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• W2212946321 abstract "iPSC are routinely generated from a variety of cell types at different ontogeny and developmental stages. Despite significant interest in generating iPSCs from cancer patients, reprogramming cancer cells has fallen way behind. Reprogramming leukemia cell lines is extremely inefficient. Here we attempted to develop iPSCs from MLL-rearranged infant acute lymphoblastic leukemias (B-ALL) to recapitulate the developmental impact of MLL fusions. Ultrapure (>99.5%) FACS-purified CD34+CD19+ leukemic blasts (MLL-AF4+ & MLL-EPS15; n=5) were used. OKSM(L)-expressing retroviral, lentiviral and episomal reprogramming strategies combined with distinct reprogramming-inducing compounds failed to render iPSCs. Only when Sendai virus (SeV) were employed iPSC were generated, and polycistronic OKSM-SeV and enhanced the iPSC efficiency. However, all resulting iPSC lacked the MLL fusion as determined by FISH, gPCR and RTPCR, indicating that these iPSC clones were derived from the contaminating non-leukemic myeloid cells (<0.5%). MLL-rearranged cell lines could not be reprogrammed either. Conversely, CD34+ CB progenitors engineered to over-express MLL-AF4 as well as human CD34+CD19+ pre/proB cells and mature CD19+ B-cells were efficiently reprogrammed into VDJH-rearranged iPSCs. Global gene expression profiling revealed only 87 transcripts (out of 54.000) differentially expressed in MLL-AF4+ B-ALL vs hematopoietic stem cells, myeloid- or lymphoid-progenitors, and GSEA revealed no significant regulation of either reprogramming modulators or B-cell- or pathway-specific gene signature. We conclude that the target cell nature, the MLL-fusion itself or the MLLAF4-mediated transcriptome may not represent unique reprogramming barriers. Because MLL and MLL chimeric fusions are crucial epigenetic regulators, extensive DNA methylation arrays are underway to determine whether epigenetic marks explain why MLL-rearranged B-ALLs are refractory to induced reprogramming. iPSC are routinely generated from a variety of cell types at different ontogeny and developmental stages. Despite significant interest in generating iPSCs from cancer patients, reprogramming cancer cells has fallen way behind. Reprogramming leukemia cell lines is extremely inefficient. Here we attempted to develop iPSCs from MLL-rearranged infant acute lymphoblastic leukemias (B-ALL) to recapitulate the developmental impact of MLL fusions. Ultrapure (>99.5%) FACS-purified CD34+CD19+ leukemic blasts (MLL-AF4+ & MLL-EPS15; n=5) were used. OKSM(L)-expressing retroviral, lentiviral and episomal reprogramming strategies combined with distinct reprogramming-inducing compounds failed to render iPSCs. Only when Sendai virus (SeV) were employed iPSC were generated, and polycistronic OKSM-SeV and enhanced the iPSC efficiency. However, all resulting iPSC lacked the MLL fusion as determined by FISH, gPCR and RTPCR, indicating that these iPSC clones were derived from the contaminating non-leukemic myeloid cells (<0.5%). MLL-rearranged cell lines could not be reprogrammed either. Conversely, CD34+ CB progenitors engineered to over-express MLL-AF4 as well as human CD34+CD19+ pre/proB cells and mature CD19+ B-cells were efficiently reprogrammed into VDJH-rearranged iPSCs. Global gene expression profiling revealed only 87 transcripts (out of 54.000) differentially expressed in MLL-AF4+ B-ALL vs hematopoietic stem cells, myeloid- or lymphoid-progenitors, and GSEA revealed no significant regulation of either reprogramming modulators or B-cell- or pathway-specific gene signature. We conclude that the target cell nature, the MLL-fusion itself or the MLLAF4-mediated transcriptome may not represent unique reprogramming barriers. Because MLL and MLL chimeric fusions are crucial epigenetic regulators, extensive DNA methylation arrays are underway to determine whether epigenetic marks explain why MLL-rearranged B-ALLs are refractory to induced reprogramming." @default.
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• W2212946321 date "2015-09-01" @default.
• W2212946321 modified "2023-10-17" @default.
• W2212946321 title "Unraveling the mechanisms underlying the refractoriness of MLL-rearranged acute B-cell leukemias to reprogramming into pluripotency" @default.
• W2212946321 doi "https://doi.org/10.1016/j.exphem.2015.06.089" @default.
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