ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

Maria Anna Zipeto; Angela C. Court; Anil Sadarangani; Nathaniel P. Delos Santos; Larisa Balaian; Hye Jung Chun; Gabriel Pineda; Sheldon R. Morris; Cayla N. Mason; Ifat Geron; Christian Barrett; Daniel J. Goff; Russell Wall; Maurizio Pellecchia; Mark Minden; Kelly A. Frazer; Marco A. Marra; Leslie A. Crews; Qingfei Jiang; Catriona H.M. Jamieson

doi:10.1016/j.stem.2016.05.004

ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

Maria Anna Zipeto
, Angela C. Court
, Anil Sadarangani
, Nathaniel P. Delos Santos
, Larisa Balaian
, Hye Jung Chun
, Gabriel Pineda
, Sheldon R. Morris
, Cayla N. Mason
, Ifat Geron
, Christian Barrett
, Daniel J. Goff
, Russell Wall
, Maurizio Pellecchia
, Mark Minden
, Kelly A. Frazer
, Marco A. Marra
, Leslie A. Crews
, Qingfei Jiang^*
, Catriona H.M. Jamieson

^*Autor correspondiente de este trabajo

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

209 Citas (Scopus)

Resumen

Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1<sup>E912A</sup> mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1’s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.

Idioma original	Inglés
Páginas (desde-hasta)	177-191
Número de páginas	15
Publicación	Cell Stem Cell
Volumen	19
N.º	2
DOI	https://doi.org/10.1016/j.stem.2016.05.004
Estado	Publicada - 4 ago. 2016
Publicado de forma externa	Sí

Nota bibliográfica

Publisher Copyright:
© 2016 Elsevier Inc.

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

ODS 3: Salud y bienestar

Palabras clave

Adenosine Deaminase
Animals
Base Sequence
Cell Self Renewal
Fusion Proteins
bcr-abl
Gene Expression Regulation
Leukemic
Janus Kinase 2
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
Mice
MicroRNAs
Neoplastic Stem Cells
RNA Editing
RNA-Binding Proteins
Signal Transduction

Acceder al documento

10.1016/j.stem.2016.05.004

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Zipeto, M. A., Court, A. C., Sadarangani, A., Delos Santos, N. P., Balaian, L., Chun, H. J., Pineda, G., Morris, S. R., Mason, C. N., Geron, I., Barrett, C., Goff, D. J., Wall, R., Pellecchia, M., Minden, M., Frazer, K. A., Marra, M. A., Crews, L. A., Jiang, Q., & Jamieson, C. H. M. (2016). ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis. Cell Stem Cell, 19(2), 177-191. https://doi.org/10.1016/j.stem.2016.05.004

@article{53c3a8a5b2b24811a5c965b8ee3408fb,

title = "ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis",

abstract = "Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912A mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1{\textquoteright}s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.",

keywords = "Adenosine Deaminase, Animals, Base Sequence, Cell Self Renewal, Fusion Proteins, bcr-abl, Gene Expression Regulation, Leukemic, Janus Kinase 2, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, MicroRNAs, Neoplastic Stem Cells, RNA Editing, RNA-Binding Proteins, Signal Transduction",

author = "Zipeto, \{Maria Anna\} and Court, \{Angela C.\} and Anil Sadarangani and \{Delos Santos\}, \{Nathaniel P.\} and Larisa Balaian and Chun, \{Hye Jung\} and Gabriel Pineda and Morris, \{Sheldon R.\} and Mason, \{Cayla N.\} and Ifat Geron and Christian Barrett and Goff, \{Daniel J.\} and Russell Wall and Maurizio Pellecchia and Mark Minden and Frazer, \{Kelly A.\} and Marra, \{Marco A.\} and Crews, \{Leslie A.\} and Qingfei Jiang and Jamieson, \{Catriona H.M.\}",

note = "Funding Information: This work was supported by the Moores Family Foundation , California Institute for Regenerative Medicine (CIRM) grants ( RN2-00910-1 ; DR1-01430 ; RS1-00228-1 ), Cancer Stem Cell Consortium funding from Genome Canada and the Ontario Genomics Institute ( OGI-047 ), NIH National Institute of General Medical Sciences grant 5K12GM068524 , NIH National Cancer Institute (NCI) grant 2P30CA023100-28 , NIH NCI grant R21CA189705 , The Sanford Stem Cell Clinical Center , The San Diego Foundation , The Ratner Family Foundation , The Mizrahi Family Foundation , and the Canadian Institute of Health Research ( CSC-105367 ). 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 No. W81XWH-14-1-0121 (C.H.M.J.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. The authors wish to thank Dr. Dennis Carson and Dr. Ida Deichaite for scientific advice, Dr. Wenxue Ma (University of California, San Diego) for assistance with humanized mouse model experiments, Dr. Stefan Maas (Lehigh University) for providing the luciferase RNA editing reporter construct, and Canada{\textquoteright}s Michael Smith Genome Sciences Centre Library Construction, Sequencing, and Bioinformatics teams. M.P. holds the Daniel Hays endowed chair in Cancer Research at UCR. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = aug,

day = "4",

doi = "10.1016/j.stem.2016.05.004",

language = "English",

volume = "19",

pages = "177--191",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "2",

}

Zipeto, MA, Court, AC, Sadarangani, A, Delos Santos, NP, Balaian, L, Chun, HJ, Pineda, G, Morris, SR, Mason, CN, Geron, I, Barrett, C, Goff, DJ, Wall, R, Pellecchia, M, Minden, M, Frazer, KA, Marra, MA, Crews, LA, Jiang, Q & Jamieson, CHM 2016, 'ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis', Cell Stem Cell, vol. 19, n.º 2, pp. 177-191. https://doi.org/10.1016/j.stem.2016.05.004

TY - JOUR

T1 - ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

AU - Zipeto, Maria Anna

AU - Court, Angela C.

AU - Sadarangani, Anil

AU - Delos Santos, Nathaniel P.

AU - Balaian, Larisa

AU - Chun, Hye Jung

AU - Pineda, Gabriel

AU - Morris, Sheldon R.

AU - Mason, Cayla N.

AU - Geron, Ifat

AU - Barrett, Christian

AU - Goff, Daniel J.

AU - Wall, Russell

AU - Pellecchia, Maurizio

AU - Minden, Mark

AU - Frazer, Kelly A.

AU - Marra, Marco A.

AU - Crews, Leslie A.

AU - Jiang, Qingfei

AU - Jamieson, Catriona H.M.

N1 - Funding Information: This work was supported by the Moores Family Foundation , California Institute for Regenerative Medicine (CIRM) grants ( RN2-00910-1 ; DR1-01430 ; RS1-00228-1 ), Cancer Stem Cell Consortium funding from Genome Canada and the Ontario Genomics Institute ( OGI-047 ), NIH National Institute of General Medical Sciences grant 5K12GM068524 , NIH National Cancer Institute (NCI) grant 2P30CA023100-28 , NIH NCI grant R21CA189705 , The Sanford Stem Cell Clinical Center , The San Diego Foundation , The Ratner Family Foundation , The Mizrahi Family Foundation , and the Canadian Institute of Health Research ( CSC-105367 ). 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 No. W81XWH-14-1-0121 (C.H.M.J.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. The authors wish to thank Dr. Dennis Carson and Dr. Ida Deichaite for scientific advice, Dr. Wenxue Ma (University of California, San Diego) for assistance with humanized mouse model experiments, Dr. Stefan Maas (Lehigh University) for providing the luciferase RNA editing reporter construct, and Canada’s Michael Smith Genome Sciences Centre Library Construction, Sequencing, and Bioinformatics teams. M.P. holds the Daniel Hays endowed chair in Cancer Research at UCR. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/8/4

Y1 - 2016/8/4

N2 - Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912A mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1’s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.

AB - Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912A mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1’s effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.

KW - Adenosine Deaminase

KW - Animals

KW - Base Sequence

KW - Cell Self Renewal

KW - Fusion Proteins

KW - bcr-abl

KW - Gene Expression Regulation

KW - Leukemic

KW - Janus Kinase 2

KW - Leukemia

KW - Myelogenous

KW - Chronic

KW - BCR-ABL Positive

KW - Mice

KW - MicroRNAs

KW - Neoplastic Stem Cells

KW - RNA Editing

KW - RNA-Binding Proteins

KW - Signal Transduction

UR - https://www.scopus.com/pages/publications/84990898357

U2 - 10.1016/j.stem.2016.05.004

DO - 10.1016/j.stem.2016.05.004

M3 - Article

C2 - 27292188

AN - SCOPUS:84990898357

SN - 1934-5909

VL - 19

SP - 177

EP - 191

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

Resumen

Nota bibliográfica

ODS de las Naciones Unidas

Palabras clave

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