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

Lookup NU author(s): Professor Majlinda LakoORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).

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.

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Author(s): Munoz-Lopez A, Romero-Moya D, Prieto C, Ramos-Mejia V, Agraz-Doblas A, Varela I, Buschbeck M, Palau A, Carvajal-Vergara X, Giorgetti A, Ford A, Lako M, Granada I, Ruiz-Xiville N, Rodriguez-Perales S, Torres-Ruiz R, Stam RW, Fuster JL, Fraga MF, Nakanishi M, Cazzaniga G, Bardini M, Cobo I, Bayon GF, Fernandez AF, Bueno C, Menendez P

Publication type: Article

Publication status: Published

Journal: Stem Cell Reports

Year: 2016

Volume: 7

Issue: 4

Pages: 602-618

Print publication date: 11/10/2016

Online publication date: 22/09/2016

Acceptance date: 23/08/2016

Date deposited: 16/01/2017

ISSN (electronic): 2213-6711

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.stemcr.2016.08.013

DOI: 10.1016/j.stemcr.2016.08.013

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