Modeling Blast Crisis Using Mutagenized Chronic Myeloid Leukemia-Derived Induced Pluripotent Stem Cells (iPSCs).

Autor: Imeri J; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France., Desterke C; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France., Marcoux P; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France., Telliam G; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France., Sanekli S; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; APHP Paris Saclay, Department of Hematology, Hôpital Bicêtre & Paul Brousse, 94800 Villejuif, France., Barreau S; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; APHP Paris Saclay, Department of Hematology, Hôpital Bicêtre & Paul Brousse, 94800 Villejuif, France., Erbilgin Y; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093 Istanbul, Turkey., Latsis T; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France., Hugues P; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France., Sorel N; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; Service de Cancérologie Biologique, CHU de Poitiers, 86000 Poitiers, France., Cayssials E; Service d'Oncologie Hématologique et Thérapie Cellulaire, CHU de Poitiers, 86021 Poitiers, France., Chomel JC; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; Service de Cancérologie Biologique, CHU de Poitiers, 86000 Poitiers, France., Bennaceur-Griscelli A; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; APHP Paris Saclay, Department of Hematology, Hôpital Bicêtre & Paul Brousse, 94800 Villejuif, France.; INGESTEM National iPSC Infrastructure, 94800 Villejuif, France.; CITHERA, Centre for iPSC Therapies, INSERM UMS-45, Genopole Campus, 91100 Evry, France., Turhan AG; INSERM UMR-S-1310, Université Paris Saclay, 94800 Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, 94800 Villejuif, France.; APHP Paris Saclay, Department of Hematology, Hôpital Bicêtre & Paul Brousse, 94800 Villejuif, France.; INGESTEM National iPSC Infrastructure, 94800 Villejuif, France.; CITHERA, Centre for iPSC Therapies, INSERM UMS-45, Genopole Campus, 91100 Evry, France.
Jazyk: angličtina
Zdroj: Cells [Cells] 2023 Feb 12; Vol. 12 (4). Date of Electronic Publication: 2023 Feb 12.
DOI: 10.3390/cells12040598
Abstrakt: Purpose: To model CML progression in vitro and generate a blast crisis (BC-CML) model in vitro in order to identify new targets.
Methods: Three different CML-derived iPSC lines were mutagenized with the alkylating agent ENU on a daily basis for 60 days. Cells were analyzed at D12 of hematopoietic differentiation for their phenotype, clonogenicity, and transcriptomic profile. Single-cell RNA-Seq analysis has been performed at three different time points during hematopoietic differentiation in ENU-treated and untreated cells.
Results: One of the CML-iPSCs, compared to its non-mutagenized counterpart, generated myeloid blasts after hematopoietic differentiation, exhibiting monoblastic patterns and expression of cMPO, CD45, CD34, CD33, and CD13. Single-cell transcriptomics revealed a delay of differentiation in the mutated condition as compared to the control with increased levels of MSX1 (mesodermal marker) and a decrease in CD45 and CD41 . Bulk transcriptomics analyzed along with the GSE4170 GEO dataset reveal a significant overlap between ENU-treated cells and primary BC cells. Among overexpressed genes, CD25 was identified, and its relevance was confirmed in a cohort of CML patients.
Conclusions: iPSCs are a valuable tool to model CML progression and to identify new targets. Here, we show the relevance of CD25 identified in the iPSC model as a marker of CML progression.
Databáze: MEDLINE
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