Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal

Frida Holm, Eva Hellqvist, Cayla N. Mason, Shawn A. Ali, Nathaniel Delos-Santos, Christian L. Barrett, Hye Jung Chun, Mark D. Minden, Richard A. Moore, Marco A. Marra, Valeria Runza, Kelly A. Frazer, Anil Sadarangani, Catriona H.M. Jamieson*

*Autor correspondiente de este trabajo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

23 Citas (Scopus)

Resumen

Formative research suggests that a human embryonic stem cellspecific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.

Idioma originalInglés
Páginas (desde-hasta)15444-15449
Número de páginas6
PublicaciónProceedings of the National Academy of Sciences of the United States of America
Volumen112
N.º50
DOI
EstadoPublicada - 15 dic. 2015
Publicado de forma externa

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