Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

Jasmin  Paris; Marcos Morgan; Joana Campos; Gary Spencer; Elena Shmakova; Ivayla Ivanova; Christopher Mapperley; Hannah Lawson; David Wotherspoon; Catarina Sepulveda; Milica Vukovic; Lewis Allen; Annika Sarapuu; Andrea Tavosanis; Arnaud Villacreces; Christian Much; Junho Choe; Ali Azar; Louie van de Lagemaat; Douglas Vernimmen; Ali Nehme; Frederic Mazurier; Tim Somervaille; Richard 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 Campos, Gary Spencer, Elena Shmakova, Ivayla Ivanova, Christopher Mapperley, Hannah Lawson, David Wotherspoon, Catarina Sepulveda, Milica Vukovic, Lewis Allen, Annika Sarapuu, Andrea Tavosanis, Arnaud Villacreces, Christian Much, Junho Choe, Ali Azar, Louie van de Lagemaat, Douglas VernimmenAli Nehme, Frederic Mazurier, Tim Somervaille, Richard Gregory, Donal O'Carroll, Kamil Kranc

Cancer Research UK Manchester Institute

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 the 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
Article number	e6
Pages (from-to)	137-148
Number of pages	12
Journal	Cell Stem Cell
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2019.03.021
Publication status	Published - 3 Jul 2019

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Paris, J., Morgan, M., Campos, J., Spencer, G., Shmakova, E., Ivanova, I., Mapperley, C., Lawson, H., Wotherspoon, D., Sepulveda, C., Vukovic, M., Allen, L., Sarapuu, A., Tavosanis, A., Villacreces, A., Much, C., Choe, J., Azar, A., van de Lagemaat, L., ... 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. Article 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 the 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.",

author = "Jasmin Paris and Marcos Morgan and Joana Campos and Gary Spencer and Elena Shmakova and Ivayla Ivanova and Christopher Mapperley and Hannah Lawson and David Wotherspoon and Catarina Sepulveda and Milica Vukovic and Lewis Allen and Annika Sarapuu and Andrea Tavosanis and Arnaud Villacreces and Christian Much and Junho Choe and Ali Azar and {van de Lagemaat}, Louie and Douglas Vernimmen and Ali Nehme and Frederic Mazurier and Tim Somervaille and Richard Gregory and Donal O'Carroll and Kamil Kranc",

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month = jul,

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

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Paris, J, Morgan, M, Campos, J, Spencer, G, Shmakova, E, Ivanova, I, Mapperley, C, Lawson, H, Wotherspoon, D, Sepulveda, C, Vukovic, M, Allen, L, Sarapuu, A, Tavosanis, A, Villacreces, A, Much, C, Choe, J, Azar, A, van de Lagemaat, L, Vernimmen, D, Nehme, A, Mazurier, F, Somervaille, T, Gregory, R, 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, e6, pp. 137-148. 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 - Campos, Joana

AU - Spencer, Gary

AU - Shmakova, Elena

AU - Ivanova, Ivayla

AU - Mapperley, Christopher

AU - Lawson, Hannah

AU - Wotherspoon, David

AU - Sepulveda, Catarina

AU - Vukovic, Milica

AU - Allen, Lewis

AU - Sarapuu, Annika

AU - Tavosanis, Andrea

AU - Villacreces, Arnaud

AU - Much, Christian

AU - Choe, Junho

AU - Azar, Ali

AU - van de Lagemaat, Louie

AU - Vernimmen, Douglas

AU - Nehme, Ali

AU - Mazurier, Frederic

AU - Somervaille, Tim

AU - Gregory, Richard

AU - O'Carroll, Donal

AU - Kranc, Kamil

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 the 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 the 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.

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

EP - 148

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

M1 - e6

ER -

Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

Abstract

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