
20
5
2022
medline:
19
7
2022
entrez:
19
5
2022
Statut:
ppublish
Résumé
Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/-, and MPLW515K, providing 20 different T21 or disomy 21 (D21) induced pluripotent stem cell (iPSC) clones. GATA1s profoundly reshaped iPSC-derived hematopoietic architecture with gradual myeloid-to-megakaryocyte shift and megakaryocyte differentiation alteration upon addition of SMC3 and MPL mutations. Transcriptional, chromatin accessibility, and GATA1-binding data showed alteration of essential megakaryocyte differentiation genes, including NFE2 downregulation that was associated with loss of GATA1s binding and functionally involved in megakaryocyte differentiation blockage. T21 enhanced the proliferative phenotype, reproducing the cellular and molecular abnormalities of DS-AMKL. Our study provides an array of human cell-based models revealing individual contributions of different mutations to DS-AMKL differentiation blockage, a major determinant of leukemic progression.
Identifiants
pubmed: 35587378
pii: 156290
doi: 10.1172/JCI156290
pmc: PMC9282925
doi:
pii:
Substances chimiques
Cell Cycle Proteins
0
Chondroitin Sulfate Proteoglycans
0
Chromosomal Proteins, Non-Histone
0
GATA1 Transcription Factor
0
GATA1 protein, human
0
SMC3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : CommentIn
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