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oai:repisalud.isciii.es:20.500.12105/85342025-04-29T10:19:37Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud author Muñoz-López, Alvaro author Romero-Moya, Damià author Prieto, Cristina author Ramos-Mejía, Verónica author Agraz-Doblas, Antonio author Varela, Ignacio author Buschbeck, Marcus author Palau, Anna author Carvajal-Vergara, Xonia author Giorgetti, Alessandra author Ford, Anthony author Lako, Majlinda author Granada, Isabel author Ruiz-Xivillé, Neus author Rodriguez Perales, Sandra author Torres-Ruiz Raul, Raul author Stam, Ronald W author Fuster, Jose Luis author Fraga, Mario F author Nakanishi, Mahito author Cazzaniga, Gianni author Bardini, Michela author Cobo, Isabel author Bayon, Gustavo F author Fernandez, Agustín F author Bueno, Clara author Menéndez, Pablo funder Unión Europea. Comisión Europea. European Research Council (ERC) funder Instituto de Salud Carlos III funder Ministerio de Economía y Competitividad (España) funder Asociación Española Contra el Cáncer funder Ministerio de Ciencia e Innovación (España) funder Fundación La Caixa funder Fundación Josep Carreras Contra la Leucemia funder Government of Catalonia (España) funder Institució Catalana de Recerca i Estudis Avançats funder Biotechnology and Biological Sciences Research Council (Reino Unido) funder Medical Research Council (Reino Unido) 2019-10-30T10:04:21Z 2019-10-30T10:04:21Z 2016-10-11 Stem Cell Reports. 2016;7(4):602-618. 10.1016/j.stemcr.2016.08.013 2213-6711 22136711 Stem cell reports 27666791 http://hdl.handle.net/20.500.12105/8534 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. eng B-ALL DNA methylome MLL-AF4 Sendai virus Cancer reprogramming iPSC Transcriptome Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency journal article 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 URL https://repisalud.isciii.es/bitstreams/d3a55241-6a65-4b39-bc0d-8b0a3462c7f1/download File MD5 ff1496959cac0ee2a831d945897d2989 3585778 application/pdf DevelopmentRefractorinessofMLL-Rearranged_2016.pdf URL https://repisalud.isciii.es/bitstreams/1d1ce5da-5ad5-4cc4-93d5-e34abfa1ed16/download File MD5 0a157244573c4ca3676808f776432850 8385432 application/pdf DevelopmentRefractorinessofMLL-Rearranged-mmc1.pdf URL https://repisalud.isciii.es/bitstreams/cbb2c043-92bf-41ad-8a16-8c6b357f7c2a/download File MD5 29d8bf424d3becec3f2eccf08b32e3de 61571 text/plain DevelopmentRefractorinessofMLL-Rearranged_2016.pdf.txt URL https://repisalud.isciii.es/bitstreams/3780e15b-afde-4471-b089-9fb0e54c60ef/download File MD5 49b5c7d64105a09a0838ffa39ca1bcb0 14220 text/plain DevelopmentRefractorinessofMLL-Rearranged-mmc1.pdf.txt