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

^*Corresponding author for this work

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

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 ADAR1^E912A 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.

Original language	English
Pages (from-to)	177-191
Number of pages	15
Journal	Cell Stem Cell
Volume	19
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2016.05.004
State	Published - 4 Aug 2016
Externally published	Yes

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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{92309b58c4ca416187a9eab371c84779,

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.",

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 = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = aug,

day = "4",

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

language = "אנגלית",

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, no. 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.

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.

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U2 - 10.1016/j.stem.2016.05.004

DO - 10.1016/j.stem.2016.05.004

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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

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