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Cell Stem Cell. 2016 Nov 3;19(5):599-612. doi: 10.1016/j.stem.2016.08.003. Epub 2016 Aug 25.

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

Author information

1
Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lcrews@ucsd.edu.
2
Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
4
Department of Orthopedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
5
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, USA.
6
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
7
Division of Bone Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
8
Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: cjamieson@ucsd.edu.

Abstract

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.

PMID:
27570067
PMCID:
PMC5097015
DOI:
10.1016/j.stem.2016.08.003
[Indexed for MEDLINE]
Free PMC Article

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