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M-M. Ji et al.
PTCL-NOS was similar to that in B-cell lymphoma, in
which predominantly missense mutations were found.17,18 Importantly, our study provided clinical evidence that his- tone modifier gene mutations, particularly those involved in histone methylation and acetylation, are significantly associated with tumor chemoresistance and disease pro- gression of PTCL-NOS.
The adverse prognostic effect of histone modifier gene mutations was further proven in a chemotherapy-indepen- dent manner, prompting us to explore bio-therapeutic agents that can overcome chemoresistance in PTCL-NOS patients. It is well known that HDAC inhibitors are potent anticancer drugs in hematopoietic malignancies, including lymphoma.19-21 The aim of using HDAC inhibitors is to restore normal histone modification patterns through inhi- bition of various components of the epigenetic machin- ery.22,23 In B-cell lymphoma, HDAC inhibitors can rescue deficits in histone acetylation induced by EP300/CREBBP mutations,24 rendering tumor cells more sensitive to suberoylanilide hydroxamic acid.25 This can explain why chidamide also has favorable efficacy on PTCL-NOS patients bearing EP300/CREBBP mutations.
Moreover, KMT2D-mutated PTCL-NOS patients responded to chidamide. Both in vitro and in vivo, the com- bination of decitabine and chidamide induced apoptosis of Jurkat cells bearing the KMT2D mutant. This is in accordance with previous reports that decitabine and 5- azacytidine produce a marked synergistic effect in combi- nation with suberoylanilide hydroxamic acid and romidepsin in T-lymphoma cell lines by modulating cell cycle arrest and apoptosis.26,27 As a mechanism of action, KMT2D mutations of B-lymphoma cells promote malig- nant outgrowth by perturbing methylation of H3K4 that affect the JAK-STAT, Toll-like receptor, or B-cell receptor pathway.28,29 Here our study indicated that dual treatment with chidamide and decitabine enhanced the interaction of KMT2D with the transcription factor PU.1, thereby inactivating the H3K4me-associated signaling pathway
MAPK, which is constitutively activated in T-cell lym- phoma.13,30,31 The transcription factor PU.1 is involved in the development of all hematopoietic lineages32 and regu- lates lymphoid cell growth and transformation.33 Aberrant PU.1 expression promotes acute myeloid leukemia and is related to the pathogenesis of multiple myeloma via the MAPK pathway.34,35 On the other hand, PU.1 is also shown to interact with chromatin remodeler and DNA methyl- transferease to control hematopoiesis and suppress leukemia.36 Our data thus suggested that the combined action of chidamide and decitabine may interfere with the differentiation and/or viability of PTCL-NOS through a PU.1-dependent gene expression program.
In conclusion, histone modifier genes indicate clinical progression of PTCL-NOS and may represent a group of actionable biomarkers of this disease subtype. Characterized as a biological subset of PTCL-NOS, patients with dysregulation of the histone modification machinery may be amenable to therapeutic intervention with HDAC inhibitors, given either alone or in combina- tion with hypomethylating agents.
Acknowledgments
The authors would like to thank all the patients involved in this study and their families.
Funding
This study was supported, in part, by research funding from the National Natural Science Foundation of China (81325003, 81520108003 and 81670716), Chang Jiang Scholars Program, the Shanghai Commission of Science and Technology (16JC1405800), Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (16CR2017A), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Collaborative Innovation Center of Systems Biomedicine and the Samuel Waxman Cancer Research Foundation.
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