Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Veronika Ecker; Lisa Brandmeier; Martina Stumpf; Piero Giansanti; Aida Varela Moreira; Lisa Pfeuffer; Marcel H.A.M. Fens; Junyan Lu; Bernhard Kuster; Thomas Engleitner; Simon Heidegger; Roland Rad; Ingo Ringshausen; Thorsten Zenz; Clemens Martin Wendtner; Markus Müschen; Julia Jellusova; Jürgen Ruland; Maike Buchner

doi:10.1016/j.celrep.2023.113017

Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Veronika Ecker, Lisa Brandmeier, Martina Stumpf, Piero Giansanti, Aida Varela Moreira, Lisa Pfeuffer, Marcel H.A.M. Fens, Junyan Lu, Bernhard Kuster, Thomas Engleitner, Simon Heidegger, Roland Rad, Ingo Ringshausen, Thorsten Zenz, Clemens Martin Wendtner, Markus Müschen, Julia Jellusova, Jürgen Ruland, Maike Buchner^*

^*Corresponding author for this work

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

Abstract

Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells.

Original language	English
Article number	113017
Number of pages	20
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113017
Publication status	Published - 31 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

We would like to thank Tanja Neumeier and Nicole Beck for excellent technical support. This work was funded by the German Cancer Aid ( Deutsche Krebshilfe , Max Eder Grant to M.B., Project ID 70114720 ), German Research Foundation ( Deutsche Forschungsgemeinschaft , DFG) – Project ID 360372040 – SFB 1335/P02 awarded to M.B., P01 to J.R., and Wilhelm Sander Foundation (Project ID 2018.111.1 to M.B.). S.H. is an employee of and holds equity interest in Roche/Genentech. S.H. has received research funding from Bristol Myers-Squibb and Novartis. S.H. has been a consultant for Bristol Myers-Squibb, Novartis, Merck, Abbvie, and Roche.

Funders	Funder number
Bristol Myers-Squibb and Novartis
Wilhelm Sander-Stiftung	2018.111.1
the Deutsche Forschungsgemeinschaft	360372040 – SFB 1335/P02
Deutsche Krebshilfe	70114720

Keywords

apoptosis
CLL
CP: Cancer
DNA damage
MAPK
phosphatases

UN SDGs

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

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10.1016/j.celrep.2023.113017Licence: CC BY-NC-ND

1-s2.0-S2211124723010288-mainFinal published version, 3.91 MBLicence: CC BY-NC-ND

Cite this

Ecker, V., Brandmeier, L., Stumpf, M., Giansanti, P., Moreira, A. V., Pfeuffer, L., Fens, M. H. A. M., Lu, J., Kuster, B., Engleitner, T., Heidegger, S., Rad, R., Ringshausen, I., Zenz, T., Wendtner, C. M., Müschen, M., Jellusova, J., Ruland, J., & Buchner, M. (2023). Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression. Cell Reports, 42(10), Article 113017. https://doi.org/10.1016/j.celrep.2023.113017

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title = "Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression",

abstract = "Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells.",

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author = "Veronika Ecker and Lisa Brandmeier and Martina Stumpf and Piero Giansanti and Moreira, {Aida Varela} and Lisa Pfeuffer and Fens, {Marcel H.A.M.} and Junyan Lu and Bernhard Kuster and Thomas Engleitner and Simon Heidegger and Roland Rad and Ingo Ringshausen and Thorsten Zenz and Wendtner, {Clemens Martin} and Markus M{\"u}schen and Julia Jellusova and J{\"u}rgen Ruland and Maike Buchner",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = oct,

day = "31",

doi = "10.1016/j.celrep.2023.113017",

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Ecker, V, Brandmeier, L, Stumpf, M, Giansanti, P, Moreira, AV, Pfeuffer, L, Fens, MHAM, Lu, J, Kuster, B, Engleitner, T, Heidegger, S, Rad, R, Ringshausen, I, Zenz, T, Wendtner, CM, Müschen, M, Jellusova, J, Ruland, J & Buchner, M 2023, 'Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression', Cell Reports, vol. 42, no. 10, 113017. https://doi.org/10.1016/j.celrep.2023.113017

TY - JOUR

T1 - Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

AU - Ecker, Veronika

AU - Brandmeier, Lisa

AU - Stumpf, Martina

AU - Giansanti, Piero

AU - Moreira, Aida Varela

AU - Pfeuffer, Lisa

AU - Fens, Marcel H.A.M.

AU - Lu, Junyan

AU - Kuster, Bernhard

AU - Engleitner, Thomas

AU - Heidegger, Simon

AU - Rad, Roland

AU - Ringshausen, Ingo

AU - Zenz, Thorsten

AU - Wendtner, Clemens Martin

AU - Müschen, Markus

AU - Jellusova, Julia

AU - Ruland, Jürgen

AU - Buchner, Maike

PY - 2023/10/31

Y1 - 2023/10/31

N2 - Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells.

AB - Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells.

KW - apoptosis

KW - CLL

KW - CP: Cancer

KW - DNA damage

KW - MAPK

KW - phosphatases

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DO - 10.1016/j.celrep.2023.113017

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AN - SCOPUS:85172771771

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

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ER -

Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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