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Stem Cell Reports. 2016 Oct 11;7(4):602-618. doi: 10.1016/j.stemcr.2016.08.013. Epub 2016 Sep 22.

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

Author information

1
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, Spain.
2
Genomic Oncology Department, Centre for Genomics and Oncology GENyO, 18016 Granada, Spain.
3
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, Spain; IBBTEC, CSIC-University of Cantabria, 39011 Santander, Spain.
4
IBBTEC, CSIC-University of Cantabria, 39011 Santander, Spain.
5
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain.
6
Cell Therapy Department, Centro de Investigación Médica Aplicada (CIMA), 31008 Pamplona, Spain.
7
Centre for Evolution and Cancer, Institute of Cancer Research, London SW7 3RP, UK.
8
Institute of Genetic Medicine, Newcastle University, Newcastle NE1 7RU, UK.
9
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Hematology Department, Hospital Germans Trias i Pujol, Institut Català d'Oncología, 08916 Badalona, Spain.
10
Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
11
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
12
Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Erasmus University, 3015 CN Rotterdam, the Netherlands.
13
Department of Pediatric Oncohematology, Clinical University Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
14
Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33003 Oviedo, Spain.
15
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraka 305-0046, Japan.
16
University di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, 20052 Monza MB, Italy.
17
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33003 Oviedo, Spain.
18
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, Spain. Electronic address: cbueno@carrerasresearch.org.
19
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain; Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, Spain; Instituciò Catalana de Recerca i Estudis Avançats (ICREA), 08036 Barcelona, Spain. Electronic address: pmenendez@carrerasresearch.org.

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.

KEYWORDS:

B-ALL; DNA methylome; MLL-AF4; Sendai virus; cancer reprogramming; iPSC; transcriptome

PMID:
27666791
PMCID:
PMC5063541
DOI:
10.1016/j.stemcr.2016.08.013
[Indexed for MEDLINE]
Free PMC Article

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