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We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.

Molecular abnormalities involved in the multistep leukemogenesis of adult T-cell leukemia (ATL) remain to be clarified. Based on our integrated database, we focused on the expression patterns and levels of Ikaros family genes, Ikaros, Helios, and Aiolos, in ATL patients and HTLV-1 carriers. The results revealed profound deregulation of Helios expression, a pivotal regulator in the control of T-cell differentiation and activation. The majority of ATL samples (32/37 cases) showed abnormal splicing of Helios expression, and four cases did not express Helios. In addition, novel genomic loss in Helios locus was observed in 17/168 cases. We identified four ATL-specific short Helios isoforms and revealed their dominant-negative function. Ectopic expression of ATL-type Helios isoform as well as knockdown of normal Helios or Ikaros promoted T-cell growth. Global mRNA profiling and pathway analysis showed activation of several signaling pathways important for lymphocyte proliferation and survival. These data provide new insights into the molecular involvement of Helios function in the leukemogenesis and phenotype of ATL cells, indicating that Helios deregulation is one of the novel molecular hallmarks of ATL.

SummaryConstitutive NF-κB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. Here, we report a pathway involving Polycomb-mediated miRNA silencing and NF-κB activation. We determine the miRNA signatures and reveal miR-31 loss in primary ATL cells. MiR-31 negatively regulates the noncanonical NF-κB pathway by targeting NF-κB inducing kinase (NIK). Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-κB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.

A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

Adult T cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm in adult that is caused by human T-cell leukemia virus type 1 (HTLV-1) and highly intractable to conventional therapeutics. Since there are 1.2 million HTLV-1 carriers in Japan and more than 50,000 carriers are expected to develop ATL from now on, it is of particular importance to understand the pathogenesis of ATL. The malignant processes of T-cell transformation in ATL are initiated by HTLV-1 infection in early childhood, and the HTLV-1 infected and immortalized T-cells are thought to accumulate a series of genetic hits during the later life, ultimately giving rise to malignant ATL clones after decades of latency periods. However, little is known about the nature of these genetic hits that take place after the early immortalization processes of T-cells mediated by HTLV-1 Tax protein. So in order to clarify the genetic alterations involved in the later processes of T-cell transformation in ATL, we analyzed a total of 130 ATL samples using Affymetrix® GeneChip® 250K Nsp arrays. Combined with CNAG/AsCNAR software, these arrays allow for accurate determination of allele-specific copy numbers in extremely high-resolution (less than 12kb) to detect copy number alterations as well as allelic imbalances in ATL genomes without depending on the availability of constitutive DNA of tumor specimens (molecular allelo-karyotyping). ATL genomes show characteristic copy number profiles and unique patterns of allelic imbalances, which are distinct from acute lymphoblastic ALL and non-Hodgikin’s lymphomas and include gains of 1q arm, 2q33, 3p and 3q arms, 9p12, 17q12, and 19p13, and losses of 1p13.1, 2q end, 3q22, 4q31, 6p22, 7q31, 9p21, 10p14, 12q13, 14q24, and 19q13. Moreover, allele-specific determination of copy numbers disclosed a number of regions showing copy number neutral LOH. Numerous homozygous deletions and gene amplifications were also identified and commonly mapped to less than 500Kb regions, which facilitated identification of candidate gene targets. Interestingly, these genetic lesions involved many T-cell related genes, indicating that the de-regulation of normal T cell functions may contribute the pathogenesis of ATL. In conclusion, molecular allelo-karyotyping of ATL genomes using SNP arrays provides valuable information about the molecular targets in ATL pathogenesis.

B-cell non-Hodgkin’s lymphoma (B-NHL) is a constellation of mature B-cell neoplasms characterized by distinct pathological and molecular genetic features, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), MATL-type lymphoma (MALT-L). These B-NHLs undergo a wide variety of genetic alterations, including gains and losses of genetic materials, as well as abnormalities in allelic composition, and these alterations may collectively comprise unique genomic profiles specific to different subtypes of B-NHL, which are tightly linked to the pathogenesis of each B-NHL subtype. Recently, we have developed a robust method (CNAG/AsCNAR) to detect allelic imbalances and other copy number changes in cancer genomes using SNP-genotyping microarrays (Nannya et al. Cancer Res, 2005 and Yamamoto et al. Am J Hum Genet, 2007). Without depending on the availability of constitutive genomic DNA, it enables sensitive detection of allelic imbalances including loss of heterozygosity (LOH) as well as copy number (CN) alterations in the face of 70–80% of normal cell components. In the current study, we performed SNP-chip/CNAG/AsCNAR analysis of 171 B-NHL specimens, including 65 cases of DLBCL, 61 cases of FL, and 45 cases of MALT-L in order to comparatively investigate the unique genomic profiles of different B-NHL subtypes. A large number of gains and losses of chromosomal/genomic segments as well as allelic imbalances were identified. While individual genomic profiles are substantially variable among different cases, they collectively showed a characteristic genomic profile in each B-NHL subtypes; +1q, +2p and +18 are common to DLBCL and FL, while +3 and +11q were more frequently found in DLBCL and +11p was more characteristic to FL. MALT-L also showed +3 and +18, but rarely had +1q and +2p. CN neutral LOH due to mitotic recombination (uniparental disomy; UPD) events are frequently found in DLBCL (70%) and FL (54%), but less common in MALT-L. UPD most commonly involves 1p, 1q, 6p, 9p and 12q. In total, 29 loci of high-grade amplification were identified. Among these recurring amplifications were observed at 1q and 2p, which involves FCGR2B, and cRel genes, respectively. These amplifications were detected in both DLBCL and FL, but rare in MALT-L. Total 14 loci of homozygous deletion were also detected and differentially distributed among different B-NHL subtypes. In conclusion, SNP-chip with CNAG/AsCNAR analysis revealed characteristic genomic signatures of distinctive B-NHL subtypes, implicating their unique pathogenesis.