RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

Leslie A. Crews*, Larisa Balaian, Nathaniel P. Delos Santos, Heather S. Leu, Angela C. Court, Elisa Lazzari, Anil Sadarangani, Maria A. Zipeto, James J. La Clair, Reymundo Villa, Anna Kulidjian, Rainer Storb, Sheldon R. Morris, Edward D. Ball, Michael D. Burkart, Catriona H.M. Jamieson

*Autor correspondiente de este trabajo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

63 Citas (Scopus)

Resumen

Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.

Idioma originalInglés
Páginas (desde-hasta)599-612
Número de páginas14
PublicaciónCell Stem Cell
Volumen19
N.º5
DOI
EstadoPublicada - 3 nov. 2016
Publicado de forma externa

Nota bibliográfica

Publisher Copyright:
© 2016 Elsevier Inc.

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