Page 135 - Haematologica-April 2018

Non-Hodgkin Lymphoma
Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified
Meng-Meng Ji,1 Yao-Hui Huang,1 Jin-Yan Huang,1 Zhao-Fu Wang,2 Di Fu,1 Han Liu,1 Feng Liu,1 Christophe Leboeuf,3,4 Li Wang,1,3 Jing Ye,3 Yi-Ming Lu,3 Anne Janin,3,4 Shu Cheng1 and Wei-Li Zhao1,3
1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology; Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, China; 2Department of Pathology, Shanghai Rui Jin Hospital; Shanghai Jiao Tong University School of Medicine, China; 3Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China and 4U1165 Inserm/Université Paris 7, Hôpital Saint Louis, Paris, France
ABSTRACT
Due to heterogeneous morphological and immunophenotypic fea- tures, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified. These conditions have an aggressive course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particu- larly methylation and acetylation, are generally involved in chromatin state regulation. Here we screened the core set of genes related to histone methylation (KMT2D, SETD2, KMT2A, KDM6A) and acetylation (EP300, CREBBP) and identified 59 somatic mutations in 45 of 125 (36.0%) patients with peripheral T-cell lymphomas, not otherwise spec- ified. Histone modifier gene mutations were associated with inferior pro- gression-free survival time of the patients, irrespective of chemotherapy regimens, but an increased response to the histone deacetylase inhibitor chidamide. In vitro, chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine. Mechanistically, decitabine acted synergistically with chidamide to enhance the interaction of KMT2D with transcription factor PU.1, regu- lated H3K4me-associated signaling pathways, and sensitized T-lym- phoma cells to chidamide. In a xenograft KMT2D-mutated T-lymphoma model, dual treatment with chidamide and decitabine significantly retarded tumor growth and induced cell apoptosis through modulation of the KMT2D/H3K4me axis. Our work thus contributes to the understand- ing of aberrant histone modification in peripheral T-cell lymphomas, not otherwise specified and the stratification of a biological subset that can benefit from epigenetic treatment (Clinical trials.gov identifiers: NCT 01746992 and NCT 02533700).
Introduction
Peripheral T-cell lymphomas (PTCL) represent a heterogeneous clinicopatholog- ical entity of non-Hodgkin lymphoma with an aggressive disease course and poor clinical outcome. Approximately 50% of PTCL are unclassifiable and categorized as PTCL, not otherwise specified (PTCL-NOS).1 Using gene expression profiling, PTCL-NOS lymphocytes can be distinguished from normal T lymphocytes, with deregulation of genes involved in apoptosis, proliferation, cell adhesion, and tran-
Ferrata Storti Foundation
*M-MJ, Y-HH, J-YH and Z-FW contributed equally to this work.
Haematologica 2018 Volume 103(4):679-687
Correspondence:
zhao.weili@yahoo.com or orenge@medmail.com.cn
Received: October 13, 2017. Accepted: January 3, 2018. Pre-published: January 5, 2018.
doi:10.3324/haematol.2017.182444
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/679
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