Dual role of EZH2 in megakaryocyte differentiation

被引:8
|
作者
Mazzi, Stefania [1 ,2 ,3 ,4 ]
Dessen, Philippe [5 ]
Vieira, Mathieu [1 ,2 ,3 ]
Dufour, Virginie [6 ]
Cambot, Marie [6 ]
El Khoury, Mira [1 ,2 ,3 ]
Antony-Debre, Ileana [1 ,2 ,3 ]
Arkoun, Brahim [1 ,2 ,3 ]
Basso-Valentina, Francesca [1 ,2 ,3 ,4 ]
BenAbdoulahab, Salwa [1 ,2 ,3 ,7 ]
Edmond, Valerie [1 ,2 ,3 ]
Rameau, Philippe [3 ]
Petermann, Rachel [6 ]
Wittner, Monika [1 ,2 ,3 ]
Cassinat, Bruno [8 ]
Plo, Isabelle [1 ,2 ,3 ]
Debili, Najet [1 ,2 ,3 ]
Raslova, Hana [1 ,2 ,3 ]
Vainchenker, William [1 ,2 ,3 ,6 ]
机构
[1] Gustave Roussy, Equipe Labellisee Ligue Natl Canc, INSERM, Unite Mixte Rech UMR 1287, Villejuif, France
[2] Univ Paris Saclay, Gustave Roussy, UMR 1287, Villejuif, France
[3] Gustave Roussy, UMR 1287, Villejuif, France
[4] Univ Paris Diderot, Paris, France
[5] Gustave Roussy, Genom Core Facil UMS AMMICA, INSERM, Ctr Natl Rech Sci CNRS, Villejuif, France
[6] Inst Natl Transfus Sanguine, Paris, France
[7] Univ Paris XIII, Villetaneuse, France
[8] Hop St Louis, AP HP, Serv Biol Cellulaire, Paris, France
关键词
METHYLTRANSFERASE GENE EZH2; HEMATOPOIETIC STEM; SOMATIC MUTATIONS; CELLS; MYELOFIBROSIS; SURVIVAL; ARREST; DNA;
D O I
10.1182/blood.2019004638
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss-of-function mutations have been found in myeloproliferative neoplasms, particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and short hairpin RNA induces megakaryocyte (MK) commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and polyploidization and decreases proplatelet formation. EZH2 inhibitors similarly reduce MK polyploidization and proplatelet formation in vitro and platelet levels in vivo in a JAK2V617F background. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression of genes involved in DNA replication and repair and an upregulation of cyclin-dependent kinase inhibitors, particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and to a lesser extent CDKN2D could partially rescue the percentage of polyploid MKs. Moreover, H3K27me3 and EZH2 chromatin immunoprecipitation assays revealed that CDKN1A is a direct EZH2 target and CDKN2D expression is not directly regulated by EZH2, suggesting that EZH2 controls MK polyploidization directly through CDKN1A and indirectly through CDKN2D.
引用
收藏
页码:1603 / 1614
页数:12
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