bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Role For Histone Deacetylase 11 (HDAC11) In Plasma Cell Differentation and Survival
Authors: Sahakian Eva , Brayer Jason B. , Powers John , Meads Mark , Distler Allison , Deng Susan , Alsina Melissa , Nishihori Taiga , Baz Rachid , Pinilla-Ibarz Javier , Sotomayor Eduardo M. , Shain Kenneth 
Published: October 2019

Abstract
The role of HDACs in cellular biology, initially limited to their effects upon histones, is now appreciated to encompass more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution, and the stage of cellular differentiation. Recently, our group has demonstrated that the newest member of the HDAC family of enzymes, HDAC11, is an important regulator of IL-10 gene expression in myeloid cells (Villagra A Nat Immunol. 2009). The role of this specific HDAC in B-cell development and differentiation is however unknown. To answer this question, we have utilized a HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allows the monitoring of the dynamic changes in HDAC11 gene expression/promoter activity in B-cells at different maturation stages (Heinz, N Nat. Rev. Neuroscience 2001). First, common lymphoid progenitors are devoid of HDAC11 transcriptional activation as indicated by eGFP expression. In the bone marrow, expression of eGFP moderately increases in Pro-B-cells and transitions to the Pre- and Immature B-cells respectively. Expression of eGFP doubles in the B-1 stage of differentiation in the periphery. Of note, examination of both the bone marrow and peripheral blood plasma cell compartment demonstrated increased expression of eGFP/HDAC11 mRNA at the steady-state. These results were confirmed in plasma cells isolated from normal human subjects in which HDAC11 mRNA expression was demonstrated. Strikingly, analysis of primary human multiple myeloma cells demonstrated a significantly higher HDAC11 mRNA expression in malignant cells as compared to normal plasma cells. Similar results were observed in 4/5 myeloma cell lines suggesting that perhaps HDAC11 expression might provide survival advantage to malignant plasma cells. Support to this hypothesis was further provided by studies in HDAC11KO mice in which we observed a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Taken together, we have unveiled a previously unknown role for HDAC11 in plasma cell differentiation and survival. The additional demonstration that HDAC11 is overexpressed in primary human myeloma cells provide the framework for specifically targeting this HDAC in multiple myeloma.

Disclosures:
Alsina: Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Baz:Celgene Corporation: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding.
Bone Marrow Fibrosis In Patients With Multiple Myeloma: A New Prognostic Factor For Survival?
Authors: Hallgrimsdottir Tinna , Porwit Anna , Björkholm Magnus , Rossmann Eva , Steingrimsdottir Hlif , Lund Sigrun Helga , Kristinsson Sigurdur Y 
Published: October 2019

Abstract

Introduction
Multiple myeloma (MM) is characterized by the proliferation of plasma cells in the bone marrow and a secretion of monoclonal immunoglobulins. Survival in MM is very variable and multiple factors are known to influence prognosis such as age, ISS stage, and genetic abnormalities. Fibrosis can be found in the bone marrow of MM patients but the literature reporting the incidence of fibrosis and its effect on prognosis is very limited.
The purpose of this study was to estimate the incidence of bone marrow fibrosis in MM patients and its effect on survival.

Materials and methods
Data was collected at the Karolinska University Hospital in Solna, Sweden and information obtained from the hospital's records. We gathered information on all patients diagnosed with MM between 2003 and 2011. All bone marrow reports were reviewed and the presence of bone marrow fibrosis (evaluated using reticulin staining) at diagnosis was recorded. Fibrosis was graded as 1 (mild), 2 (significant) and 3 (advanced), in accordance with WHO 2008 criteria. Patients with fibrosis were paired with patients without fibrosis (matched by sex, birth year, and year of diagnosis). Survival comparing MM patients with and without fibrosis was evaluated using Kaplan-Meier estimate and Cox regression model.

Results
A total of 586 individuals, 327 males and 259 females, were diagnosed with MM at the Karolinska University Hospital, Solna during 2003 – 2011. Evidence of bone marrow fibrosis was noted in 223 (38%) patients at diagnosis, and 175 had fibrosis grade 1, 33 grade 2, and 15 grade 3. No significant difference was observed between males (N = 135) and females (N = 88) (p = 0.085). Mean age at diagnosis was significantly lower for patients with fibrosis (67.1 years) than in patients without fibrosis (69.7 years) (p = 0.013).
Compared with paired patients without fibrosis (N = 217), patients with fibrosis had significantly worse survival (Figure), being 5.0 years vs. 4.4 years, respectively (relative risk (RR)=1.3, 95% confidence interval (CI) 1.00-1.70; p= 0.049). The difference was greatest in male patients and patients younger than 65 years at diagnosis. Survival was worse in patients with advanced fibrosis, 4.5 (95% CI 3.6-6.4) years for grade 1 fibrosis, and 3.0 (95% CI 1.6-NA) years for higher degree of fibrosis.

Conclusion
In this study, based on almost 600 patients with MM we show that bone marrow fibrosis is common at diagnosis (38%). Importantly, our findings show that the presence of fibrosis was associated with inferior survival. More studies are needed regarding the underlying causes for these findings, including treatment response, treatment-related complications and relation to other known prognostic factors.

Disclosures:
No relevant conflicts of interest to declare.
Arming An Anti-CD38, Myeloma-Targeting Antibody With An Attenuated IFNα Provides >10,000-Fold Enhanced Tumor-Specific Activity Compared To Native IFNα
Authors: Pogue Sarah L. , Taura Tetsuya , Bi Mingying , Mikesell Glen E. , Yun Yong , Sho Angela , Sanchez Eric , Chen Haiming , Berenson James R. , Wilson David S. 
Published: October 2019

Abstract
Interferon-α (IFNα) exerts profound apoptosis-inducing activity on myeloma cells, but only at concentrations 10-100-fold above those clinically achievable due to dose-limiting toxicities. In colony forming assays, all multiple myeloma (MM) samples tested (8 primary myelomas and 2 cell lines) were sensitive to high doses of IFNα. Furthermore, very high doses of IFNα prevented MM tumor growth in 2 primary MM xenograft models (LAGk-2 and LAGk-1A). In order to exploit this potential of IFNα, we sought to improve its therapeutic index by increasing its activity towards myeloma cells relative to normal cells. Tumor-specificity can be modestly increased by attaching IFNα to an anti-CD38 antibody, thus targeting it to MM cells. Here we demonstrate that by introducing an attenuating mutation into the IFNα portion of this fusion protein, the IFNα activity is reduced by >10,000 fold on CD38 negative cells while it exerts similar potency on CD38+ MM cells compared to native IFNα. We show that direct in vitro killing activity of this anti-CD38-attenuated IFNα fusion protein on CD38+ myeloma cells is comparable to free IFNα, however, the activity of this fusion protein is reduced by ∼10,000 fold if the CD38 antibody is replaced by an antibody of irrelevant specificity, or if CD38- cells are used in the assay. In addition, we tested activity of the anti-CD38-attenuated INFα fusion protein in the H929 MM xenograft model and found that a single dose at 10mg/kg was sufficient to completely eradicate established tumors (150mm3) in 10/10 mice. Furthermore, when mice with starting tumor volumes of >700mm3 were treated for 3 weeks, we saw complete regression of these large tumors, an effect not observed with other MM agents tested. Our findings suggest that by administering this fusion protein to patients, it may be possible to target the robust tumor-killing activity of IFNα to the myeloma cells, with minimal toxic effects resulting from IFN’s activity on normal cells.

Disclosures:
Pogue: Teva Pharmaceuticals: Employment. Taura:Teva Pharmaceuticals: Employment. Bi:Teva Pharmaceuticals: Employment. Mikesell:Teva Pharmaceuticals: Employment. Yun:Teva Pharmaceuticals: Employment. Sho:Teva Pharmaceuticals: Employment. Wilson:Teva Pharmaceuticals: Employment.
Clinical Presentation and Treatment Responses In IgM-Related AL Amyloidosis
Authors: Sissoko Moussa , Sanchorawala Vaishali , Seldin David C , Sworder Brian , Berk John L , Sloan John Mark 
Published: October 2019

Abstract
AL amyloidosis is a multiorgan disease due to deposition of misfolded monoclonal immunoglobulin light chains. AL amyloidosis associated with IgM paraproteinemia is a rare variant of this disease, constituting approximately 6% of AL amyloidosis cases in the literature. The clonal cell of origin may be a plasma cell or a lymphoplasmacytic cell, and treatments targeting each of these populations have been employed. This study defines the clinical and laboratory characteristics of IgM-related AL amyloidosis patients as well as their response to different therapeutic regimens.
We identified 94 patients with IgM-related AL amyloidosis evaluated at the BUMC Amyloidosis Center from 2003 through 2012 for which data was available on 50 who completed treatment. The median age at diagnosis was 65 years (range: 42-79 years) with 31 (62 %) males. The most commonly involved organ was the kidney (59%) followed by heart (37%) and GI tract (22%). The mean IgM was 1049 g/dL (range: 29-9130). The clonal population had lambda light chain restriction in 34 (68%) of patients. Patients were categorized into 5 treatment groups: high-dose melphalan/stem cell transplant (HDM/SCT), bortezomib-based, non-transplant alkylating agents based (melphalan or cyclophosphamide), immunomodulatory agents (IMiDs), and rituximab-based. This grouping was not mutually exclusive. The highest hematologic response rate was observed with HDM/SCT (10/10: 100%), followed by non-transplant alkylating agents (16/22: 73%), bortezomib (7/10: 70%) rituximab (9/13: 69%) then by IMiDs (2/4: 50%). We did not observe an association between positive response to treatment and organ involvement, sex or age at diagnosis.
In conclusion, IgM-related ALamyloidosis is an unusual variant of AL amyloidosis. Multiple active therapies with different mechanisms of action exist; treatment should be tailored based upon clinicopathologic and patient-specific factors.

Disclosures:
Sloan: Millenium: Consultancy.
Two Photon Intravital Microscopy Reveals CD4+ T Cells Making Cognate Interactions With Tissue Dendritic Cells In Skin Graft-Versus-Host-Disease
Authors: Morin-Zorman Sarah , Wysocki Christian , Kisanga Edwina , Gonzalez David , Rothstein David , Lakkis Fadi , Haberman Ann , Shlomchik Warren D 
Published: October 2019

Abstract
Graft-versus-host disease (GVHD) limits the broader application of allogeneic hematopoietic stem cell transplantation. In prior studies we defined roles for both host and donor-derived antigen presenting cells (APCs) in the activation of alloreactive donor T cells and promotion of GVHD. While initial T cell activation in GVHD occurs predominantly in secondary lymphoid organs (SLO), we have consistently observed MHCII+ donor-derived tissue APCs (t-APCs), including tissue dendritic cells (t-DCs) in histopathologic GVHD lesions, frequently adjacent to infiltrating T cells. We hypothesize that productive interactions occur between donor APCs and T cells in situ in GVHD target tissues, which propagate disease locally. We could not use knockout or APC depletion approaches to study T cell: t-APCs interactions as they impact APCs systemically and might therefore affect T cell stimulation in SLO. We therefore utilized two-photon intravital microscopy to analyze interactions between fluorescent donor CD4+ T cells and t-DCs in skin. 129 (H-2b) hosts were irradiated and reconstituted with B6 (H-2b) CD11c-YFP transgenic (Tg) Bone Marrow (BM) with B6 RFP Tg CD4 cells and nonfluorescent B6 CD8 cells. We imaged ear skin in GVHD mice 4 weeks later. In general CD4 cells co-localized with DCs. We observed CD4+ T cells that were highly motile and only in transient contact with DCs and others that made stable contact with DCs. To determine how much TCR: MHCII interactions drive sustained CD4+ T cell: DC interactions and arrest CD4+ T cell motility, mice were imaged and then injected with an MHCII blocking antibody (Ab; Y3P) with continued imaging of the same regions. After injection, T cell mean speed significantly increased and the proportion of T cells in stable contact with DCs decreased, indicating that transient disruption of TCR: MHCII is sufficient to restore motility to some T cells. In a second approach to assess the specificity of CD4+ T cell: t-DC interactions we transplanted 129 mice with B6 RFP+ CD4 cells, nonfluorescent CD8 cells and a mix of CD11c-YFP MHCII-/- and RFP wt BM or a mix of CD11c-YFP wt and RFP Tg MHCII-/- BM. We are currently comparing the motility of CD4 cells that make contact with MHCII+ as compared to MHCII- DCs, with the prediction that contact times will be shorter with the latter. Our data suggest that CD4+ T cells make cognate interactions with t-DCs in skin and we hypothesize that these interactions promote GVHD locally. Because the graft-versus-leukemia effect occurs primarily in bone marrow and secondary lymphoid tissues, targeting of tissue-infiltrating APCs could represent a unique strategy to ameliorate GVHD while preserving GVL.

Disclosures:
No relevant conflicts of interest to declare.
Role Of Double Stem Cell Transplantation For Newly Diagnosed Multiple Myeloma In The Era Of Novel Agents
Authors: Hagiwara Shotaro , Hirai Risen , Nakamura Miki , Tanimura Akira , Takeshita Masataka , Miwa Akiyoshi 
Published: October 2019

Abstract

Background
Autologous stem cell transplantation (ASCT) has been a part of the standard therapy for newly diagnosed multiple myeloma and several studies showed double ASCT improved the outcome in comparison with single ASCT, especially the patients who failed to achieve very good partial remission (VGPR). Recently, the introduction of novel agents significantly improved the response rate of the treatment for the multiple myeloma. Although ASCT is still crucial for newly diagnosed myeloma patients, the role of the double ASCT is unclear in the era of novel agents. We performed a single institution-based retrospective study.

Methods
We reviewed the medical records of patients who treated with ASCT for multiple myeloma between January 2001 and April 2013 in National Center for Global Health and Medicine, Tokyo, Japan. The regimen of the remission induction therapy, number of stem cell transplantations, survival after the first ASCT, progression free survival, the response after the induction therapy and the first ASCT were analyzed.

Results
Since 2001, we performed ASCT for 167 patients. Ninety-three patients were treated with double ASCT, and 2 patients were treated with tandem ASCT–allogeneic SCT. In 127 patients were treated with vincristine, adriamycin, and dexamethasone (VAD) as an induction therapy, and 40 patients were treated with bortezomib and dexamethasone (BD). Very-good-partial-remission (VGPR) or complete remission (CR) was obtained in 25.2%, 34.6% of the patients treated with VAD, and in 45.7%, 54.3% with BD regimen before and after the transplantation respectively. Overall survival (OS) and progression free survival (PFS) did not differ significantly between VAD and BD induction, the estimated 2 year-OS was 89.8% vs. 79.5%, and the 2 year-PFS was 43.2% vs. 63.5% respectively. Double transplantation improved PFS and OS in VAD induction than single transplantation (p=0.000, p=0.002). In BD induction, patients who failed to achieve VGPR or better after the first ASCT, double transplantation improved OS (p=0.010) but not PFS. In both VAD induction and BD, there was no significant survival benefit in double transplantation in patients who achieved VGPR or better.

Conclusion
The achievement of VGPR or better after the ASCT resulted in significantly better PFS. The role of double transplantation is still crucial for patients with inadequate response after the first ASCT even in the era of novel agents.

Disclosures:
No relevant conflicts of interest to declare.
Incidence Of Symptomatic Venous Thromboembolism In Patients With Hemophilia Undergoing Joint Replacement Surgery: A Retrospective Study
Authors: Botero Juliana Perez , Spoon Daniel B , Patnaik Mrinal M , Trousdale Robert T , Pruthi Rajiv K 
Published: October 2019

Abstract

Background
Hip and knee arthroplasty (THA and TKA), in general, pose a high risk for venous thromboembolism (VTE), and pharmacologic VTE prophylaxis is often strongly recommended. In patients (pt) with hemophilia undergoing THA/TKA, given the underlying bleeding diathesis, the routine use of pharmacologic VTE prophylaxis is controversial. In this study, we report THA/TKA outcomes in pt with hemophilia in our institution.

Methods
Retrospective chart review of Mayo Comprehensive hemophilia center pt undergoing THA and TKA. Medical records were reviewed for objectively documented VTE for up to 3 months after surgery.

Results
42 consecutive pt with hemophilia A (n=38) or B (n=4) underwent 71 operations: THA (n=32) and TKA (n=39) over a period of 39 years. All pt received compression stockings up to 6 weeks after surgery; 6/71 (8.4%) received sequential intermittent compression and 2/71 (2.8%) received postoperative low molecular weight heparin (LMWH). Symptomatic femoral vein DVT occurred in 1/42 pt (2%); (1/71, 1.4% of operations (1.4%)), 10 days after THA for traumatic hip fracture and after the LMWH was discontinued. The patient was subsequently found to be heterozygous for the factor V Leiden gene mutation. For up to 3 months after surgery, there were no additional cases of symptomatic DVT. There was no unexpected bleeding in the 2 patients receiving LMWH.

Conclusion
In this this study, routine use of compression stockings without the use of pharmacologic prophylaxis resulted in a low rate of symptomatic VTE in patients with hemophilia. This may be similar to the incidence in the general population receiving LMWH (Heit, JA et al Annals of Internal Medicine 2000) A limited sample size precludes definitive recommendations for practice. For appropriate high risk patients, limited use of pharmacologic prophylaxis may still be important.

Disclosures:
No relevant conflicts of interest to declare.
Arginine Methylation Of RBM15 By PRMT1 Controls Alternative Splicing Of Genes Involved In Megakaryocyte Differentiation
Authors: Zhao Xinyang , Zhang Li , Wang Rui , Trans Ngoc Tung , Su Hairui , Abdel-Wahab Omar , Hrick Todd , Levine Ross L. , Deng Haiteng , Liu Yanyan , Zheng Yujun , Luo Minkui 
Published: October 2019

Abstract
More than 90% of under one year old infants with acute megakaryoblastic leukemia (AMKL) have chromosome translocation t(1;22)(p13;q13) with RBM15 fused to MKL1. RBM15 encodes an RNA binding protein important for hematopoietic stem cell self-renewal and differentiation. In agreement with its roles in AMKL, RBM15 is required for normal megakaryocyte differentiation. We found that higher expression of PRMT1 (Protein Arginine Methyltransferase) is commonly seen in M7 leukemia patient samples than other types of myeloid leukemia and that RBM15 is a bona fide methylation target for PRMT1. Using mass spectrometry analysis, we mapped the PRMT1 mediated mono-methylated site. The enzymatic activity of the PRMT1 V2 isoform is required for RBM15 degradation, as both shRNA molecules knocking down PRMT1 and small chemical PRMT1 inhibitors stabilize the RBM15 protein. Mutation of the methylation site to lysine blocks the ubiquitylation mediated degradation. Thus the degradation is a methylation dependent process. We identified the E3 ligase responsible for the degradation. Down-regulation of the RBM15 protein changes the isoform ratio of genes including GATA1 critical megakaryocyte differentiation. We found that RBM15 regulates its interaction with SF3B1A in methylation dependent manner during alternative splicing of GATA1 pre-mRNA. Thus, via methylation triggered RBM15 degradation, the megakaryocyte progenitor cells maintain a delicate balance between differentiation and proliferation by keeping the proper ratio of GATA1s and GATA1-full length mRNA. SF3B1A has been shown to be mutated in myeloid dysplasia syndrome and in several different types of leukemia. Methylation by PRMT1 links the two types of leukemic genes into a single pathway. Our results imply that targeting PRMT1/RBM15 pathway might be a potential therapy for AMKL and other blood malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Multivariate Analysis Reveals a miRNA Profile Correlated To Karyotype and Outcome In Pediatric B-Cell Precursor ALL
Authors: Vasquez Marina Lipkin , Volinia Stefano , Fernandez Cecilia , Zanesi Nicola , Fazio Grazia , Zalcberg Ilana Renault , Garzon Ramiro , Cazzaniga Giovanni , Biondi Andrea , Croce Carlo M. 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer and is characterized by the presence of recurring structural genetic alterations that have been associated to clinical response.Recently it has been shown that the deregulation of microRNAs (miRNA), a class of small RNAs that negatively control gene expression, is a common characteristic of hematological malignancies and may be related to the pathogenesis of leukemias. The aim of the current study was to explore which microRNAs are expressed by each subtype of pediatric B-cell precursor ALL and to determine their roles into clinical outcome. We analyzed samples from 94 children diagnosed as B-cell precursor ALL in Italy between 2000 and 2010 that were included in the AIEOP-BFM protocol of treatment. The patients were divided by cytogenetic subgroups of ALL. Cells CD34+ and CD19+ from healthy donors were used as negative controls. The miRNA signature was studied using microchips for miRNA microarray. We first performed a two-class comparison of miRNA expression between leukemic and non-leukemic samples and found 84 miRNAs differently expressed (P<0.01). A multivariate analysis of karyotype showed that 59 of these miRNAs were correlated to leukemia (P<0.01). All major subtypes of precursor B-cell ALL were analyzed: MLL-rearranged (10), TEL-AML1(15), E2A-PBX1(10), BCR-ABL(23), hyperdiploid(17), ‘normal Karyotype’ (19, defined as those not carrying the foregoing cytogenetic aberrations), and also the presence of IKAROS deletions was evaluated. Each subgroup was found to have unique microRNA-signature that differed from each other and from those of healthy hematopoietic cells. Both Kaplan Meier and Cox regression tests were performed to check how many of these miRNAs were correlated to clinic response, based on the induction failure, relapse, and survival. A multivariate analysis revealed that genetic subtypes and poor-responders patients display characteristic miRNA signatures. Specifically the mir-125b, 16-2, 24, 28-5p, 128a, 138-1 and 658 (all P<0.01) came out as independent prognostic factors predictive of event-free survival (EFS). IKAROS deletions did not come out as an independent prognostic factor, probably for being already associated to Ph+ and “BCR-ABL like” patients, who already have a poor prognosis. In addition, our group has previously shown that miR-125b may act as an oncogene and is correlated to a poor response in Ph+ samples, also increasing therapy resistance and leukemia aggressiveness in vivo. Further functional studies are needed to better explain the role of these miRNA and to provide new insights into the biology of pediatric ALL.

Disclosures:
Garzon: Karyopharm : Research Funding.