Saori Maegawa

8q24 amplified segments involve novel fusion genes between NSMCE2 and long noncoding RNAs in acute myelogenous leukemia

The pathogenetic roles of 8q24 amplified segments in leukemic cells with double minute chromosomes remain to be verified. Through comprehensive molecular analyses of 8q24 amplicons in leukemic cells from an acute myelogenous leukemia (AML) patient and AML-derived cell line HL60 cells, we identified two novel fusion genes between NSMCE2 and long noncoding RNAs (lncRNAs), namely, PVT1-NSMCE2 and BF104016-NSMCE2. Our study suggests that 8q24 amplicons are associated with the emergence of aberrant chimeric genes between NSMCE2 and oncogenic lncRNAs, and also implicate that the chimeric genes involving lncRNAs potentially possess as-yet-unknown oncogenic functional roles.

Clinical manifestation of angioimmunoblastic T-cell lymphoma with exuberant plasmacytosis.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma characterized by aggressive symptoms and various abnormal laboratory test results. One of the rare immunologic abnormalities in AITL is exuberant polyclonal plasmacytosis, but its clinical significance has not been evaluated. This report concerns three AITL cases with exuberant polyclonal plasmacytosis and investigates its clinical impact by comparison with 12 patients without plasmacytosis. Our study found that the performance status (PS) of the former was significantly worse and their serum immunoglobulin levels were significantly higher. All other parameters, including B symptoms, various prognostic scores, blood cell counts other than plasmacyte, and serum levels of lactate dehydrogenase, C-reactive protein and soluble interleukin-2 receptor, showed no significant differences. More importantly, although the diagnosis of AITL with plasmacytosis was not straightforward in our series, outcomes of treatment with conventional chemotherapy or immunosuppressive therapy with cyclosporine A were favorable. To conclude, AITL should be considered a candidate underlying disease of exuberant polyclonal plasmacytosis. Provided a correct diagnosis is made early and is followed by adequate treatment, the prognosis for AITL with plasmacytosis may not be worse than that for those without plasmacytosis despite the severe exhaustion at first presentation.

Clinical manifestation and prognostic factors of 32 Japanese patients with autoimmune disease-associated diffuse large B-cell lymphoma

1 Division of Hematology and Oncology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan, 2 Department of Hematology, Kyoto First Red Cross Hospital, Kyoto, Japan, 3 Department of Hematology, Social Insurance Kyoto Hospital, Kyoto, Japan, 4 Department of Hematology, Kyoto Second Red Cross Hospital, Kyoto, Japan, 5 Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Japan, 6 Department of Hematology, Otsu Municipal Hospital, Otsu, Japan and 7 Department of Infl ammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance.

The deleted in colorectal carcinoma (DCC) gene at 18q21 encodes a netrin‐1 receptor, a tumor suppressor that prevents cell growth. While allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies, including leukemias and malignant lymphomas, its involvement has not been evaluated in multiple myeloma (MM), a plasma cell malignancy characterized by complex and heterogenous molecular abnormalities. We here show that 10 of 11 human myeloma‐derived cell lines (HMCLs) expressed non‐translated aberrant DCC transcriptional variants, in which exon 2 fuses with intron 1 instead of exon 1 (mt.DCC). Among them, two co‐expressed wild type transcripts (wt.DCC), while eight co‐expressed the splicing variant (sv.DCC) lacking exon 1. The remaining HMCL expressed only sv.DCC. In addition, analyses revealed that there were two types of mt.DCC that differed in their fusion of intron 1 with exon 2. In patient‐derived samples from 30 MM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients, wt.DCC was expressed in 53% of MM, but not in MGUS, while 23% of MM and 75% of MGUS expressed only sv.DCC. Considering that 25% of MGUS, 57% of MM, and 91% HMCLs expressed mt.DCC, our results suggest that the acquisition of mt.DCC might be a secondary genetic change in plasma cell dyscrasia.

Chromosomal abnormality variation detected by G-banding is associated with prognosis of diffuse large B-cell lymphoma treated by R-CHOP-based therapy

Diffuse large B‐cell lymphoma (DLBCL), which is the most prevalent disease subtype of non‐Hodgkin lymphoma, is highly heterogeneous in terms of cytogenetic and molecular features. This study retrospectively investigated the clinical impact of G‐banding‐defined chromosomal abnormality on treatment outcomes of DLBCL in the era of rituximab‐containing immunochemotherapy. Of 181 patients who were diagnosed with DLBCL and treated with R‐CHOP or an R‐CHOP‐like regimen between January 2006 and April 2014, metaphase spreads were evaluable for G‐banding in 120. In these 120 patients, 40 were found to harbor a single chromosomal aberration type; 63 showed chromosomal abnormality variations (CAVs), which are defined by the presence of different types of chromosomal abnormalities in G‐banding, including 19 with two CAVs and 44 with ≥3 CAVs; and 17 had normal karyotypes. No specific chromosomal break point or numerical abnormality was associated with overall survival (OS) or progression‐free survival (PFS), but the presence of ≥3 CAVs was significantly associated with inferior OS rates (hazard ratio (HR): 2.222, 95% confidence interval (CI): 1.056–4.677, P = 0.031) and tended to be associated with shorter PFS (HR: 1.796, 95% CI: 0.965–3.344, P = 0.061). In addition, ≥3 CAVs more frequently accumulated in high‐risk patients, as defined by several conventional prognostic indices, such as the revised International Prognostic Index. In conclusion, our results suggest that the emergence of more CAVs, especially ≥3, based on chromosomal instability underlies the development of high‐risk disease features and a poor prognosis in DLBCL.

Quadruple Cancers of Non-producing Multiple Myeloma, Cholangiocellular Carcinoma, and Two Different Thyroid Cancers

We report the case of a 72-year-old man who presented with non-producing multiple myeloma (MM) with three additional concomitant solid tumors that were identified by postmortem autopsy. The disease was refractory to anti-MM therapy including bortezomib and lenalidomide, and he finally died of bacterial pneumonia with diffuse alveolar damage 8 months after the diagnosis. An autopsy revealed that he was also affected by three other solid cancers, cholangiocellular carcinoma, medullary thyroid cancer and papillary thyroid cancer that were clinically asymptomatic and remained undiagnosed before death. A review of the literature suggests that primary quadruple cancers including MM are extremely rare.

Burkitt Lymphoma Preceded by Autoimmune Hemolytic Anemia due to Anti-D Antibody

We herein report a rare case of Burkitt lymphoma (BL) preceded by autoimmune hemolytic anemia (AIHA) caused by autoantibodies against D antigen. After a partial response to AIHA with prednisolone (PSL) treatment for 7 months, the patient developed BL with a t(8;22)(q24;q11.2) chromosomal translocation. Intensive immunochemotherapy, including rituximab, led to a complete response (CR) of BL; however, anti-D antibody remained detectable in the plasma and antibody-dissociated solution from erythrocytes, thus continuous therapy with PSL was necessary even after achievement of the CR. BL with AIHA is extremely rare, with only one previously reported case in the literature.

Dual targeting of bromodomain-containing 4 by AZD5153 and BCL2 by AZD4320 against B-cell lymphomas concomitantly overexpressing c-MYC and BCL2

SummaryDespite the recent therapeutic progress, the prognoses of diffuse large B-cell lymphomas (DLBCLs) that concomitantly overexpress c-MYC and BCL2, i.e., double hit lymphoma (DHL) and double expressing lymphoma (DEL), remain poor. This study examined triple targeting of c-MYC, BCL2 and the B-cell receptor (BCR) signaling pathway for DHL and DEL. We first used AZD5153, a novel bivalent inhibitor for bromodomain-containing 4 (BRD4), in DHL- and DEL-derived cell lines, because BRD4 regulates disease type-oriented key molecules for oncogenesis. AZD5153 was more effective than conventional monovalent BRD4 inhibitors, JQ1 and I-BET151, in inhibiting cell proliferation of a DHL-derived cell line and two DEL-derived cell lines, with at least 10-fold lower half growth inhibitory concentrations. AZD5153 caused G1/S cell cycle blockade, while the apoptosis-inducing effect was relatively modest. At the molecular level, AZD5153 was potent in downregulating various molecules for oncogenesis, such as c-MYC, AKT2 and MAP3K; those involved in the BCR signaling pathway, such as CD19, BLNK and CD79B; and those associated with B-cell development, such as IKZF1, IKZF3, PAX5, POU2AF1 and EBF1. In contrast, AZD5153 did not decrease anti-apoptotic BCL2 proteins, and did not activate pro-apoptotic BH3-only proteins, except BAD. To augment cell death induction, we added a novel BH3-mimicking BCL2 inhibitor AZD4320 to AZD5153, and found that these two agents had a mostly synergistic antitumor effect by increasing cells undergoing apoptosis in all three cell lines. These results provide a rationale for dual targeting of BRD4 and BCL2 using AZD5153 and AZD4320 as a therapeutic strategy against DHL and DEL.

Extranodal marginal zone lymphoma of the uterine cervix with concomitant copy number gains of the MALT1 and BCL2 genes: A case report

Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT) of the uterus is rare, and the etiology, pathophysiology and cytogenetic features remain unknown at present. The present study reports a case of a 71-year-old female with EMZL of the uterine cervix that was 80 mm in diameter and invaded directly into the rectal serosa. Complete remission was successfully induced by 6 courses of immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone. Although the metaphase spread of the tumor cells was unavailable for whole cytogenetic analysis, fluorescence in situ hybridization (FISH) detected triple signals for MALT1 and B-cell lymphoma 2, located at chromosome 18q21, and the centromere of chromosome 18, which was suggestive of trisomy 18, and in combination with previous studies, suggested a possible association between trisomy 18 and the large tumor at initial presentation in the present patient. In addition, FISH examination detected immunoglobulin heavy chain gene rearrangement, although the translocation partner was unconfirmed. A total of 18 previously-studied patients with EMZL of the uterus, including that of the present study, were reviewed with respect to their clinical features and treatment and cytogenetic abnormality. In the evaluation of the English scientific literature, this is the first reported patient with EMZL of the uterus with partly determined cytogenetic abnormalities.

High Frequencies of Drug-resistant Pathogens in Blood Stream Infections Associated with Hematologic Disorders: Five-year single institutional surveillance from 2010 to 2014

In order to improve the management of infectious complications associated with hematologic disorders, we conducted a retrospective 5-year analysis of Blood Culture (BC) tests obtained from febrile patients with hematological disorders treated in our institute between 2010 and 2014. BCs were performed using the BacT/ALERT 3D system (bioMérieux, Marcy l’Etoile, France) and identification and antibiotic susceptibility testing were performed using VITEK2 (bioMérieux). In 8,549 BC tests obtained from 1,517 febrile events, 325 BC tests showed positive results in 154 febrile episodes with 91 patients. In BC-positive episodes, the incidence of BC-positivity for 3 consecutive BC tests per febrile episode was 98.1 %. The frequencies of Gram-positive and Gram-negative bacteria as the causative pathogen were almost equal (44.5 % vs 43.3 % ). The frequency of drug-resistant bacteria, such as either methicillin-resistant cocci or extended spectrum beta-lactamase producing organism, was more than 50 %. The use of a central venous catheter showed a positive relationship with the methicillin-resistant cocci in our series. Our study found increasing frequencies of drug-resistant bacteria as the pathogens of blood stream infection in hematological disorders. These results are instructive for the appropriate selection of empiric antibiotic therapy for febrile events in patients with hematologic malignancies. *Corresponding author: Tsutomu Kobayashi M.D. Ph.D, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, Tel: + 81-75-251-5740, Fax: + 81-75-251-5743; E-mail: t-koba@koto.kpu-m.ac.jp Received Date: May 11, 2017 Accepted Date: June 30, 2017 Published Date: July 04, 2017