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

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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.

Original languageEnglish
Pages (from-to)599-612
Number of pages14
JournalCell Stem Cell
Volume19
Issue number5
DOIs
StatePublished - 3 Nov 2016
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank I. Deichaite, F. Holm, Q. Jiang, S. Ali, P. Mondala, W. Ma, L. Sutton, B. Crain, C. Barrett, K. Frazer, and D. Carson (all at UC San Diego) for technical assistance and E. Nelson for constructive input. This work was funded by The Leukemia & Lymphoma Society’s Quest for CURES Research Grant Program (0754-14, C.H.M.J.), the Moores Foundation, the Mizrahi Family Foundation, the Sanford Stem Cell Clinical Center, an NCI Cancer Center Support Grant to the Moores Cancer Center (P30-CA 023100), NCI grant R21 CA 189705 (C.H.M.J.), the Federico Foundation (to E.D.B.), the UC San Diego AML Research Fund (E.D.B.), and leukemic cell repository funding from the NCI/NIH (CA 078902 and CA 018029, R.S.). This work was also supported in part by the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Cancer Research Program, under award W81XWH-14-1-0121 (C.H.M.J.). Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Publisher Copyright:
© 2016 Elsevier Inc.

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