bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome Comparison of Lymphoma and Myeloma Patients after Autologous Stem Cell Transplantation (ASCT) with Peripheral Blood Stem Cell Mobilization Between Plerixafor (P) Mobilized in Poor Mobilizer Patients and Non-Plerixafor Mobilized Patients
Authors: Malik Shahbaz A. , Yanovich Saul , Rapoport Aaron P. , Badros Ashraf Z , Hardy Nancy M. , Kocoglu Mehmet H. , Duffy Alison , Ruehle Kathleen , Nishioka Jennifer , Goloubeva Olga , Yared Jean 
Published: October 2019

Abstract
Background: P is used in combination with G-CSF to improve the mobilization of peripheral blood hematopoietic stem cells in poor mobilizers. Limited data are available in regard to effects of P on post-transplant outcomes in comparison with non-P chemomobilized patients.
Methods: In this retrospective study, we compare the engraftment and the outcomes of 34 patients mobilized with P + G-CSF or just-in-time rescue P in combination with chemotherapy and G-CSF to 143 patients (control group) mobilized with G-CSF with or without chemotherapy in lymphoma and myeloma patients who underwent ASCT between February 2012 and April 2014 at the University of Maryland Greenebaum Cancer Center. Post-transplantation outcomes including infections, hematologic recovery, relapse, progression and survival were recorded.
Results: The median number of collected of CD34+ cells/Kg was 5.9 x 10(6) in the P group and 12.3 x 10(6) in the control group (p=0.0002). Median time to neutrophil engraftment (>0.5 × 10(9) /L) was comparable between the 2 groups: 12 days for the P group and 11 for the control group (p=0.28). There was a trend toward a shorter time to platelet engraftment (>20 × 10(9) /L) in the control (12 days) compared to the P group (14 days) (p=0.056). Progression-free survival at 1 year after (ASCT) was 88.2% in the P group and 81.8% in the control group. There was no difference in the overall survival of both groups (p=0.62)
Conclusions: Short and long-term engraftment and outcomes after ASCT seem to be comparable in lymphoma and myeloma patients receiving plerixafor compared to chemomobilized patients without plerixafor. This observation support the use of plerixafor + G-CSF or just-in-time rescue P in patients who mobilize poorly without P.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Effect of Body Mass Index on Overall Survival of Patients with Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Xue Shengli , Yang Jing , Zhang Xiang , Shen Yueping , Depei Wu 
Published: October 2019

Abstract
AIM: The present study was performed to investigate the association between body mass index (BMI) before transplantation and the overall survival (OS) of patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT).
METHODS: Data from 310 adults who were diagnosed with acute leukemia and underwent allo-HSCT between March 2001 and December 2011 were analyzed. Demographic and clinical data were collected from medical records. In accordance with the suggested BMI categories for Asian population, patients with BMIs of ≥23 and ≥25 kg/m2 were identified as overweight and obese, respectively. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, which were adjusted for possible confounding factors.
RESULTS: The median follow-up time among the patients was 19.7 months (interquartile range = 8.1 to 37.7). A total of 93 (34.8%) patients died within the follow-up period. After adjusted for the potential confounders, normal-weight, overweight, and obese patients showed significantly lower HRs than underweight patients, with a significant trend of OS improvement upon increasing BMI (P = 0.019). Overweight and obese patients survived longer, with a significantly decreased HR by approximately 40% (HR = 0.60;95% CI: 0.38 to 0.95) compared with underweight and normal-weight patients.
CONCLUSIONS: An increased OS was seen in allo-HSCT patients with BMI≥23 compared to those with lower BMI. Further studies are required to obtain better understanding of the effects of BMI or body composition on the survival of allo-HSCT patients.

Disclosures
No relevant conflicts of interest to declare.
A Novel Compound Inhibits Chronic Myeloid Leukemia Via Upregulating Apoptosis
Authors: Xin Jiajia , Yin Dandan , Fu Wei , Zhang Hui-Jie , Chen Yaozhen , Wang Yazhou , Li Mingkai , Hu Xingbin 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is a myeloid proliferative disorder mainly result from chimeric protein BCR-ABL1 encoded by a fusion gene at the t(9;22) (q34;q11) chromosomal translocation. Intrinsically, this recombined protein results in an increased tyrosine kinase (TK) activity that directly related to hematopoietic stem cell malignant proliferation. Consequently, the drugs derived from tyrosine kinase inhibitors (TKI) have been developed as an infective therapy, and greatly improved patients survival in clinic. Unfortunately, single TKI administration led to toxicities or tolerance in long-term treated CML patients. Even worse is, about 5% CML patients were not caused by bcr-abl gene mutation. Thus better medicines are badly needed to compensate CML therapy. Herein, we investigated the undefined function of a biscoumarins. The new synthesized compound exhibited a null toxicity on HUVECs but intensive toxicity on K562 leukemic cells. Subsequent results demonstrated that it efficiently inhibited the expansion of human CML cell line and bone marrow cells of SCL-tTA-BCL/ABL transgenic model mice via increased apoptosis. Critically, we also showed that CD34+ bone marrow leukemic cells collected from patients underwent more apoptosis after treated by the biscoumarins derivate. To extend these results into vivo, we observed a prolonged survival of bcr-abl transgenic mice treated by derivate mono-therapy or combination with imatinib compared to those of untreated or imatinib-treated CML mice. All together, these results indicated that this biscoumarins derivate may have novel potential as a therapeutic agent against CML.

Disclosures
No relevant conflicts of interest to declare.
Blastic Plasmacytoid Dendritic Cell Neoplasm: A Single-Center Experience Documenting Frequent CNS Involvement
Authors: Eulitt Patrick , McNally Gretchen A. , Porcu Pierluigi , Klisovic Rebecca B. , Vasu Sumithra , Baiocchi Robert A 
Published: October 2019

Abstract
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is a rare myeloid malignancy that often manifests with skin, lymph node, and bone marrow involvement. Patients diagnosed with BPDCN have a poor prognosis, with a median overall survival ranging from 12-14 months (Julia et al., 2014). Aoki et. al (2015) published a retrospective review reporting overall survival at 4 years for patients who underwent autologous and allogeneic hematopoietic stem cell transplant (HSCT) as 82% and 53%, respectively. Progressive disease, including central nervous system (CNS) involvement, excludes patients from receiving HSCT. Published case reports suggest that CNS presentation at diagnosis is rare, with estimates of only 10% of patients with CNS involvement at diagnosis (Feng et al., 2014; Starck et al., 2014). A retrospective case series of all patients treated for BPDCN at The Ohio State University from 1990 to present (n=11) was performed. Demographic data is summarized in table 1. Four of five patients undergoing CNS evaluation at diagnosis were found to have CNS involvement. All eleven patients underwent chemotherapy with the majority receiving induction chemotherapy (table 1). Three of the four patients with known CNS involvement at diagnosis expired within three months. The fourth patient survived with significant neurological complications secondary to intrathecal chemotherapy and was not a HSCT candidate. Two of eleven patients underwent HSCT. One died from relapsed disease in bone marrow, and one achieved long-term progression free survival. Two patients were lost to follow up, and were 7 and 16 months past diagnosis at last contact. CNS involvement with BPDCM at diagnosis may be more common than the literature suggests and should be investigated at diagnosis to allow these patients the best chance of long-term survival.
Table 1. Patient characteristics and treatment summary Mean age at diagnosis 61.4 years Stage at diagnosis IV: 81.8% I: 18.2% BM involvement at diagnosis Yes: 81.8% No: 18.2% CNS involvement at diagnosis Yes: 36.4% No: 9.1% Unknown: 54.5% CNS involvement during clinical course Yes: 63.7% No: 18.2% Unknown: 18.2% Chemotherapy Hyper-CVAD: 45.5% CHOP: 18.2% EPOCH: 18.2% Clinical Trial: 18.2% SCT Yes: 18.2% No: 72.7% Unknown:9.1% Survival < 12 months: 45.5% 12-24 months: 27.3% >24 months: 18.2% Lost to follow up: 18.2% Median time to death in months 10.0* (range 1-26) *Time to death calculation excluded two patients lost to follow-up and two patients that are still living

Disclosures
Porcu: Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Shape: Research Funding; Celgene: Research Funding.
EGFR Signaling in Osteoblasts Regulates Circadian Rhythm of HSPC in Circulation
Authors: Kumar Sachin , Vassallo Jeff , Nattamai Kalpana , Cancelas Jose A , Geiger Hartmut 
Published: October 2019

Abstract
EGFR signaling regulates growth, differentiation, proliferation and migration in multiple organ systems. We previously demonstrated that inhibition of EGFR signaling on hematopoietic stem and progenitor cells (HSPCs) enhances G-CSF induced stem cell mobilization, while preliminary data suggested that inhibition of EGFR signaling in the stem cell niche actually had the opposite effect of inhibiting mobilization (Ryan et al., Nat Med, 2010). We thus tested the novel hypothesis that there is a role for EGFR signaling in the bone marrow (BM) niche with respect to regulating hematopoiesis. We utilized a set of mouse strains that express the recombinase Cre under distinct promoters to specifically delete EGFR in various types of stroma cells including Col-Cre; EGFRf/f (deletion in osteoprogenitor/osteoblasts (OBs)), Dermo-Cre; EGFRf/f (mesenchymal stem cells (MSCs) including chondrocytes and OB), Tie2-Cre; EGFRf/f (Endothelial cells) and Nestin-Cre; EGFRf/f (Schwann/neural cells) and compared them to no Cre-EGFRf/f mice as control wild type for EGFR.
Basic parameters of steady-state hematopoiesis were not altered in mice devoid of EGFR signaling in the various types of stroma cells listed above. We further investigated HSPC mobilization in EGFRf/f mice and interestingly, Col-cre and Dermo-cre EGFRf/f mice exhibited a lower number of circulating HSPC in blood in comparison to wild type mice, as determined by colony forming units (CFUs) or flow cytometry. Deletion of the EGFR in endothelial (Tie2-Cre) and neuronal (Nestin-Cre) compartments did not result in a decline in the number of circulating HSPCs. Upon G-CSF challenge, Col-cre and Dermo-cre EGFRf/f mice mobilized HSPCs similar to controls, suggesting that EGFR signaling in OBs/MSCs is dispensable for G-CSF induced mobilization. HSPCs circulation under steady state follows a circadian rhythm. We next tested whether EGFR signaling in OBs might play a role in circadian rhythm driven HSPC circulation. After 5 hours of light cycle i.e. Zeitgeber time-5 (ZT-5), when the number of circulating HSPCs is high, Col-Cre EGFRf/f and Dermo-Cre EGFRf/f mice presented with low numbers of circulating HSPCs. After 13 hours of light cycle (ZT-13) (low number of circulating HSPCs), the number of HSPCs in blood in Col-Cre EGFRf/f and Dermo-Cre EGFRf/f mice were similar to controls. Together, this suggests that EGFR signaling in OBs is essential for the rhythmic increase in circulating HSPC in blood at ZT5. Currently, we are investigating molecular mechanisms driven by EGFR signaling in OBs that regulate HSPC retention in BM and circadian regulation of EGFR signaling. In summary, our data suggest an important and also very specific (no other phenotype altered) role of EGFR signaling for regulating the circadian rhythm of HSPC circulation in peripheral blood.

Disclosures
No relevant conflicts of interest to declare.
New CNV Regions Identified in ITP Provide Evidence for Genetic Predisposition
Authors: Ar M. Cem , Yucesan Emrah , Yalniz Firat , Hatirnaz Ng Ozden , Salihoglu Ayse , Berk Selin , Eskazan Ahmet Emre , Ongoren Seniz , Baslar Zafer , Ozbek Ugur , Soysal Teoman , Aydin Yildiz , Sayitoglu Muge 
Published: October 2019

Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease resulting from inhibition of megakaryopoiesis and destruction of platelets by platelet reactive autoantibodies. Adult-onset ITP usually exhibits a relapsing chronic course and is often associated with other disorders of autoimmune or infectious origin, including systemic lupus erythematosus (SLE), lymphoproliferative diseases, common variable immunodeficiency (CVID) disease, and human immunodeficiency virus (HIV) infection. The exact pathophysiology of ITP has not been fully elucidated. Heterogeneity in disease presentation and in response to immunosuppressive therapy suggests different underlying mechanisms; and thus justifies the investigation of relevant genetic associations. Here we tried to unravel the genetic background of the immune dysfunction in ITP by using SNP array technology.
We analyzed the blood samples of 12 adults (6 males and 6 females) with primary refractory ITP, by SNP array approach to identify candidate genomic regions. None of the patients showed clinical and laboratory findings of autoimmune diseases, malignancy or infections. All individuals were genotyped using Illumina Human HumanCytoSNP-12 BeadChip (300K). Whole genome SNP genotyping data were delineated using GenomeStudio software platform. The genotyping data was obtained by further analyzes in terms of copy number variation (CNV).
In total we observed 14 CNVs in 12 patients. All CNVs were on autosomal chromosomes; 8 duplications and 6 deletions (gain 2p, 9q, 13q, 14q, 17p, 17q, 20q; loss 5q, 7p, 7q, 15q, 17q, 19q). The rearrangements sizes were between 45.42 Mb and 1.08 Mb. Moreover in five patients the duplications were in the form of mosaic structural genomic rearrangements. These mosaic duplications were found at 17q21.31 (0.2 Mb), 2p23.2 (0.34 Mb), 9q21.2 (10.89 Mb), 9q31.2 (17.77 Mb), 14q13.2 (0.37 Mb), 17p12 (1.46 Mb), 20q11.21 (14.24 Mb). None of the detected CNV regions could be demonstrated in two independent cohorts of 30 individuals with non-hematological disorders and healthy controls.
Little is known on the genetic background of immune thrombocytopenia. Our aim was to investigate the impact of CNVs on the pathophysiology of ITP. We found several gains/losses in different chromosomal regions. However, the most striking result of our study was the detection of mosaic patterns that have been reported to most commonly associate with hematological cancers. These mosaic patterns may be associated with clonal expansion of T- or B-cells, leading to the immune dysfunction seen in ITP. Evaluation of the detected regions and their relation to B and T- cell clonality is ongoing. These preliminary results provide early evidence for the presence of predisposing CNVs in adult onset ITP.

Disclosures
No relevant conflicts of interest to declare.
Interleukin-1 Drives Precocious Myeloid Differentiation of Hematopoietic Stem Cells at the Expense of Self-Renewal
Authors: Pietras Eric Martin , Mirantes-Barbeito Cristina , Fong Sarah , Loffler Dirk , Kovtonyuk Larisa Vladimirovna , Lakshminarashimhan Ranjani , Chin Chih Peng , Techner Jose-Marc , Will Britta , Nerlov Claus , Steidl Ulrich , Manz Markus , Schroeder Timm , Passegue Emmanuelle 
Published: October 2019

Abstract
Hematopoietic stem cells (HSCs) maintain lifelong blood homeostasis. While many of the cell-intrinsic mechanisms regulating HSC function at steady state have been well characterized, the role of inflammatory cytokines and other environmental factors in tailoring blood production following physiological insults has become a topic of emerging interest. The cytokine interleukin-1 (IL-1) is a prototypical pro-inflammatory cytokine that plays a key role in host inflammatory responses to injury and infection, and is associated with elevated myeloid cell production. Importantly, IL-1 also drives a wide range of chronic inflammatory conditions such as diabetes, obesity, and arthritis that are often characterized by deregulated blood homeostasis. Here, we show at single-cell resolution using continuous tracking technology that IL-1 drives accelerated HSC cell division kinetics and myeloid differentiation via the rapid activation of a precocious PU.1-dependent myeloid gene program. Activation of this program requires direct IL-1R signaling and subsequent activation of IKK kinases, and instructively primes HSCs to adopt a myeloid fate. Strikingly, we demonstrate that IL-1 produced by myeloid cells and endothelial cells of the bone marrow (BM) niche exerts similar effects in vivo, and is required for efficient myeloid recovery following acute challenges such as transplantation or myeloablation. On the other hand, we find that chronic IL-1 exposure substantially remodels HSC blood output, resulting in myeloid overproduction and expansion of myeloid-biased multipotent progenitor (MPP) compartments at the expense of lymphoid and erythroid lineages. Critically, chronic IL-1 erodes HSC self-renewal, significantly impairing their regenerative capacity following transplantation. On the other hand, chronically exposed HSCs recover their function upon IL-1 withdrawal. Collectively, these findings identify IL-1 as a critical regulator of HSC fate and lineage specification via activation of a PU.1 circuit. They also demonstrate a role for IL-1 as a double-edged sword in HSC biology, promoting HSC regeneration in response to acute insults while severely disrupting HSC self-renewal and lineage output during chronic exposure, hence identifying IL-1 as an important and therapeutically targetable factor underwriting myeloid overproduction and other deregulations that contribute to the pathogenesis of a variety of chronic inflammatory diseases and blood disorders.

Disclosures
No relevant conflicts of interest to declare.
Tumor Suppressors BTG1 and IKZF1 Cooperate during Mouse Leukemia Development and Impact Relapse Rate in Childhood Acute Lymphoblastic Leukemia
Authors: Scheijen Blanca , Tijchon Esther , van Ingen Schenau Dorette , Marke Rene , van Emst Liesbeth , Van Der Meer Laurens T , Kuiper Roland P , Boer Judith M. , Pieters Rob , Hoogerbrugge Peter M , Den Boer Monique L. , van Leeuwen Frank N 
Published: October 2019

Abstract
Deletions and mutations affecting transcription factor IKZF1 are associated with increased relapse risk and poor outcome in B cell precursor acute lymphoblastic leukemia (BCP-ALL). However, additional genetic events may either enhance or negate the effects of IKZF1 on prognosis. We observed that deletions of the gene encoding the transcriptional coregulator BTG1 frequently co-occured with loss of IKZF1 function, suggesting a synergistic role for these events during leukemia development or progression. Targeted deletion of Btg1 predisposed both Btg1+/- and Btg1-/- mice to T cell malignancies, similar to what has been observed in Ikzf1 heterozygous knockout animals. Hence, while somatic single single-copy losses of either BTG1 and IKZF1 in the patient are predominantly found in BCP-ALL, targeted deletion of these genes in the mouse gives rise to T cell malignancies.
To establish whether loss of BTG1 function affected the tumor suppressive role of IKZF1, the Btg1 knockout allele was crossed onto mice heterozygous for a loss-of-function Ikzf1 allele. Leukemia penetrance in these compound mice increased in a Btg1 dose-dependent manner. These leukemias were characterized by clonal TCRb rearrangement and aggressive infiltration into secondary organs, indicating synergistic roles for these tumor suppressors during mouse leukemia development.
To investigate the effects of combined IKZF1/BTG1 loss in human BCP-ALL, we examined a large pediatric cohort of BCP-ALL cases, and found that the combined presence of BTG1 and IKZF1 deletions was associated with a markedly higher incidence of relapse, relative to IKZF1-deleted cases without BTG1 aberrations. Similar to BTG1 copy number losses, deletions in EBF1, PAX5, RB1 and CDKN2A/B appeared to be selectively enriched in IKZF1 deleted ALL. However, in contrast to BTG1, none of these other copy number alterations affected relapse incidence or outcome in this patient group. In conclusion, our data demonstrate synergy between the tumor suppressors BTG1 and IKZF1 during mouse leukemia development while the combined (single copy) loss of these two tumor suppressors identifies a patient group with an extremely poor outcome.
Event free survival in a cohort of 514 children newly diagnosed with BCP-ALL, divided into four categories based on IKZF1 and BTG1 deletion status.
Figure 1. Combined loss of IKZF1 and BTG1 predicts poor outcome in BCP-ALL Figure 1. Combined loss of IKZF1 and BTG1 predicts poor outcome in BCP-ALL

Disclosures
Pieters: Eusa Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
Hepcidin and Atoh8 mRNA Expression Are Decreased in Murine Models of Hemochromatosis However Hepcidin Expression Is Unaffected By Atoh8 Knockout
Authors: Fleming Robert E , Li Yihang , Miller Ian , Prasad Princy , McKie Andrew 
Published: October 2019

Abstract
Atoh8 is a member of the bHLH transcription factor family, and hepatic expression of atoh8 mRNA is up-regulated by dietary iron and down-regulated by stimulation of erythropoiesis in mice, in parallel with changes in hepcidin mRNA(hamp1). It is a candidate transcription factor in the regulation of Hamp1 by iron status. Here we performed studies evaluating the contribution of genes regulating hepcidin to the regulation of Atoh8, as well as the role of Atoh8 in the regulation of hepcidin. In the former studies, wild type FVB and three hereditary hemochromatosis (HH) mouse models, Hfe-/-, TfR2Y245X/Y245X and Hfe-/- TfR2Y245X/Y245X mice, were placed on diets containing 60 ppm or 25,000 ppm iron at weaning for two weeks before euthanasia and tissue collection. Liver expression of Hamp1 and Atoh8 were evaluated. Additionally, the WT and HH mice were intraperitoneally injected with 30 mg/kg phenylhydrazine (PHZ) on days 49 and 50, and then euthanized on day 53. Liver and spleen non-heme iron concentrations, and serum hematologic and iron parameters were measured. The liver mRNAs for hamp1, atoh8, and bmp6 were measured by quantitative RT-PCR. Hfe-/- and Tfr2Y245X/Y245X mice each demonstrated lower Hamp1 and Atoh8 expression than did WT mice, despite hepatic iron loading. WT mice demonstrated the expected increases in Hamp1 and Atoh8 expression in response to dietary iron loading. Hamp1 increased in the HH mice with iron loading; however Atoh8 expression was not statistically different. The addition of Hfe knockout to the TfR2Y245X/Y245X mutation suppressed Hamp1 expression further, but had no additive effect on Atoh8. PHZ treatment at 30 mg/kg mouse significantly decreased red blood cells and hematocrit, caused severe splenomegaly, and down-regulated Hamp1 and Atoh8 in WT mice, as well as in HH mice. These results are consistent with a role for Hfe and TfR2 in normal signaling to Hamp1 and Atoh8, but also suggest some regulation of Hamp1 in response to dietary iron independent of a change in Atoh8 expression. To evaluate the role of Atoh8 in the regulation of hepcidin, Atoh8 Δexon1 homozygous, heterozygous and WT mice were placed on diets containing standard (250 ppm) and euthanized at 5-6 weeks of age. The Atoh8 Δexon1 homozygous mice were significantly smaller in size than the WT or heterozygous littermates, but did not differ in any measured iron parameter (serum iron, hematocrit, liver iron, liver hamp1 mRNA, liver bmp6 mRNA). The Atoh8 Δexon1 homozygous mice also did not differ from heterozygous mice in PHZ response. These observations indicate that HFE and TFR2 are necessary for normal Atoh8 as well as hepcidin expression; however they do not support an essential role for Atoh8 in hepcidin regulation by iron demand.

Disclosures
No relevant conflicts of interest to declare.