Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa

• Published in: PloS one Vol. 12; no. 1; p. e0169286
• Main Authors: Marcussen, Mette, Bødker, Julie Støve, Christensen, Heidi Søgaard, Johansen, Preben, Nielsen, Søren, Christiansen, Ilse, Bergmann, Olav Jonas, Bøgsted, Martin, Dybkær, Karen, Vyberg, Mogens, Johnsen, Hans Erik
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.01.2017; Public Library of Science (PLoS)
• Subjects: Aged; Alternative splicing; Analysis; Antigens; Apoptosis; Biology and Life Sciences; Biomarkers; Biopsy; Blood; Cancer genetics; Cancer therapies; Care and treatment; Chemotherapy; Clinical medicine; Dendritic cells; Deoxyribonucleic acid; Disease; DNA; Dosage and administration; Dose-Response Relationship, Drug; Drb1 protein; Drug dosages; Female; Follow-Up Studies; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genetic aspects; Genomes; Hematology; Hematopoietic Stem Cell Transplantation; Histocompatibility antigen HLA; HLA antigens; HLA-DRB5 Chains - immunology; Hospitals; Humans; Immunohistochemistry; Immunoregulation; Lasers; Male; MDM2 protein; Medical research; Medicine; Medicine and Health Sciences; Melphalan; Melphalan - administration & dosage; Melphalan - adverse effects; Metabolism; Middle Aged; Mouth Mucosa - immunology; Mouth Mucosa - metabolism; Mouth Mucosa - pathology; Mucosa; Mucositis; Multiple myeloma; Multiple Myeloma - drug therapy; p53 Protein; Pathology; Patients; Psoriasis; Quality; Receptors; Stem cells; Stomatitis - blood; Stomatitis - chemically induced; Stomatitis - genetics; Stomatitis - immunology; Subgroups; Toxicity; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169286

Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5-6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity.