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

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 di...

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Detalles Bibliográficos
Autores principales: Imeri, Jusuf, Desterke, Christophe, Marcoux, Paul, Telliam, Gladys, Sanekli, Safa, Barreau, Sylvain, Erbilgin, Yucel, Latsis, Theodoros, Hugues, Patricia, Sorel, Nathalie, Cayssials, Emilie, Chomel, Jean-Claude, Bennaceur-Griscelli, Annelise, Turhan, Ali G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9953961/
https://www.ncbi.nlm.nih.gov/pubmed/36831265
http://dx.doi.org/10.3390/cells12040598
Descripción
Sumario: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.