Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML - HAL-SHS - Sciences de l'Homme et de la Société Access content directly
Journal Articles Blood Year : 2021

Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Margaux Sevin
  • Function : Author
Franck Debeurme
  • Function : Author
Séverine Badel
  • Function : Author
Margot Morabito
  • Function : Author
Hanna Newman
  • Function : Author
Miguel Torres-Martin
Qin Yang
  • Function : Author
Bouchra Badaoui
Orianne Wagner-Ballon
Véronique Saada
  • Function : Author
Dorothée Sélimoglu-Buet
Laurence Kraus-Berthier
  • Function : Author
Sébastien Banquet
  • Function : Author
Alix Derreal
  • Function : Author
Pierre Fenaux
  • Function : Author
Raphael Itzykson
Thorsten Braun
  • Function : Author
Gabriel Etienne
Celine Berthon
Sylvain Thépot
Oliver Kepp
Guido Kroemer
Eric Padron
  • Function : Author
Maria Figueroa
  • Function : Author
Nathalie Droin
Eric Solary

Abstract

Abstract Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
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Dates and versions

halshs-03500342 , version 1 (02-08-2023)

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Attribution - NonCommercial

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Margaux Sevin, Lucie Laplane, Franck Debeurme, Séverine Badel, Margot Morabito, et al.. Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML. Blood, 2021, 137 (24), pp.3390-3402. ⟨10.1182/blood.2020008729⟩. ⟨halshs-03500342⟩
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