Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation

• Published in: PloS one Vol. 9; no. 1; p. e86619
• Main Authors: El-Serafi, Ibrahim, Abedi-Valugerdi, Manuchehr, Potácová, Zuzana, Afsharian, Parvaneh, Mattsson, Jonas, Moshfegh, Ali, Hassan, Moustapha
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.01.2014; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Alkylating agents; Alkylation; Apoptosis; Biology; Breast cancer; c-Jun protein; CD28 antigen; CD3 antigen; Cell cycle; Chemotherapy; Child; Cluster Analysis; Conditioning; Consent; CTLA-4 protein; Cyclophosphamide; Cyclophosphamide - pharmacology; Cyclophosphamide - therapeutic use; Deoxyribonucleic acid; DNA; DNA methylation; Drug dosages; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes; Graft rejection; Health aspects; Hematologic Neoplasms - diagnosis; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - genetics; Hematologic Neoplasms - therapy; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Humans; Interleukin 1; Interleukin 2 receptors; Irradiation; Kinases; Laboratories; Leukemia; Major histocompatibility complex; Male; Medical research; Medicin och hälsovetenskap; Medicine; Middle Aged; Morbidity; Mortality; Patients; Proteins; Radiation; Radiation therapy; Stem cell transplantation; Stem cells; Studies; Toxicity; Transcription factors; Transcriptome; Transplantation; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation; Young Adult; Sweden
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086619

Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation. We present the gene expression profile during cyclophosphamide treatment in 11 patients conditioned with cyclophosphamide for 2 days followed by total body irradiation prior to hematopoietic stem cell transplantation. 299 genes were identified as specific for cyclophosphamide treatment and were arranged into 4 clusters highly down-regulated genes, highly up-regulated genes, early up-regulated but later normalized genes and moderately up-regulated genes. Cyclophosphamide treatment down-regulated expression of several genes mapped to immune/autoimmune activation and graft rejection including CD3, CD28, CTLA4, MHC II, PRF1, GZMB and IL-2R, and up-regulated immune-related receptor genes, e.g. IL1R2, IL18R1, and FLT3. Moreover, a high and significant expression of ANGPTL1 and c-JUN genes was observed independent of cyclophosphamide treatment. This is the first investigation to provide significant information about alterations in gene expression following cyclophosphamide treatment that may increase our understanding of the cyclophosphamide mechanism of action and hence, in part, avoid its toxicity. Furthermore, ANGPTL1 remained highly expressed throughout the treatment and, in contrast to several other alkylating agents, cyclophosphamide did not influence c-JUN expression.