title: RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML.
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.
authors: 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.
authors: Leslie A
authors: LA
authors: Crews
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Larisa
authors: L
authors: Balaian
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Nathaniel P
authors: NP
authors: Delos Santos
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Heather S
authors: HS
authors: Leu
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Angela C
authors: AC
authors: Court
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Elisa
authors: E
authors: Lazzari
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Anil
authors: A
authors: Sadarangani
authors: Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Maria A
authors: MA
authors: Zipeto
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: James J
authors: JJ
authors: La Clair
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Reymundo
authors: R
authors: Villa
authors: Department of Orthopedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Anna
authors: A
authors: Kulidjian
authors: 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.
authors: Rainer
authors: R
authors: Storb
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Sheldon R
authors: SR
authors: Morris
authors: Division of Bone Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Edward D
authors: ED
authors: Ball
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Michael D
authors: MD
authors: Burkart
authors: 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.
authors: Catriona H M
authors: CHM
authors: Jamieson
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D018920:Coculture Techniques; D057809:HEK293 Cells; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D017381:Spliceosomes / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D020033:Protein Isoforms