MMSET, identified by its fusion to the IgH locus in t( IntroductionMultiple myeloma (MM) is associated with recurrent chromosomal translocations that link the immunoglobulin promoter/enhancer with several partner genes, deregulation of which likely plays a key role in disease pathogenesis. MMSET (multiple myeloma SET domain) was identified as a gene involved in the t(4;14)(p16;q32) translocation present in approximately 15% to 20% of MM. 1,2 This subtype of myeloma has a poor prognosis with frequent relapse after autologous stem-cell transplantation. [3][4][5] The breakpoint within 14q32.3 occurs in the immunoglobulin switch region and dissociates the intronic enhancer (E) from the 3Ј enhancer (E). The 4p16.3 breakpoint falls centromeric to the fibroblast growth factor receptor 3 (FGFR3) gene, placing it adjacent to the strong 3Ј enhancer on the derivative chromosome 14. Concurrently, the intronic enhancer on derivative chromosome 4 is juxtaposed to the MMSET gene. The breakpoint on chromosome 4 can vary in different cases and can yield transcripts that can exclude up to 6 of the initial exons of MMSET. 1 As a result of the translocation, both FGFR3 and MMSET can be deregulated; however, microarray analysis of t(4;14)-associated myeloma showed that all cases overexpress MMSET, but up to 25% of these cases do not overexpress FGFR3, implying a critical role for MMSET in this subset of myeloma. 4,6 The MMSET gene, also known as Wolf-Hirschhorn Syndrome Candidate 1 (WHSC1) 2 or Nuclear Receptor-binding SET Domain 2 (NSD2), 7 spans 120 kb, consists of 24 exons and undergoes complex alternative splicing. Two major transcripts were identified: type I encodes a protein of 647 amino acids and type II encodes a protein of 1365 amino acids. 1 Both proteins share a common amino terminus. A third transcript initiated within a middle intron of MMSET, encoding a mRNA comprising the 3Ј half of the MMSET gene was identified 8 and encodes a protein named RE-IIBP.The 1365 amino acid MMSET protein contains a SET domain that is found in many histone methyltransferases (HMTs) and determines their enzymatic activity. Histone methylation of chromatin yields docking sites for modules found on transcriptional regulators, attracting these proteins to chromatin. Depending on the histone site modified and genetic context, methylation may be associated with activation or repression of genes. 9 Other potential functional motifs in the MMSET proteins include nuclear localization signals (NLSs), an HMG box (high mobility group) often representing a DNA-binding domain, 2 PWWP domains 2,10 (proline-tryptophan-tryptophanproline) found in other nuclear proteins and 4 PHD (plant homeodomain) zinc fingers recently defined as binding modules for methylated lysines. 11,12 We found that the MMSET protein is strikingly up-regulated in myeloma cell lines harboring t(4;14). MMSET is concentrated in the nucleus, has specific HMT activity against core histones H3 and H4, and coimmunoprecipitates and interacts functionally with corepressors and histone For pe...

The online version of this article has a Supplementary Appendix. BackgroundPatients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Design and MethodsClinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. ResultsAmong the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. ConclusionsWe found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.Key words: acute myeloid leukemia, allogeneic hematopoietic cell transplantation, first relapse, second remission, cytogenetic risk. 2010;95(11):1857-1864. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Kurosawa S, Yamaguchi T, Miyawaki S, Uchida N, Sakura T, Kanamori H, Usuki K, Yamashita T, Okoshi Y, Shibayama H, Nakamae H, Mawatari M, Hatanaka K, Sunami K, Shimoyama M, Fujishima N, Maeda Y, Miura I, Takaue Y, and Fukuda T. Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse. Haematologica Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

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