bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Equal Activity of Azacytidine in 4 Risk Groups of IPSS in MDS.
Authors: Bang Soo-Mee , Kim In-Ho , Park Seonyang , Kim Byoung Kook , Lee Je-Hwan , Lee Jung-Hee , Lee Kyoo-Hyung , Kim Yeo-Kyeoung , Ahn Jae-Sook , Kim Hyeoung Joon , Bae Sung-Hwa , Ryoo Hun-Mo , Lee Mark , Shin Ho-Jin , Min Yoo-Hong , Lee Jae Hoon , Mun Yeung-Chul , Won Jong-Ho , Oh Doyeun ,   Korean AML/MDS Working Party
Published: October 2019

Abstract
Introduction: The methylated proportion of the gene, turning on the cell cycle, increases with a progression of MDS. Newly introduced demethylaing agent, azacytidine (AZA) may be more active in advanced cases of MDS. Early data for the hematologic responses in several stages of MDS supported this. The powerful tool predicting the outcome of MDS is international prognostic scoring system (IPSS). Our study is to compare the response to AZA among the IPSS risk groups using international working group criteria.
Methods: One hundres five patients with MDS were treated with AZA from May 2006 till August 2007. Seven patients had insufficient data. Finally, 108 patients were enrolled.
Results: Their median age was 59 years-old (range; 20∼83), and male to female ratio was 2.09. The previous hematologic diseases documented in 8 patients; apalastic anemia (7), and megaloblstic anemia (1). The secondary MDS occurred in 3 patients; after the chemotherapy (2) and radiotherapy (1). A median time from the diagnosis to treatment was 3 months (0∼183). The previous treatment (percentage of patients given) was the transfusion of RBC (74%) and PLT (35%), oxymetholone (17%), steroid (13%), erythropoietin (7%), cyclosporine (7%), ATG (5%), valproic acid (5%), chemotherapy (3%), and allogeneic SCT (2%). Their ECOG performance scale was 0 (58 patients), 1 (45) and 2 (5), respectively. Their diagnoses just before the AZA were RA (20 patients), RARS (5), RCMD (27), RCMD-RS (6), RAEB-1 (27), RAEB-2 (20), MDS-U (1), MDS with isolated 5q− (1) and CMMoL (1). A number of patients with a LOW, INT-1, INT-2, and HIGH risk was 4 (4%). 70 (65%) 23 (21%) and 11 (10%), respectively. The rate of hematologic response (CR+PR+marrow CR+HI) and cytogenetic response (continued normal karyotype and CR) were similar; 100%/75%/93%/67% and 100%/59%/50%/50% in LOW/INT-1/INT-2/HIGH risk groups, respectively. There were 6 treat-related mortalities, and their causes of death were infection in 4 patients and bleeding in 2 patients. Two patients stopped after one cycle of treatment because of grade 4 hepatoxicity and pulmonary toxicity, respectively. During a median follow-up of 9 months, 4 patients were confirmed as transformation to AML and 1 patient suffered from persistent marrow aplasia. One-year expected overall and failure-free survival was 82 ± 5% and 79 ± 6%, respectively in 108 patients.
Conclusion: AZA showed the equal activity in 4 risk groups on IPSS in patients with MDS. Not only the hematologic response but the cytogenetic response was similar between 4 groups.
SDF-1 Is Responsible for the Constitutively High NF-kB Activity in Human Myeloma Cells.
Authors: Islam Abul , Otsuyama Ken-ichiro , Amin Jakia , Abroun Saeid , Shamsasenjan Karim , Iqbal Mohd S. , Kawano Michio M. 
Published: October 2019

Abstract
The chemokine, stromal cell-derived factor 1 (SDF-1; CXCL12) and its receptor, CXCR4 are considered to be essentially required for plasma cell homing to the bone marrow (BM). It is well known that plasma cells in the BM (long-lived plasma cells) survive for a long time and have the constitutively high NF-kB activity. Since human myeloma cells are considered to be derived from these committed long-lived plasma cells, we investigated the role of SDF-1 on the survival of primary myeloma cells from myeloma patients and the possible relationship with NF-kB activity. First, we confirmed that all primary myeloma cells expressed CXCR4 but not CCR9 or CCR10 receptors on their surface and the levels of CXCR4 expression apparently correlated with maturity of BM plasma cells; mature myeloma cells (MPC-1+) as well as polyclonal plasma cells expressed higher levels of CXCR4 than those on immature myeloma cells (MPC-1-). The production of SDF-1 was found strongly in BM stromal cells but not in primary myeloma cells as well as myeloma cell lines. On the other hand, high DNA binding activity of NF-kB was constitutively detected in primary myeloma cells as well as myeloma cell lines, and these NF-kB activities significantly correlated with the expression levels of CD54 on their surface, for CD54 gene is one of the strict NF-kB target genes. Based on the expression levels of CD54 protein, interestingly, primary myeloma cells showed weaker NF-kB activities than those in monoclonal plasma cells from MGUS and polyclonal plasma cells from polyclonal gammopathy. Plasma concentrations of SDF-1 were also significantly correlated to the expression levels of CD54 on primary myeloma cells significantly (P<0.01). Furthermore, it was confirmed that addition of SDF-1 significantly increased the expression levels of CD54 in the in vitro culture of primary myeloma cells. Therefore, these results indicate that SDF-1 is responsible for high expression levels of CD54 and possibly the constitutively high NF-kB activity in primary myeloma cells.
The Mechanism of Constitutive NF-kB Activity in Myeloma Cell Lines.
Authors: Amin Jakia , Otsuyama Ken-ichiro , Islam Abul , Shamsasenjan Karim , Iqbal Shamim Mohd , Kawano Michio M. 
Published: October 2019

Abstract
[Purpose] NF-kB has a key function in the transformation, proliferation and invasion of cancer cells as well as in resistance to radiotherapy and chemotherapy. Although constitutive NF-kB activation has been reported in many human tumors, the underlying factors and mechanisms responsible for constitutive NF-kB activation in myeloma cells has not been known. The purpose of this study was to determine the mechanism of constitutive NF-kB activity in myeloma cell lines and quantification of NF-kB activity in primary myeloma cells by expression of CD54 (a NF-kB target gene).
[Methods] We checked the constitutive expression of NF-kB family proteins by western blot analysis and possible dimer formation of different NF-kB family members by Immunoprecipitation-western blot reaction. Constitutive NF-kB DNA-binding activity and dimers that are responsible for NF-kB activity were analyzed by electrophoretic mobility shift assay (EMSA). Moreover, expression of different NF-kB target genes was done by RT-PCR.
[Results and discussion] Constitutive NF-kB activity was determined in myeloma cell lines and our results suggested that p50/RelB, p50/p50, p50/p52 dimers might be responsible for this. We also analyzed several NF-kB target gene expressions and found that the intensity of CD54 expression was positively correlated with total NF-kB DNA binding activity. Although there is no method to quantified NF-kB activity, it can be determine in terms of its target genes e.g. CD54. Therefore, this study provide the frame work for understanding the molecular mechanism of constitutive activation of NF-kB and would help to quantify NF-kB activation in primary myeloma cells.
Monoclonal Gammopathy of Undetermined Significance with an IgE Paraprotein.
Authors: Ayto Robert M. , Lambert Christopher , Lampert Irvin , Salooja Nina 
Published: October 2019

Abstract
Monoclonal Gammopathy of Unknown Significance (MGUS) is a non-malignant condition characterized by a serum paraprotein, low numbers of plasma cells on bone marrow examination(<10%) and the absence of end organ damage. The transformation rate of MGUS to multiple myeloma is frequently quoted as about 1% per year. IgG, IgM and IgA paraproteins account for virtually all cases of MGUS with only the rare literature report of IgD or IgE isotypes. To our knowledge there is only one published case of IgE MGUS (Ludwig and Vormittag 1980; BMJ, 281:6239, 539–540). IgE Myeloma is an extremely rare entity and reported to have a comparatively poorer prognosis, but the incidence of pre-existing IgE MGUS is unknown. Here we report the case of a 74 year old gentleman with a stable low level IgE paraprotein. The patient presented in March 2003 for investigation of a persistent borderline normocytic anaemia recorded as 13.3g/dl at initial review (lower range of normal 13.5g/dl) with an ESR of 27mm/h. Co-morbidity included hypertension, ischaemic heart disease and hypercholesterolemia but general examination was unremarkable. Screening investigations revealed normal haematinics, renal function and corrected calcium. Analysis of immunoglobulins revealed mild immunoparesis of his IgM titre only (0.33g/l; Reference range 0.5–2.0g/l) and the presence of both a blood and urinary paraprotein. The blood paraprotein was quantified as 3g/l with immunofixation identifying kappa light chain restriction without the presence of one of the commonly encountered heavy chain isotypes (IgG, IgM or IgA). Further probing of the abnormal gamma globulin region revealed the paraprotein to be IgE in isotype. Immunofixation of a spot urine sample revealed kappa light chain restriction with a protein concentration of 0.03g/l. Bone marrow examination demonstrated 1% plasma cells on the aspirate with mild dysplastic change within the erythroid series. Cytogenetics were not performed. The trephine specimen revealed 10% plasma cells with strong immunostaining for IgE, dysplastic features within the megakaryocytic and erythroid lineages together with confirmation of kappa light chain restriction. Interestingly, recent further immunostaining of the original specimen revealed the plasma cells to be CD56-ve but cyclin D1 positive. Skeletal survey was normal. His investigations fulfil the WHO diagnostic criteria for MGUS, although it could be argued that with 10% plasma cells in the trephine biopsy, he could be classified as a borderline smouldering myeloma. Four years later, however, this gentleman remains well on routine follow-up with no evidence of myeloma related organ or tissue impairment. His most recent paraprotein from August 2007 is stable at 4g/l. The reporting of plasma cell dyscrasias with rare immunoglobulin isotypes should be encouraged to contribute to the bank of knowledge of these infrequently encountered entities.
The BCL9 Oncogene Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic and Angiogenic Properties to Myeloma Cells
Authors: Mani Mala , Dutta Jui , Zhang Yunyu , Carrasco Daniel E , Zhou Yiming , Gatt Moshe , Barlogie Bart , Shaughnessy John D. , Anderson Kenneth C , Carrasco Daniel Ruben 
Published: October 2019

Abstract
Wnt signaling plays an important role in tissue development and maintenance during embryogenesis, cell differentiation, and stem cell growth. Several components of the Wnt signaling cascade have been shown to function as either tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis. Deregulation of the canonical Wnt/b-catenin pathway has been implicated in numerous human epithelial malignancies as well as hematologic malignancies including multiple myeloma (MM), generating immense interest in these molecules as targets for cancer therapy. Activation of Wnt/b-catenin in cancer has been associated with mutations that enable b-catenin to escape degradation by the proteasome, thereby allowing its accumulation in the nucleus where it functions as a transcriptional regulator in conjunction with coactivators by constitutively activating target genes such as c-Myc and Cyclin D1. To date, however, no mutations in Wnt pathway have been documented in MM, suggesting that mechanisms other than gene mutation may contribute to Wnt pathway deregulation. BCL9, a key component of the Wnt pathway, is required for b-catenin transcriptional activity and resides on chromosome 1q21, a region frequently involved in secondary chromosomal aberrations associated with MM tumor progression. Here we provide evidence that dysregulation of BCL9 expression is a novel oncogenic mechanism of Wnt pathway activation in MM. Using in vitro and in vivo functional analyses, we demonstrate that BCL9 is a bonafide oncogene that is aberrantly expressed in MM and associated with survival. Using the TCF- specific luciferase reporter, we show that enforced expression of BCL9 in MM cells enhanced b-catenin mediated transcription by >12 fold, suggesting a possible role of BCL9 overexpression in the pathogenesis of MM. BCL9 enhanced proliferation (1.5 fold, P<0.02), migration (3.5 fold, P<0.0001) and the metastatic potential of MM cells. We also showed that BCL9 plays an important role in tumor progression by regulating Cyclin D1 and c-Myc mediated cell proliferation, CD44 mediated tumor metastasis, as well as VEGF mediated host angiogenesis. Importantly, BCL9 knockdown significantly increased the survival in a xenograft mouse model of human MM (P=0.001), associated with decreased tumor burden and host angiogenesis. In summary, we have demonstrated that BCL9 is a novel and potent oncogene of the Wnt pathway in MM, playing fundamental roles in tumor progression by regulating proliferation, migration, invasion, angiogenesis and the metastatic potential of tumor cells. The pleiotropic roles of BCL9 and its aberrant expression highlight its importance as an attractive and novel therapeutic target in the treatment of MM.
MicroRNA-29a Is An Oncogene in Acute Myeloid Leukemia
Authors: Park Christopher Y. , Han Yoon-Chi , Bhagat Govind , Fan Jian-Bing , Weissman Irving L , Gu Hua 
Published: October 2019

Abstract
microRNAs (miRNAs) are short, non-protein encoding RNAs that bind to the 3′UTR’s of target mRNAs and negatively regulate gene expression by facilitating mRNA degradation or translational inhibition. Aberrant miRNA expression is well-documented in both solid and hematopoietic malignancies, and a number of recent miRNA profiling studies have identified miRNAs associated with specific human acute myeloid leukemia (AML) cytogenetic groups as well as miRNAs that may prognosticate clinical outcomes in AML patients. Unfortunately, these studies do not directly address the functional role of miRNAs in AML. In fact, there is no direct functional evidence that miRNAs are required for AML development or maintenance. Herein, we report on our recent efforts to elucidate the role of miRNAs in AML stem cells. miRNA expression profiling of AML stem cells and their normal counterparts, hematopoietic stem cells (HSC) and committed progenitors, reveals that miR-29a is highly expressed in human hematopoietic stem cells (HSC) and human AML relative to normal committed progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors is sufficient to induce a myeloproliferative disorder (MPD) that progresses to AML. During the MPD phase of the disease, miR-29a alters the composition of committed myeloid progenitors, significantly expedites cell cycle progression, and promotes proliferation of hematopoietic progenitors at the level of the multipotent progenitor (MPP). These changes are manifested pathologically by marked granulocytic and megakaryocytic hyperplasia with hepatosplenomegaly. Mice with miR-29a-induced MPD uniformly progress to an AML that contains a leukemia stem cell (LSC) population that can serially transplant disease with as few as 20 purified LSC. Gene expression analysis reveals multiple tumor suppressors and cell cycle regulators downregulated in miR-29a expressing cells compared to wild type. We have demonstrated that one of these genes, Hbp1, is a bona fide miR-29a target, but knockdown of Hbp1 in vivo does not recapitulate the miR-29a phenotype. These data indicate that additional genes are required for miR-29a’s leukemogenic activity. In summary, our data demonstrate that miR-29a regulates early events in normal hematopoiesis and promotes myeloid differentiation and expansion. Moreover, they establish that misexpression of a single miRNA is sufficient to drive leukemogenesis, suggesting that therapeutic targeting of miRNAs may be an effective means of treating myeloid leukemias.
The Mir-17-19b Microrna Cluster Quantitatively Regulates the Self- Renewing Leukemia Stem Cell Compartment in MLL Leukemia
Authors: Wong Piu , Iwasaki Masayuki , Chen Chang-Zheng , Cleary Michael 
Published: October 2019

Abstract
The critical molecular determinants for leukemia stem cell (LSC) generation and maintenance are largely unknown. While the majority of studies focus on investigating key transcription factors and cytokines involved in hematological malignancies, very little is known about the roles of recently discovered microRNAs in leukemogenesis. Bioinformatic analysis of the Mouse Retroviral Tagged Cancer Gene Database (Neal Copeland et al.) revealed the 5′ regulatory region of the miR-142 gene as a recurrent target for retroviral integrations in a variety of mouse leukemia and lymphoma cancer models, including MLL-induced leukemia, thereby implicating miR-142 as a potential collaborating oncomir in hematologic malignancies. Subsequent expression analyses of differentially expressed microRNAs in LSC-enriched cell fractions (c-kit+) from MLL leukemias in comparison with various stages of normal hematopoietic progenitors indicated that the miR-17-5p family of microRNAs is highly expressed in LSC-enriched fractions and their possible normal counterparts, granulocyte-macrophage progenitors. Moreover, the expression of miR-142 and miR-17-5p family microRNAs was substantially reduced upon differentiation and loss of self-renewal in cells transformed by the conditional MLL-ENL-ER oncogene following withdrawal of tamoxifen. Forced expression of the miR-17-19b polycistron or miR-142 substantially shortened the latency for MLL leukemia development. In particular, leukemias expressing high levels of the miR-17-19b polycistron displayed a higher frequency of LSCs due to an efficient block of differentiation and enhanced proliferation associated with reduced expression of p21, a cyclin dependent kinase inhibitor previously implicated as a direct target of miR-17-19b microRNAs. Knock down of p21 in MLL oncogene transduced cells recapitulates the MLL-leukemic phenotype induced by over-expression of the miR-17-19b cluster including a significant decrease in MLL leukemia latency. This observation validates p21 as a biologically relevant in vivo target of the miR-17-19b polycistron in MLL leukemia. Thus, microRNAs are pathogenically important for quantitatively modulating the self-renewing LSC compartment in a murine model of MLL leukemia. Potential requirements of the miR-17-19b microRNA cluster for induction and/or maintenance of MLL leukemia are currently under study.
TRAF-1 Deficient Mice Show Impaired Monocyte Recruitment and Decreased Atherogenesis
Authors: Missiou Anna , Köstlin Natascha , Münkel Christian , Pfeifer Dietmar , Zirlik Katja , Bode Christoph , Libby Peter , Zirlik Andreas 
Published: October 2019

Abstract
Members of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFa, and IL-1b potently promote atherogenesis in mice and likely also in humans. TNF receptor associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. We recently reported over-expression of TRAFs in murine and human atheromata and demonstrated dependency of classic inflammatory functions on TRAFs in endothelial cells and macrophages. Here we test the hypothesis that TRAF-1 modulates atherogenesis in vivo. TRAF-1--/LDLR--mice fed a high cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions compared with LDLR--controls. Intimal lesion size decreased by up to 56±6% and 33±5% in sections of the aortic arch and aortic root, respectively (n>10 per group, P<0.01 each). Plaques of TRAF-1-deficient animals contained up to 46±9% and 55±4% fewer macrophages while smooth muscle cell content increased by up to 32±6 and 36±7%, characteristics associated with non disrupted plaques in humans. Lipid content, collagen content, and lymphocyte content remained unchanged. In vitro, gene expression profiling revealed reduced expression of adhesion molecules (VCAM-1, ICAM-1), chemokines (CCL2, CXCL2), and growth factors (M-CSF) in TRAF-1-deficient endothelial cells as well as of integrins (CD29, CD11b) and chemokines/chemokine receptors (CXCL2, CCR1) in TRAF-1-deficient macrophages, verified by siRNA studies in human cells. Finally, both deficiency of TRAF-1 in endothelial cells and neutrophils/monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic adhesion assays. We present the novel finding that TRAF 1 deficiency attenuates atherogenesis in mice, an effect most likely mediated by impaired monocyte recruitment to the vessel wall. These data identify TRAF-1 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.
ZKSCAN3, a Novel Zinc Finger Transcription Factor, Regulates Cyclin D2 Expression in Multiple Myeloma (MM) Cells
Authors: Yang Lin , Orlowski Robert Z. 
Published: October 2019

Abstract
Background: Dysregulation of cyclin D has been proposed to represent an early oncogenic event in MM, and often occurs as a result of chromosomal translocations. Cyclin D2 can be induced as a result of translocations involving c-maf, mafB, and FGFR3/MMSET, but its expression is also increased in hyperdiploid and nonhyperdiploid cells without these translocations through unknown mechanisms. We previously identified a novel zinc finger transcription factor, ZKSCAN3, as a new “driver” of colon cancer progression, and found that the cyclin D2 promoter harbored several ZKSCAN3 binding sites, prompting us to investigate a possible role of ZKSCAN3 in MM pathogenesis.
Methods: ZKSCAN3 expression was studied in patient-derived primary tumors and normal cells, as well as in human MM cell lines.
Results: Tissue microarray studies showed that ZKSCAN3 was strongly expressed in the neoplastic cells of 7/10 MM patients by immunohistochemistry, while in all samples the surrounding normal bone marrow cells showed only background staining. Real-time polymerase chain reaction (qPCR) analysis revealed some level of ZKSCAN mRNA expression in 5/5 MM cell lines studied (RPMI 8226, U266, KAS-6/1, INA-6, ANBL-6), but not in pooled CD19+ normal B-cells. By Western blotting, ZKSCAN3 was most highly expressed in RPMI 8226 and KAS-6/1 cells, which notably do not bear cyclin D dysregulating translocations, while U266 and ANBL-6, which have such translocations, showed the lowest levels of ZKSCAN3 expression. In RPMI 8226 cells, but not the other MM lines, six copies of the ZKSCAN3 gene were detected, suggesting the presence of a previous amplification event. cisRED analysis predicted that ZKSCAN3 may be transcriptionally regulated by paired box gene 5 (Pax5), an essential factor for maintaining the commitment of the B cell lineage which is inactivated during plasma cell differentiation. Consistent with a role for Pax5 in controlling ZKSCAN3 level, a reporter assay showed that Pax5 inhibited ZKSCAN3 promoter activity, and Pax5 expression negatively correlated with ZKSCAN3 expression. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed direct binding of ZKSCAN3 to the endogenous cyclin D2 promoter in these MM cell lines. Knockdown of ZKSCAN3 using short hairpin RNAs reduced Cyclin D2 mRNA and protein expression in RPMI 8226 and KAS-6/1 cells, and also decreased their proliferative rates.
Conclusions: These findings support the possibility that ZKSCAN3 contributes to myeloma pathogenesis by dysregulation of cyclin D2, and that events impacting upon ZKSCAN3 may provide MM cells with an alternative pathway for induction of Cyclin D2 in the absence of an activating translocation. ZKSCAN3 may therefore be an attractive candidate for MM therapy.