Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

Jared M. Andrews, Jennifer A. Schmidt, Kenneth R. Carson, Amy C. Musiek, Neha Mehta-Shah, Jacqueline E. Payton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Background: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. Methods: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. Findings: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR < 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p < 0·01) compared to controls. Interpretation: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. Funding: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842.

Original languageEnglish (US)
Pages (from-to)170-183
Number of pages14
JournalEBioMedicine
Volume46
DOIs
StatePublished - Aug 2019

Funding

N. Mehta-Shah reports research funding from Celgene, Verastem Pharmaceuticals, Roche/Genentech, and Bristol Myers Squibb and is a consultant for Kiowa Hakka Kirin. K. R. Carson is also employed by Flatiron Health. A. C. Musiek reports research funding from Pfizer, Helsinn, miRagen, Solgenix, Kyowa, Elorac, and Actelion and is also on the advisory boards for Actelion and Kyowa. No potential conflicts of interest were disclosed by the other authors. We thank the Washington University School of Medicine Lymphoma Banking Program of the Division of Medical Oncology in the Department of Medicine for support of the biopsy and banking program. We are grateful to the patients, their caregivers and families, and the patient coordinators who participated in this study. This work was supported by NIH grants CA156690 , CA188286 (J.E.P.), the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) (Pilot Award to J.E.P.), and Siteman Cancer Center ( CA091842 ) (Pilot Award to J.E.P.) grants. Sequencing provided by the Genome Technology Access Center, which is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1 TR000448 from the National Center for Research Resources (NCRR) , a component of the National Institutes of Health (NIH) , and NIH Roadmap for Medical Research. The ICTS is funded by the NIH's NCATS Clinical and Translational Science Award (CTSA) program grant #UL1 TR002345 . This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. None of these sources had any role in data collection, analysis, interpretation, trial design, patient recruitment, writing the manuscript, the decision to submit the manuscript, or any other aspect pertinent to the study. None of the authors was paid to write the article by a company or any other agency. The corresponding author (Jacqueline Payton) had full access to all of the data in the study and had final responsibility for the decision to submit for publication.

Keywords

  • Epigenetics
  • Lymphoma
  • Predictive biomarker
  • Therapeutic resistance

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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