Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

Jasmin Paris; Marcos Morgan; Joana Monteiro De Campos; Gary J. Spencer; Alena Shmakova; Ivayla Ivanova; Christopher Mapperley; Hannah Lawson; David Wotherspoon; Catarina Pires Sepulveda; Milica Vukovic; Lewis Allen; Annika Sarapuu; Andrea Tavosanis; Amelie Guitart; Arnaud Villacreces; Christian Much; Junho Choe; Ali Anvari Azar; Louie Van De Lagemaat; Douglas Vernimmen; Ali Nehme; Frederic Mazurier; Tim C. P. Somervaille; Richard I. Gregory; Donal O'Carroll; Kamil Kranc

doi:10.1016/j.stem.2019.03.021

Targeting the RNA m⁶A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

Jasmin Paris, Marcos Morgan, Joana Monteiro De Campos, Gary J. Spencer, Alena Shmakova, Ivayla Ivanova, Christopher Mapperley, Hannah Lawson, David Wotherspoon, Catarina Pires Sepulveda, Milica Vukovic, Lewis Allen, Annika Sarapuu, Andrea Tavosanis, Amelie Guitart, Arnaud Villacreces, Christian Much, Junho Choe, Ali Anvari Azar, Louie Van De LagemaatDouglas Vernimmen, Ali Nehme, Frederic Mazurier, Tim C. P. Somervaille, Richard I. Gregory, Donal O'Carroll, Kamil Kranc

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

Abstract

Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation generating self-renewing leukemic stem cells (LSCs). Here we show that the mRNA m⁶A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation, as well as propagation in mouse and human AML.

YTHDF2 decreases the half-life of diverse m⁶A transcripts that contribute to the overall integrity of LSC function, including tumor necrosis factor receptor Tnfrsf2 whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function with YTHDF2-deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

Original language	English
Pages (from-to)	137-148.E6
Number of pages	12
Journal	Cell Stem Cell
Volume	25
Issue number	1
Early online date	25 Apr 2019
DOIs	https://doi.org/10.1016/j.stem.2019.03.021
Publication status	Published - 3 Jul 2019

Keywords / Materials (for Non-textual outputs)

m6A modification
mRNA decay
acute myeloid leukemia
Leukemic stem cells
hematopoietic stem cells

Access to Document

10.1016/j.stem.2019.03.021Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

KrancEtalCSC2019TargetingTheRNAm6AReaderYTHDF2SelectivelyCompromisesFinal published version, 5.71 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

RNA regulation and modification in tissue development and homeostasis
O'Carroll, D. (Principal Investigator)
UK-based charities
24/09/15 → 23/09/22
Project: Research
Hypoxia signalling pathways in normal and leukaemic stem cell functions
Kranc, K. (Principal Investigator)
UK-based charities
1/03/13 → 31/08/19
Project: Research
Core funding renewal for the Wellcome Trust Centre for Cell Biology
Tollervey, D. (Principal Investigator) & Earnshaw, B. (Co-investigator)
UK-based charities
1/10/11 → 30/04/17
Project: Research

Donal O'Carroll
- School of Biological Sciences - Chair of Stem Cell Biology
- Centre for Regenerative Medicine
Person: Academic: Research Active
Jasmin Paris
- Royal (Dick) School of Veterinary Studies - Senior Lecturer
Person: Academic: Research Active
Douglas Vernimmen
- douglas.vernimmenroslin.ed.acuk
- Royal (Dick) School of Veterinary Studies - Group Leader
- Edinburgh Haematopoiesis Network
Person: Academic: Research Active

Cite this

Paris, J., Morgan, M., Monteiro De Campos, J., Spencer, G. J., Shmakova, A., Ivanova, I., Mapperley, C., Lawson, H., Wotherspoon, D., Pires Sepulveda, C., Vukovic, M., Allen, L., Sarapuu, A., Tavosanis, A., Guitart, A., Villacreces, A., Much, C., Choe, J., Anvari Azar, A., ... Kranc, K. (2019). Targeting the RNA m⁶A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell, 25(1), 137-148.E6. https://doi.org/10.1016/j.stem.2019.03.021

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title = "Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia",

abstract = "Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation generating self-renewing leukemic stem cells (LSCs). Here we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation, as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including tumor necrosis factor receptor Tnfrsf2 whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function with YTHDF2-deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion. ",

keywords = "m6A modification, mRNA decay, acute myeloid leukemia, Leukemic stem cells, hematopoietic stem cells",

author = "Jasmin Paris and Marcos Morgan and \{Monteiro De Campos\}, Joana and Spencer, \{Gary J.\} and Alena Shmakova and Ivayla Ivanova and Christopher Mapperley and Hannah Lawson and David Wotherspoon and \{Pires Sepulveda\}, Catarina and Milica Vukovic and Lewis Allen and Annika Sarapuu and Andrea Tavosanis and Amelie Guitart and Arnaud Villacreces and Christian Much and Junho Choe and \{Anvari Azar\}, Ali and \{Van De Lagemaat\}, Louie and Douglas Vernimmen and Ali Nehme and Frederic Mazurier and Somervaille, \{Tim C. P.\} and Gregory, \{Richard I.\} and Donal O'Carroll and Kamil Kranc",

note = "Gold. Add final PUB PDF, DoI, PubMed, etc upon publication 4/04/2019 EN - Not published yet 18/04/2019 EN - Not yet 24/04/2019 EN - not yet available - Uploaded Proof - add final publication when available 16/05/2019 EN",

year = "2019",

month = jul,

day = "3",

doi = "10.1016/j.stem.2019.03.021",

language = "English",

volume = "25",

pages = "137--148.E6",

journal = "Cell Stem Cell",

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Paris, J, Morgan, M, Monteiro De Campos, J, Spencer, GJ, Shmakova, A, Ivanova, I, Mapperley, C, Lawson, H, Wotherspoon, D, Pires Sepulveda, C, Vukovic, M, Allen, L, Sarapuu, A, Tavosanis, A, Guitart, A, Villacreces, A, Much, C, Choe, J, Anvari Azar, A, Van De Lagemaat, L, Vernimmen, D, Nehme, A, Mazurier, F, Somervaille, TCP, Gregory, RI, O'Carroll, D & Kranc, K 2019, 'Targeting the RNA m⁶A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia', Cell Stem Cell, vol. 25, no. 1, pp. 137-148.E6. https://doi.org/10.1016/j.stem.2019.03.021

TY - JOUR

T1 - Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

AU - Paris, Jasmin

AU - Morgan, Marcos

AU - Monteiro De Campos, Joana

AU - Spencer, Gary J.

AU - Shmakova, Alena

AU - Ivanova, Ivayla

AU - Mapperley, Christopher

AU - Lawson, Hannah

AU - Wotherspoon, David

AU - Pires Sepulveda, Catarina

AU - Vukovic, Milica

AU - Allen, Lewis

AU - Sarapuu, Annika

AU - Tavosanis, Andrea

AU - Guitart, Amelie

AU - Villacreces, Arnaud

AU - Much, Christian

AU - Choe, Junho

AU - Anvari Azar, Ali

AU - Van De Lagemaat, Louie

AU - Vernimmen, Douglas

AU - Nehme, Ali

AU - Mazurier, Frederic

AU - Somervaille, Tim C. P.

AU - Gregory, Richard I.

AU - O'Carroll, Donal

AU - Kranc, Kamil

N1 - Gold. Add final PUB PDF, DoI, PubMed, etc upon publication 4/04/2019 EN - Not published yet 18/04/2019 EN - Not yet 24/04/2019 EN - not yet available - Uploaded Proof - add final publication when available 16/05/2019 EN

PY - 2019/7/3

Y1 - 2019/7/3

N2 - Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation generating self-renewing leukemic stem cells (LSCs). Here we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation, as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including tumor necrosis factor receptor Tnfrsf2 whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function with YTHDF2-deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

AB - Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation generating self-renewing leukemic stem cells (LSCs). Here we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation, as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including tumor necrosis factor receptor Tnfrsf2 whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function with YTHDF2-deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

KW - m6A modification

KW - mRNA decay

KW - acute myeloid leukemia

KW - Leukemic stem cells

KW - hematopoietic stem cells

U2 - 10.1016/j.stem.2019.03.021

DO - 10.1016/j.stem.2019.03.021

M3 - Article

SN - 1934-5909

VL - 25

SP - 137-148.E6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -

Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

RNA regulation and modification in tissue development and homeostasis

Hypoxia signalling pathways in normal and leukaemic stem cell functions

Core funding renewal for the Wellcome Trust Centre for Cell Biology

Profiles

Donal O'Carroll

Jasmin Paris

Douglas Vernimmen

Cite this

Targeting the RNA m⁶A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia