Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency

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...

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Detalles Bibliográficos
Autores: 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, Rodriguez Perales, Sandra, Torres-Ruiz Raul, Raul, Stam, Ronald W, Fuster, Jose Luis, Fraga, Mario F, Nakanishi, Mahito, Cazzaniga, Gianni, Bardini, Michela, Cobo, Isabel, Bayon, Gustavo F, Fernandez, Agustín F, Bueno, Clara, Menéndez, Pablo
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/8534
Acceso en línea:http://hdl.handle.net/20.500.12105/8534
Access Level:acceso abierto
Palabra clave:Animals
Biomarkers
Cell Line, Transformed
Cell Line, Tumor
Cell Transdifferentiation
Cluster Analysis
DNA Methylation
Gene Expression
Gene Expression Profiling
Hematopoietic Stem Cells
Heterografts
Humans
Induced Pluripotent Stem Cells
Mice
Myeloid Progenitor Cells
Myeloid-Lymphoid Leukemia Protein
Oncogene Proteins, Fusion
Phenotype
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cells, B-Lymphoid
Transcriptome
Translocation, Genetic
Cellular Reprogramming
Gene Rearrangement
Descripción
Sumario: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.

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