yoko inaguma

Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.

症例は56歳女性で、健康診断で白血球減少が明らかになり、骨髄検査の結果、急性骨髄性白血病(AML)と診断された。白血病細胞はアズール顆粒を欠損し、t(8;21)の典型的特徴に相当しなかった。RNA-seq分析では、RUNX1-RUNX1T1に加えて、12p11でのTM7SF3は8q22でVPS13Bへ融合され、またVPS13BはRUNX1に融合されることが明らかになった。VPS13BはRUNX1T1の近くに局在し、両者は同じ染色体バンドに局在した。TM7SF3およびVPS13Bのリーディングフレームは、それぞれVPS13BおよびRUNX1のリーディングフレームとマッチしなかった。VPS13Bの破壊はCohen症候群を起こし、骨髄において左にシフトした顆粒球形成を伴う間欠性好中球減少を示した。VPS13Bの破壊はRUNX1-RUNX1T1白血病の稀な特徴を起こした。本症例は、VPS13Bの再配列が変異t(8;21)における追加の遺伝的イベントである可能性が示唆された。

© 2015 John Wiley & Sons, Ltd. Epstein–Barr virus (EBV)-encoded small RNA in situ hybridization (EBER-ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B-cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER-ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/μg. Although EBV DNA load was significantly higher for EBER-positive patients than for EBER-negative patients (p<0.001), EBV DNA was detected in up to 72% of EBERnegative patients. Progression-free survival and overall survival were significantly worse for patients with EBV DNA load above 700 copies/μg than for those with EBV DNA load below 700 copies/μg (p = 0.009 and p = 0.003); they were also significantly worse for EBER-positive patients than for EBER-negative patients (p<0.001 and p = 0.001). Even among EBER-negative patients, higher EBV DNA load conferred worse progression-free survival and overall survival (p = 0.041 and p = 0.013). These findings indicate that EBV DNA load in diagnostic specimens is not a simple surrogate for the EBER status and may be a potential biomarker associated with EBV involvement and prognosis in DLBCL.

Several studies have evaluated the utility of extrapolating the Calvert formula in calculating carboplatin (CBDCA) dosages in solid tumours; however, data regarding haematological cancers are less. Therefore, we conducted a preliminary study of the utility of extrapolating the Calvert formula in calculating CBDCA dosages for DeVIC +/- R therapy. A retrospective study on 57 non-Hodgkin lymphoma patients who had received DeVIC +/- R therapy was conducted. The area under the curve (AUC) of CBDCA was back-calculated from actual dosages using the Calvert formula. Patients were divided into two groups according to an AUC aeyen 4 or an AUC &lt; 4, respectively. The Revised Response Criteria of the International Working Group and CTCAE version 4.0 were used for assessing the treatment efficacy and adverse events, respectively. The use of AUC instead of body surface area had greater utility in calculating CBDCA dosage, with a response rate of greater than 50 % in patients receiving DeVIC +/- R therapy with an AUC aeyen 4 for CBDCA. The response rate of the AUC aeyen 4 group was significantly higher than that of the AUC &lt; 4 group. Decreased platelet and neutrophil counts of grade aeyen3 occurred at higher rates in the AUC aeyen 4 group. The extrapolation of the Calvert formula has utility in calculating the CBDCA dosage for DeVIC +/- R therapy, and therapeutic efficacy was increased by maintaining the AUC of CBDCA at aeyen4.

The present study investigated the anticancer activity of 2,3-dihydroxy-9,10-anthraquinone against different cancer cells such as MCF-7, COLO320, HepG-2, Skov-3, MOLM-14, NB-4, CEM, K562, Jurkat, HL-60, U937, IM-9 and Vero. 2,3-dihydroxy-9,10-anthraquinone showed good antiproliferative activity against COLO320 cells when compared to other tested cells. The cytotoxicity results showed 79.8% activity at the dose of 2.07 mu M with IC50 value of 0.13 mu M at 24 h in COLO320 cells. So we chose COLO320 cells for further anticancer studies. mRNA expression was confirmed by qPCR analysis using SYBR green method. Treatment with 2,3-dihydroxy-9,10-anthraquinone was found to trigger intrinsic apoptotic pathway as indicated by down regulation of Bcl-2, Bcl-xl; up regulation of Bim, Bax, Bad; release of cytochrome c and pro-caspases cleaving to caspases. Furthermore, 2,3-dihydroxy-9,10-anthraquinone stopped at G0/G1 phase with modulation in protein levels of cyclins. On the other hand PI3K/AKT signaling plays an important role in cell metabolism. We found that 2,3-dihydroxy-9,10-anthraquinone inhibits PI3K/AKT activity after treatment. Also, COX-2 enzyme plays a major role in colorectal cancer. Our results showed that the treatment significantly reduced COX-2 enzyme in COLO320 cells. These results indicated antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone involving apoptotic pathways, mitochondrial functions, cell cycle checkpoint and controlling the over expression genes during the colorectal cancer. Molecular docking studies showed that the compound bound stably to the active sites of Bcl-2, COX-2, PI3K and AKT. This is the first report of anticancer mechanism involving 2,3-dihydroxy-9,10-anthraquinone in COLO320 cells. The present results might provide helpful suggestions for the design of antitumor drugs toward colorectal cancer treatment. (C) 2016 Elsevier Ireland Ltd. All rights reserved.