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Title: Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.
Authors: Muñoz-López, Alvaro
Romero-Moya, Damià
Prieto, Cristina
Ramos-Mejía, Verónica
Agraz-Doblas, Antonio
Varela, Ignacio
Buschbeck, Marcus
Palau, Anna
Carvajal-Vergara, Xonia
Giorgetti, Alessandra
Ford, Anthony
Lako, Majlinda
Granada, Isabel
Ruiz-Xivillé, Neus
Rodríguez-Perales, Sandra
Torres-Ruíz, Raul
Stam, Ronald W
Fuster, Jose Luis
Fraga, Mario F
Nakanishi, Mahito
Cazzaniga, Gianni
Bardini, Michela
Cobo, Isabel
Bayon, Gustavo F
Fernandez, Agustin F
Bueno, Clara
Menendez, Pablo
Keywords: B-ALL;DNA methylome;MLL-AF4;Sendai virus;cancer reprogramming;iPSC;transcriptome
metadata.dc.subject.mesh: Animals
Cell Line, Transformed
Cell Line, Tumor
Cell Transdifferentiation
Cellular Reprogramming
Cluster Analysis
DNA Methylation
Gene Expression
Gene Expression Profiling
Gene Rearrangement
Hematopoietic Stem Cells
Induced Pluripotent Stem Cells
Myeloid Progenitor Cells
Myeloid-Lymphoid Leukemia Protein
Oncogene Proteins, Fusion
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cells, B-Lymphoid
Translocation, Genetic
Issue Date: 22-Sep-2016
Abstract: Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.
metadata.dc.identifier.doi: 10.1016/j.stemcr.2016.08.013
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