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

doi:10.1016/j.stem.2016.08.003

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

78 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 language	English
Pages (from-to)	599-612
Number of pages	14
Journal	Cell Stem Cell
Volume	19
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2016.08.003
State	Published - 3 Nov 2016
Externally published	Yes

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.

Keywords

Animals
Cell Aging
Cell Survival
Coculture Techniques
HEK293 Cells
Hematopoiesis
Hematopoietic stem cells
Humans
Leukemia, Myeloid, Acute
Mice
Myelodysplastic syndromes
Neoplastic stem cells
Protein isoforms
RNA splicing
spliceosomes
stromal Cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.stem.2016.08.003

Cite this

Crews, L. A., Balaian, L., Delos Santos, N. P., Leu, H. S., Court, A. C., Lazzari, E., Sadarangani, A., Zipeto, M. A., La Clair, J. J., Villa, R., Kulidjian, A., Storb, R., Morris, S. R., Ball, E. D., Burkart, M. D., & Jamieson, C. H. M. (2016). RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML. Cell Stem Cell, 19(5), 599-612. https://doi.org/10.1016/j.stem.2016.08.003

@article{63c694b85cb3473e877177abf5109676,

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.",

keywords = "Animals, Cell Aging, Cell Survival, Coculture Techniques, HEK293 Cells, Hematopoiesis, Hematopoietic stem cells, Humans, Leukemia, Myeloid, Acute, Mice, Myelodysplastic syndromes, Neoplastic stem cells, Protein isoforms, RNA splicing, spliceosomes, stromal Cells",

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

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{\textquoteright}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: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = nov,

day = "3",

doi = "10.1016/j.stem.2016.08.003",

language = "English",

volume = "19",

pages = "599--612",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "5",

}

Crews, LA, Balaian, L, Delos Santos, NP, Leu, HS, Court, AC, Lazzari, E, Sadarangani, A, Zipeto, MA, La Clair, JJ, Villa, R, Kulidjian, A, Storb, R, Morris, SR, Ball, ED, Burkart, MD & Jamieson, CHM 2016, 'RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML', Cell Stem Cell, vol. 19, no. 5, pp. 599-612. https://doi.org/10.1016/j.stem.2016.08.003

TY - JOUR

T1 - RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

AU - Crews, Leslie A.

AU - Balaian, Larisa

AU - Delos Santos, Nathaniel P.

AU - Leu, Heather S.

AU - Court, Angela C.

AU - Lazzari, Elisa

AU - Sadarangani, Anil

AU - Zipeto, Maria A.

AU - La Clair, James J.

AU - Villa, Reymundo

AU - Kulidjian, Anna

AU - Storb, Rainer

AU - Morris, Sheldon R.

AU - Ball, Edward D.

AU - Burkart, Michael D.

AU - Jamieson, Catriona H.M.

N1 - 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.

PY - 2016/11/3

Y1 - 2016/11/3

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Aging

KW - Cell Survival

KW - Coculture Techniques

KW - HEK293 Cells

KW - Hematopoiesis

KW - Hematopoietic stem cells

KW - Humans

KW - Leukemia, Myeloid, Acute

KW - Mice

KW - Myelodysplastic syndromes

KW - Neoplastic stem cells

KW - Protein isoforms

KW - RNA splicing

KW - spliceosomes

KW - stromal Cells

UR - http://www.scopus.com/inward/record.url?scp=84995551031&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2016.08.003

DO - 10.1016/j.stem.2016.08.003

M3 - Article

C2 - 27570067

AN - SCOPUS:84995551031

SN - 1934-5909

VL - 19

SP - 599

EP - 612

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this