title: Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors.
abstract: DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis. We found that 5‑Aza‑dC inhibits growth of cHL cell lines at clinically relevant concentrations of 0.25‑2 µM. The antitumor effect of 5‑Aza‑dC was associated with induction of genes, which negatively regulate cell cycle progression (e.g. CDKN1A and GADD45A). Surprisingly, we also observed significant enrichment of pro‑survival pathways like MEK/ERK, JAK‑STAT and NF‑κB, as well as signatures comprising transcription‑activating genes. Among the upregulated pro‑survival genes were the anti‑apoptotic genes BCL2 and BCL2L1, as well as genes involved in transduction of growth and survival signals like STAT1, TLR7, CD40 and IL-6. We therefore analyzed whether interference with these pro‑survival pathways and genes would potentiate the antitumor effect of 5‑Aza‑dC. We could show that the BCL2/BCL2L1 inhibitor ABT263, the JAK‑STAT inhibitors fedratinib and SH‑4‑54, the AKT inhibitor KP372‑1, the NF‑κB inhibitor QNZ, as well as the bromodomain and extraterminal (BET) family proteins inhibitor JQ1 acted synergistically with 5‑Aza‑dC. We conclude that targeting of oncogenic pathways of cHL may improve efficacy of DNA-demethylating therapy in cHL.
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Tatjana Maria
authors.initials: TM
authors.lastname: Swerev
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.affiliation: Institute of Physiological Chemistry, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Alexey
authors.initials: A
authors.lastname: Ushmorov
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D009857:Oncogenes / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D054852:Small Molecule Libraries; D000077209:Decitabine; D001374:Azacitidine