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.

Muñoz-López, A., Romero-Moya, D., Prieto, C., Ramos-Mejía, V., Agraz-Doblas, A., Varela, I., et al. (2016). Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency. STEM CELL REPORTS, 7(4), 602-618 [10.1016/j.stemcr.2016.08.013].

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

Cazzaniga, Gianni;Bardini, Michela;
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.
Articolo in rivista - Articolo scientifico
B-ALL; cancer reprogramming; DNA methylome; iPSC; MLL-AF4; Sendai virus; transcriptome;
B-ALL; cancer reprogramming; DNA methylome; iPSC; MLL-AF4; Sendai virus; transcriptome; 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; Biochemistry; Genetics; Developmental Biology; Cell Biology
English
2016
7
4
602
618
open
Muñoz-López, A., Romero-Moya, D., Prieto, C., Ramos-Mejía, V., Agraz-Doblas, A., Varela, I., et al. (2016). Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency. STEM CELL REPORTS, 7(4), 602-618 [10.1016/j.stemcr.2016.08.013].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/226326
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