Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.
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Date
2016-10-11ICR Author
Author
Muñoz-López, A
Romero-Moya, D
Prieto, C
Ramos-Mejía, V
Agraz-Doblas, A
Varela, I
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
Fernandez, AF
Bueno, C
Menendez, P
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Hematopoietic Stem Cells
Myeloid Progenitor Cells
Cell Line, Transformed
Cell Line, Tumor
Animals
Humans
Mice
Translocation, Genetic
Oncogene Proteins, Fusion
Cluster Analysis
Gene Expression Profiling
DNA Methylation
Gene Expression
Gene Rearrangement
Phenotype
Myeloid-Lymphoid Leukemia Protein
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Cell Transdifferentiation
Precursor Cells, B-Lymphoid
Induced Pluripotent Stem Cells
Transcriptome
Heterografts
Cellular Reprogramming
Biomarkers
Research team
Biology of Childhood Leukaemia
Language
eng
Date accepted
2016-08-23
License start date
2016-10
Citation
Stem cell reports, 2016, 7 (4), pp. 602 - 618
Publisher
CELL PRESS