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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Detalhes bibliográficos
Autores: Muñoz López, A, Romero Moya, D, Prieto, C., Ramos Mejía, V, Agraz Doblas, Antonio Manuel, Varela Egocheaga, Ignacio|||0000-0002-0969-506X, Buschbeck, M., Palau, A, Carvajal Vergara, X, Giorgetti, A, Ford, A, Lako, M, Granada, I, Ruiz Xivillé, N, Rodríguez Perales, S, Torres Ruíz, R, Stam, RW, Fuster, JL, Fraga, MF, Nakanishi, M, Cazzaniga, G, Bardini, M, Cobo, I, Bayon, GF, Fernández Fernández, Agustín, Bueno, C, Menéndez, P
Tipo de documento: artigo
Data de publicação:2016
País:España
Recursos:Universidad de Cantabria (UC)
Repositório:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglês
OAI Identifier:oai:repositorio.unican.es:10902/9272
Acesso em linha:http://hdl.handle.net/10902/9272
Access Level:Acceso aberto
Palavra-chave:iPSC
cancer reprogramming
MLL-AF4
B-ALL
Sendai virus
transcriptome
DNA methylome
Descrição
Resumo: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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