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To effectively direct targeted repression, the class I histone deacetylases (HDACs) associate with many important regulatory proteins. In this paper we describe the molecular characterization of a member of the Jumonji domain 2 (JMJD2) family of proteins, and demonstrate its binding to both class I HDACs and the retinoblastoma protein (pRb). JMJD2 proteins are characterized by the presence of two leukemia-associated protein/plant homeodomain (LAP/PHD) zinc fingers, one JmjN, one JmjC (containing an internal retinoblastoma-binding protein 2 (RBBP2)-like sequence), and two Tudor domains. The first member of this group, JMJD2A, is widely expressed in human tissues and cell lines, and high endogenous expression of JMJD2A mRNA was found in several cell types, including human T-cell lymphotropic virus 1 (HTLV-1)-infected cell lines. JMJD2A and JMJD2B exhibit cell type-specific responses to the HDAC inhibitor trichostatin A. We show that the JMJD2A protein associates in vivo with pRb and class I HDACs, and mediates repression of E2F-regulated promoters. In HTLV-1 virus-infected cells, we find that JMJD2A binds to the viral Tax protein. Antibodies to JMJD2A recognize the native protein but also a half-sized protein fragment, the latter up-regulated in THP-1 cells during the G2/M phase of the cell cycle. The ability of JMJD2A to associate with pRb and HDACs and potentiate pRb-mediated repression of E2F-regulated promoters implies an important role for this protein in cell proliferation and oncogenesis. [ABSTRACT FROM AUTHOR]

Abstract Purpose We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit–risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS). Methods Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit–risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit–risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs. Findings The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit–risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model. Implications The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings. [ABSTRACT FROM AUTHOR]