bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tumor Suppressor Role of the Msr1 Gene in Cancer Stem Cells of Chronic Myeloid Leukemia.
Authors: Chen Yaoyu , Sullivan Con , Li Shaoguang 
Published: October 2019

Abstract
Abstract 188
We have previously shown that the arachidonate 5-lipoxygenase gene (Alox5) functions as a critical regulator of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML) in mice (Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). We believe that the Alox5 pathway represents a major molecular network in LSCs. Therefore, we decided to further dissect this pathway by comparing gene expression profiles between wild type and Alox5−/− LSCs from CML mice using the DNA microarray analysis. We identified a small group of candidate genes that were changed in expression in the absence of Alox5. Among these genes, we have identified the Msr1 gene and chosen to test the function of this gene in regulating LSC function, because this gene was up-regulated, indicating that it might play a tumor suppressor role in LSCs. In our CML mouse model, we observed that recipients of BCR-ABL transduced Msr1−/− bone marrow cells developed CML much rapidly than recipients of BCR-ABL transduced wide type bone marrow cells. To test whether this accelerated CML is related to abnormal function of LSCs, we carried out a serial transplantation assay by transferring bone marrow cells from primary recipients of BCR-ABL-transduced wild type or Msr1−/− donor bone marrow cells into secondary and next-generation of recipient mice to biologically assess the effect of Msr1 on LSCs. BCR-ABL-expressing wild type leukemia cells from bone marrow of CML mice were only able to transfer CML once, whereas BCR-ABL-expressing Msr1−/− leukemia cells were able to transfer lethal CML for five genrations. This observation indicates that BCR-ABL-expressing Msr1−/− LSCs have markedly increased stem cell function. To further compare the stem cell function, we performed the leukemia stem cell competition assay by 1:1 mixing wild type (CD45.1) and Msr1−/− (CD45.2) bone marrow cells from CML mice. At day 25 or 30 after transplantation, more than 60% and 95% of GFP+Gr-1+ cells in peripheral blood of the mice were CD45.2+Msr1−/− myeloid leukemia cells, and all these mice developed CML and died of CML derived from Msr1−/− LSCs. To confirm the tumor suppressor role of Msr1 in CML development, we co-expressed BCR-ABL and Msr1 in MSR1−/− bone marrow cells by retroviral transduction, followed by transplantation of these cells into recipient mice. The ectopically-expressed Msr1 in MSR1−/− bone marrow cells rescued the accelerated CML phenotype, and some recipient mice did not even develop the CML. Together, these results demonstrate that Msr1 plays a tumor suppressor role in LSCs. The Msr1 pathway is a novel molecular network in LSCs, and it will be important to fully study this pathway for developing curative therapeutic strategies for CML.

Disclosures:
No relevant conflicts of interest to declare.
Lymphopenia Predicts Survival in Peripheral T-Cell Lymphoma, Unspecified.
Authors: Beltran Brady , Morales Domingo , Quinones Pilar , Desposorio Carlos , Sotomayor Eduardo , Castillo Jorge 
Published: October 2019

Abstract
Abstract 1930
Poster Board I-953
Background: Lymphopenia is an independent prognostic factor for survival for different hematological malignancies like follicular lymphoma, Hodgkin lymphoma and diffuse large B-cell lymphoma. The role of lymphopenia at diagnosis on survival in peripheral T-cell lymphoma, unspecified (PTCLU) is not known. Methods: Eighty seven patients with a diagnosis of PTCLU were evaluated at the Edgardo Rebagliati Martins Hospital in Lima, Peru from October 1997 until April 2008. The primary objective of the study was to assess the role of lymphopenia at diagnosis in survival in cases with PTCLU. Lymphocyte count at diagnosis was obtained from the standard complete blood cell count (CBC). Lymphopenia was defined as a lymphocyte count of less than 1 × 109/L. Kaplan-Meier survival estimates and the log-rank test were performed for univariate survival analyses and Cox proportion-hazard regression test was performed for the multivariate analysis. Results: Eighty four patients with a histological diagnosis of PTCLU were included in this study. The median follow-up was 13.4 months (range 1–68 months). The sample population included 54% males and 46% females with a median age of 57 years (range 18–87 years). The median number of lymphocytes at diagnosis was 1.3 × 109/L (range 0.06–5.2 × 109/L). Lymphopenia was present in 37% of cases. In the univariate analysis, lymphopenia was identified as a poor factor for survival (median OS 59 vs. 1 month; p<0.0001). In the multivariate analysis, lymphopenia was compared to the Prognostic Index for PTCLU (PIT) and it remained as an independent predictor for survival (Hazard Ratio 4.8, 95% confidence intervals 2.2–10.6; p<0.0001). Conclusion: This study demonstrates that lymphopenia is an independent prognostic factor for survival in patients with PTCLU, suggesting that the host immune system might play a preponderant role in survival in this group of patients.

Disclosures:
No relevant conflicts of interest to declare.
Comparison of Outcomes After Allogeneic HSCT for Adult Patients with AML in Remission Using in the Conditioning Regimen Either I.V. Busulfex (BU) Plus Cyclophosphamide (Cy) or TBI Plus Cy: An- ALWP-EBMT Survey.
Authors: Nagler Arnon , Labopin Myriam , Shimoni Avichai , Volin Liisa , Bunjes Donald W. , Huynh Anne , Buzyn Agnes , Rambaldi Alessandro , Rocha Vanderson 
Published: October 2019

Abstract
Abstract 195
TBI/CY and oral (p.o) Bu/Cy are the traditional allogeneic HSCT (alloHSCT) myeloablative conditioning regimens for adults with AML with comparable survival and relapse probabilities. Intravenous (i.v.) Bu in contrast to p.o Bu has more predictable pharmacokinetics and a more favorable toxicity profile. Post transplantation outcomes with i.v. Bu/Cy, thus, may be superior to those achieved with TBI/Cy. In order to address these issues, the ALWP of the EBMT performed a survey comparing i.v. Bu/Cy to TBI/Cy as conditioning regimen for adult pts. with AML undergoing alloHSCT. Overall, 603 alloHSCT were analyzed. One hundred pts. underwent alloHSCT with Bu/Cy while 503 with TBI/Cy. Age was 41 (range, 18–57) and 41 (range, 16–61) years and median transplant year was 2004 (2000 – 2005) and 2003 (2000 – 2005) for the Bu/Cy and TBI/Cy groups, respectively. Disease status at alloHSCT were CR1 – 81% vs. 78% and CR2–19% vs. 22% for the Bu/Cy and TBI/Cy groups, respectively. WBC count at diagnosis was 11×109/L and 15×109/L, respectively. Regarding the cytogenetic classification, 10% and 10% were good, 60% and 55% were intermediate and 9% and 6% were poor risk, respectively (data were NA for 21%–26% of pts). Sixty nine percent and 68% of both groups underwent alloHSCT from sibling donors, while 31% and 32% from MUD, respectively. Length of follow up was 37(15–86) and 57 (1–105) months for both groups, respectively. Sixty nine percent and only 41% of the Bu/Cy and TBI/Cy groups received PB, while 31% and 59% received BM grafts, respectively (p<0.0001). Engraftment was similar in the Bu/Cy vs. the TBI/Cy groups, 95% and 96%, respectively. Cumulative incidence of TRM at 2y was 17+4% and 23+2%, respectively (p=0.23). Acute GVHD (II–IV) was also similar between the 2 groups, 28% and 32%, respectively. Two year relapse incidence was 30+5% and 22+2% for Bu/Cy vs. TBI/Cy, respectively (p=0.03) while LFS was comparable 57+5% and 61+2%, respectively (p=0.5). In multivariate analysis Cy/TBI was found to be an independent good prognostic factor for reduce relapse rate (p=0.03, HR-1.67) and there was a trend for higher TRM (p=0.16). Poor prognostic factors for LFS and TRM were age >40y, disease status (CR2 vs. CR1) and MUD vs. Sib. donor. In conclusion, in this retrospective EBMT survey outcomes of alloHSCT in adult pts. with AML in CR using either i.v Bu/Cy or TBI/Cy were comparable.

Disclosures:
No relevant conflicts of interest to declare.
Inhibition of CRM1-Mediated Nuclear Export of Transcription FACTORS by Leukemogenic NUP98 Fusion Proteins.
Authors: Takeda Akiko , Abdul-Nabi Anmaar M , Yaseen Nabeel R. 
Published: October 2019

Abstract
Abstract 1959
Poster Board I-982
NUP98 is a nucleoporin that plays complex roles in the nucleocytoplasmic trafficking of macromolecules. Rearrangements of the NUP98 gene in human leukemia result in the expression of numerous fusion oncoproteins whose effect on nucleocytoplasmic trafficking is poorly understood. The present study was undertaken to determine the effects of leukemogenic NUP98 fusion proteins on CRM1-mediated nuclear export. NUP98-HOXA9, a prototypic NUP98 fusion, inhibited the nuclear export of two known CRM1 substrates: mutated cytoplasmic nucleophosmin (NPMc) and HIV-1 Rev. In-vitro binding assays revealed that NUP98-HOXA9 binds CRM1 through the FG-repeat motif in a Ran-GTP dependent manner similar to but stronger than the interaction between CRM1 and its export substrates. Two NUP98 fusions, NUP98-HOXA9 and NUP98-DDX10, whose fusion partners are structurally and functionally unrelated, interacted with endogenous CRM1 in cells as shown by co-immunoprecipitation. These leukemogenic NUP98 fusion proteins interacted with CRM1, Ran, and the nucleoporin NUP214 in a manner fundamentally different from that of wild-type NUP98. NUP98-HOXA9 and NUP98-DDX10 formed characteristic aggregates within the nuclei of myeloid cells and caused aberrant localization of CRM1 to these aggregates. These NUP98 fusions caused nuclear accumulation of two transcription factors, NFAT and NFΚB, that are regulated by CRM1-mediated export. The nuclear entrapment of NFAT and NFΚB correlated with enhanced transcription from promoters responsive to these transcription factors. Taken together, the results suggest a new mechanism by which NUP98 fusions dysregulate transcription and cause leukemia, namely, inhibition of CRM1-mediated nuclear export with aberrant nuclear retention of transcriptional regulators.

Disclosures:
No relevant conflicts of interest to declare.
miRNA29a Regulates Oncogenic SKI Expression in Acute Myeloid Leukemia (AML).
Authors: Teichler Sabine , Illmer Thomas , Stiewe Thorsten , Roemhild Josephine , Neubauer Andreas 
Published: October 2019

Abstract
Abstract 1968
Poster Board I-991

Introduction:
AML patients with deletion of chromosome 7 (−7) or deletion of 7q (−7q) have a poor prognosis. We have found that the nuclear oncogene SKI is overexpressed in AML, especially in AML with −7/−7q. SKI acts in AML as a repressor of retinoic acid induced myeloid differentiation (Ritter et al., (2006) Leukemia). As we found SKI up regulated in AML, we asked how SKI expression may be regulated. The aim of our study was to find a molecular background for increased SKI level. On chromosome 7 is a cluster of micro-RNAs (miRNAs) localized particularly around the fragile site 7q32 (Calin et al., (2003) PNAS). Therefore we investigated whether there exists a link between expression of miRNAs localized on chromosome 7 and up regulation of SKI expression in AML.

Methods:
We used micro RNA profiling analysis, FACS, Western blot, RQ-PCR and luciferase assays to determine the role of miRNA29a in regulating SKI expression.

Results:
We found that the expression of miRNA25, miRNA29a, miRNA183 and miRNA335 was downregulated in AML patients with -7/-7q. Transfection studies with these four miRNAs in HL60 cells revealed in FACS that miRNA29a inhibits SKI expression (60,4%) compared to nonsense control (100%) and other miRNAs (miRNA25: 91%, miRNA183: 101%, miRNA335: 93%). Western blot experiments confirmed that miRNA29a reduces SKI level in HL60 cells. In keeping, miRNA29a also represses expression of the SKI target gene Nr-CaM in IFB melanoma cells. Knock down of miRNA29a using miRNA29a inhibitor molecules induces SKI expression in the high miRNA29a and low SKI expressing cell line NW1539. Luciferase assays in NW1539 and HeLa transfected with 3′UTR-constructs and HeLa cells cotransfected with miRNA29a demonstrated that miRNA29a binds to 3′UTR of SKI in vitro. Furthermore, comparison of SKI and miRNA29a expression of AML patient samples indicates that miRNA29a expression is associated with low SKI level in vivo.

Conclusion:
Our data show that miRNA29a which is located on 7q32 regulates expression of the oncogene SKI in vitro and in vivo. We suggest the deletion of miRNA29a as mechanism for up regulation of SKI in AML with -7/-7q and thus propose that in AML, this effect may contribute to the tumor suppressive function of miRNA29a.

Disclosures:
No relevant conflicts of interest to declare.
Reduced Sensitivity of the Ferroportin Q248H Mutant to Low Concentrations of Hepcidin.
Authors: Xu Min , Foster Altreisha , Diaz Sharmin , Nekhai Sergei , Gordeuk Victor R. 
Published: October 2019

Abstract
Abstract 2002
Poster Board I-1024
The iron exporter protein, ferroportin (Fpn), is expressed by enterocytes and macrophages. It transports iron taken up from the gut by enterocytes to portal plasma transferrin and iron recycled by macrophages to systemic plasma transferrin. Hepcidin, which is secreted by hepatocytes, interacts with Fpn, leading to its internalization and degradation. Mutations that lead to decreased production of hepcidin or that reduce the sensitivity of Fpn to hepcidin lead to higher dietary iron uptake and increased parenchymal cell iron stores. The Fpn Q248H mutation, which is common in Africans and African-Americans, has been associated with increase serum ferritin concentrations in adults and with protection from iron deficiency in Zimbabwean children (Kasvosve et al., Am J Clin Nutr. 2005 82:1102-6). Other investigators have reported that the Fpn Q248H has normal sensitivity to hepcidin concentration of 0.5 mM (Drakesmith et al., Blood 2005 106:1092-7). We hypothesized that there may be differential sensitivity on the part of Fpn Q248H to lower levels of hepcidin (0.03-0.1 uM versus 0.5 uM). We subcloned WT and Q248H ferroportins to EGFP-expression vector, transfected 293T cells and measured EGFP fluorescence in response to hepcidin. We observed about 50% less reduction of Fpn Q248H-EGFP comparing to WT Fpn in response to 0.03 mM hepcidin treatment for 3 h but the effect was lost at 0.1 mM or higher concentrations of hepcidin or when the cells were treated with hepcidin for 18 h. This observation possibly explains why this mutation was previously not identified as having lower sensitivity to hepcidin. Similar results were obtained when Fpn was detected by immunoblotting or when ferritin concentrations were measured. Ferritin concentrations were higher in monocytes and macrophages derived from patients with Fpn Q248H mutation, suggesting that there may be differential sensitivity to hepcidin of Fpn expressed on macrophages versus enterocytes. Our results suggest that Africans and African-Americans with Fpn Q248H mutation may develop higher iron stores due to lower sensitivity of this Fpn mutant to low concentrations of hepcidin.

Acknowledgments.
This work was supported by NHLBI Research Grant 2 R25 HL003679-08 from the National Institutes of Health and The Office of Research on Minority Health (to VRG) and by Howard University Seed Grant (to SN).

Disclosures:
No relevant conflicts of interest to declare.
Allogeneic Stem Cell Transplantation (allo-SCT) for Chronic Lymphocytic Leukemia: a Long Term Analysis From the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).
Authors: Mohty Mohamad , Vernant Jean-Paul , Yakoub-Agha Ibrahim , Blaise Didier , Socié Gérard , Cordonnier Catherine , Deconinck Eric , Bourhis Jean-Henri , Guilhot François , Buzyn Agnes , Ifrah Norbert , Guyotat Denis , Harousseau Jean-Luc , Sutton Laurent , Milpied Noel-Jean , Michallet Mauricette 
Published: October 2019

Abstract
Abstract 201
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with a heterogeneous natural history. While some patients never require treatment or can be managed effectively with conventional chemotherapy, others experience early disease progression and death. Allo-SCT is increasingly considered as a therapeutic option for younger patients with poor-risk CLL.
This multicenter retrospective analysis assessed the long term outcome of 160 CLL patients who received allo-SCT between 1987 and 2005, and were reported to the SFGM-TC registry.
This series included 127 males (79%) and 33 females (20.6%) with a median age at CLL diagnosis of 45.5 (range, 24.4–65.1) y. The median age at time of allo-SCT was 50.9 (range, 29.8–68.3) y. Before allo-SCT, 26 patients (16.3%) received previous stem cell transplantation in the course of their disease. Patients received either a standard myeloablative conditioning regimen (n=58; 38%; Cy-TBI in 90% of cases) or a so-called reduced-intensity conditioning. A matched-related donor was used in 142 cases (89%) and PBSCs were used as source of stem cells in 92 cases (57.5%). At time of allo-SCT, only 10 patients (6.3%) were in CR1, 17 in CR2 and CR3 (10.6%), 27 in first PR (16.9%) and 106 (66.2%) in more advanced phases, including 46 patients (28.8%) in progressive disease.
With a median follow-up of 60 (range, 1.6–208) months for surviving patients, 96% of patients engrafted (ANC>500/μL) at a median of 18 (range, 1–41) days after allo-SCT. 71 patients (44.4%) experienced grade 2–4 acute GVHD, including 28 cases (17.5%) of grade 3–4 acute GVHD. 73 patients (56.2%) experienced some form of chronic GVHD. At time of last follow-up, 70 patients (43.8%) were still alive, of whom 24 (34%) were in continuous CR. Disease progression accounted for 24 deaths, while transplant-related causes (infections, n=23; GVHD, n=13; MOF, n=12; other causes, n=18) were observed in 66 cases, for a TRM rate of 41%. The KM estimates of disease-free survival (DFS) at 2, 5, and 10 years after allo-SCT were 44.3%, 39.6%, and 30.5%, respectively. Estimates of overall survival (OS) were 54.4%, 46.2%, and 35.8.1%, respectively. In a Cox multivariate analysis for OS (including demographic features, transplant and donor types, and disease status at time of allo-SCT), disease status at time of allo-SCT (CR or PR) was the most significant parameter associated with improved OS (RR=0.56; 95%CI, 0.36–0.89).
We conclude that allo-SCT has the potential to induce long-term disease control and overall survival in patients with high risk or advanced CLL.

Disclosures:
No relevant conflicts of interest to declare.
Splenectomy Exacerbates the Hypercoagulable State and Causes Significant Organ Dysfunction in Patients with Hemoglobin E/β-Thalassemia.
Authors: Atichartakarn Vichai , Chuncharunee Suporn , Archararit Napaporn , Udomsubpayakul Umaporn , Ingsathit Atiporn , Lee Ratchanee , Tunhasiriwet Anusith , Tanomsup Supachai , Aryurachai Katcharin , Ungkanont Artit , Niparuck Pimjai , Angchaisuksiri Pantep 
Published: October 2019

Abstract
Abstract 2014
Poster Board I-1036

Introduction:
Clinical manifestations of blood hypercoagulability, such as pulmonary arterial hypertension (PAH) and ischemic stroke, are well known in patients with thalassemia. We herein present evidence that the hypercoagulable state in β-Thalassemia disease patients is to a significant extent the result of prior splenectomy.

Patients and Methods:
One hundred and ten clinically stable hemoglobin E/β-Thalassemia outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). Clinical features and laboratory data were stratified according to the presence or absence of the spleen, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value <0.05 as statistically significant.

Results:
Of the 110 patients, 61 were asplenic and females comprised 51% in both groups. Selected statistically significant results are shown in the table.

Conclusions:
In comparison with non-splenectomized hemoglobin E/β-Thalassemia patients, asplenic ones have higher SPAP, more severe hemolysis, more liver impairment and chronic iron overload, significant chronic low grade inflammation, and evidence of coagulation activation. Splenectomy should be more judiciously applied than heretofore, and if performed, measures to blunt or prevent a subsequent hypercoagulable and inflammatory state, which could lead to PAH should be initiated.

Disclosures:
No relevant conflicts of interest to declare.
Count Recovery in AML Patients Achieving a Complete Response.
Authors: Rosinski Steven Lawrence , Ravandi Farhad , Faderl Stefan , Garcia-Manero Guillermo , Pierce Sherry , Kantarjian Hagop M. , Estey Elihu H. 
Published: October 2019

Abstract
Abstract 2062
Poster Board II-39
AML is typically defined as “de novo” or “secondary”, the latter referring to patients diagnosed only after persistent blood count abnormalities (AHD) or after prior “chemotherapy” (PCT) for other illnesses. Patients with secondary AML may have a different bone marrow microenvironment leading to prolonged neutrophil and platelet recovery times following induction chemotherapy. Accordingly, we compared time from start of chemotherapy to neutrophil recovery (>1,000/μl) and platelet recovery (>100,000/μl) in 424 patients who achieved a complete response (CR) following treatment with ara-C-containing induction therapy at MD Anderson Hospital from 1995 to 2008. We divided the 424 patients as follows: (1) no AHD, no PCT (236 patients); (2) AHD, no PCT (131 patients); (3) PCT, no AHD (28 patients); and (4) AHD and PCT (29 patients). Because time to recovery may also be influenced by cytogenetics and age we subdivided patients in each of the four groups according to age (< vs. ≥ 60) and cytogenetics (normal vs. complex or -5/-7). Despite very differing CR rates, time to neutrophil recovery in patients achieving CR while statistically longer in PCT patients (p=0.05) was from a medical standpoint essentially uninfluenced by AHD and PCT status (table, median delays 2 days with PCT). Platelet recovery was affected by such status (p<0.001) being delayed by a median of 6-8 days in patients who had received PCT. Age had no effect on time to neutrophil (p=0.42) or platelet (p=0.23) recovery, while complex or -5/-7 cytogenetics had a statistically significant (p=0.002 neutrophils, 0.009 platelets) but medically insignificant (median delays of 2 days) effect on recovery time. There was no interaction between age or cytogenetics and AHD or PCT status. A similar analysis in patients who do not achieve CR would be of interest, but might be confounded by the difficulty in distinguishing between the effects of chemotherapy and those of residual AML on count recovery. Our data suggest that older patients, patients with complex or -5/-7 cytogenetics, and patients with secondary AML should not be excluded from clinical trials because of concern about prolonged time to count recovery.
Group CRs CR Rate Median Days to > 1000 Neut Median Days to > 100,000 Plt No AHD no PCT 236 68% 27 28 AHD no PCT 131 50% 27 30 PCT no AHD 28 44% 29 34 AHD + PCT 29 35% 30 36 Age < 60 255 64% 28 29 Age ≥ 60 169 48% 26 30 Normal cyto 281 69% 27 29 Complex cyto or -5/-7 143 41% 29 31

Disclosures:
No relevant conflicts of interest to declare.