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Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model
Brahim Arkoun, … , Thomas Mercher, William Vainchenker
Brahim Arkoun, … , Thomas Mercher, William Vainchenker
Published May 19, 2022
Citation Information: J Clin Invest. 2022;132(14):e156290. https://doi.org/10.1172/JCI156290.
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Research Article Hematology Oncology Article has an altmetric score of 3

Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model

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Abstract

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.

Authors

Brahim Arkoun, Elie Robert, Fabien Boudia, Stefania Mazzi, Virginie Dufour, Aurélie Siret, Yasmine Mammasse, Zakia Aid, Matthieu Vieira, Aygun Imanci, Marine Aglave, Marie Cambot, Rachel Petermann, Sylvie Souquere, Philippe Rameau, Cyril Catelain, Romain Diot, Gérard Tachdjian, Olivier Hermine, Nathalie Droin, Najet Debili, Isabelle Plo, Sébastien Malinge, Eric Soler, Hana Raslova, Thomas Mercher, William Vainchenker

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Figure 2

Assessment of iMK differentiation alterations.

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Assessment of iMK differentiation alterations.
(A–D) Immunophenotypes of...
(A–D) Immunophenotypes of iMKs for the CD34, KIT, CD7, CD41, and CD42 markers found in DS-AMKL patient blasts. (A) Contour plots showing the expression of CD34, CD41, and CD42 markers. (B) Histogram shows the MFI of CD41 and CD42. (C) Histogram shows the percentage of CD34+CD41+ per total CD41+ population. Data in B and C are represented as mean ± SEM; n = 3–4. The number of clones tested per genotype was as follows: T/parental = 1; TS = 2; TG = 2; TGM = 3; TGS = 3. Statistical significance was determined using 1-tailed Mann-Whitney’s U test: *P < 0.05; **P < 0.01; ***P < 0.001. (D) Representative contour plots of KIT and CD7 expression in the iMK population from 2 independent experiments. (E and F) scRNA-Seq of CD43+ iPSC-derived hematopoietic cells at day 13 of culture. (E) UMAP integration of cells from all conditions. Clusters were defined using the Louvain algorithm and numbered and labeled with unique colors. (F) UMAP integration with cells colored according to the predicted cell-cycle stage (Seurat method). (G) UMAP integration with cells colored according to the enrichment in a MK signature. Red, cells are significantly enriched for the signature; blue, cells are significantly depleted for the signature; gray, no significant enrichment. (H) Bar plot shows the proportion of cells in the indicated hematopoietic lineages for each condition. (I) Bar plots of the proportion of cells in the 2 clusters of cycling MKs. (J) Bar plots of the proportion of cells in the 2 clusters of noncycling MKs. (K) Bar plots of the proportion of cells in the 2 clusters of maturing MKs. Cluster 7 represents normal maturing MKs. Cluster 20 represents an abnormal MK population.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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