bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Three E Proteins Define a Heterogeneity of the AML1-ETO-Containing Transcription Factor Complex (AETFC) and Differentially Regulate t(8;21) Leukemogenesis
Authors: Liu Na , Song Junhong , Xie Yangyang , Wang Xiao-Lin , Rong Bowen , Man Na , Zhang Meng-Meng , Zhang Qunling , Gao Fei-Fei , Du Mei-Rong , Zhang Ying , Shen Jian , Xu Chun-Hui , Hu Cheng-Long , Wu Ji-Chuan , Liu Ping , Zhang Yuan-Liang , Xie Yin-Yin , Liu Ping , Huang Jinyan , Huang Qiu-Hua , Lan Fei , Shen Shuhong , Nimer Stephen D. , Chen Zhu , Chen Sai-Juan , Roeder Robert G. , Wang Lan , Sun Xiao-Jian 
Published: October 2019

Abstract
The leukemogenic AML1-ETO fusion protein is produced by the t(8;21) translocation, which is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AETFC, that contains multiple transcription factors and cofactors. Among these AETFC components, E2A (also known as TCF3) and HEB (also known as TCF12), two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA (E-box) binding capacity to AETFC, and are functionally essential for leukemogenesis. However, we find that the third E protein, E2-2 (also known as TCF4), is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the basic helix-loop-helix (bHLH) DNA-binding domain of E2-2. Gene expression profiling and ChIP-seq analysis reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, consistent with the fact that E2-2 is a critical transcription factor in dendritic cell (DC) development, our studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with DC differentiation, and that restoration of E2-2 triggers a partial differentiation of the AML1-ETO-expressing leukemic cells into the DC lineage. Meanwhile, E2-2, but not E2A or HEB, represses MYC target genes, which may also contribute to leukemic cell differentiation and apoptosis. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates the development of leukemia. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a molecular heterogeneity of AETFC, which merits further study in different t(8;21) AML patients, as well as in its potential regulation of cellular heterogeneity of AML. These studies should improve our understanding of the precise mechanism of leukemogenesis and assist development of diagnostic and therapeutic strategies.

Disclosures
No relevant conflicts of interest to declare.
Adrenomedullin Receptor Calcrl Drives Drug Resistance of Leukemic Stem Cells in Acute Myeloid Leukemia
Authors: Sarry Jean-Emmanuel , Recher Christian , Larrue Clément 
Published: October 2019

Abstract
After intensive chemotherapy, the emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein, we first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients compared to normal cells and preferentially in the immature CD34+CD38- compartment. Then, we demonstrated its role in the maintenance of leukemic stem cell function in vivo (Figure A). Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo. Accordingly, we showed that ADM-CALCRL axis drove BCL2 pathway, cell cycle and DNA integrity in E2F1-dependent manner, and high OxPHOS status that we previously described as a feature of minimal residual disease after chemotherapy (Farge et al., 2017). Moreover, CALCRL expression predicted the response to chemotherapy in vivo in mice (n=10 Patient Derived Xenografts; Figure B) and in patients. Further, using the combination of limiting dilution assays, single cell RNA-seq analysis of primary AML samples at diagnosis and relapse and before and after transplantation in NSG mice, we revealed the pre-existence of a chemoresistant leukemic stem cell sub-population harboring a CALCRL gene signature (Figure C-D). All of these data highlight the critical role of CALCRL in stem cell function and metabolism. They also identify this receptor as a new druggable marker of chemoresistant leukemic stem cell population and a promising therapeutic target to specifically eradicate them and overcome relapse in AML.

Disclosures
No relevant conflicts of interest to declare.
Hematopoeitic Cell Transplant - Comorbidity Index (HCT-CI) Score Is a Useful Tool for Predicting Induction Mortality and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia Patients
Authors: Saini Neeraj Y , Cerny Jan , Furtado Vanessa , Puthawala Imran , Desmond Angela , Ramanathan Muthalagu , Nath Rajneesh 
Published: October 2019

Abstract
Intro:
Assessment of induction mortality risk in acute myeloid leukemia (AML) patients is challenging. Hematopoietic cell transplant comorbidity index (HCT-CI) score was designed for risk assessment of patients undergoing an allogeneic transplant. However, it is often used in clinical practice to assess induction mortality risk in AML patients. We analyzed the predictive power of the score to assess induction mortality risk as well as overall survival in AML patients at our institution.
Methods:
Between Jan 2009 and March 2013, 101 consecutive newly diagnosed AML patients treated at our institution were included for analysis. All patients received bolus HiDAC (3gm/m2) on day 1-5 and high dose mitoxantrone (80mg/m2) on day 2. The median age was 65 years (range18-90). The total number of patients in the age group <60, 60-69 and ≥70 were 30(29.7%), 35(34.6%) and 36(35.6%) respectively. HCT-CI scores were calculated before induction chemotherapy. Kaplan Meir curve was used to calculate OS and PFS. 4-week induction mortality was calculated from the date of the induction chemotherapy. The patient cohort was divided into those with HCT-CI scores of > or ≤3.
Results:
The number of patients with the HCT-CI score of 0,1,2 and 3 were 8,13,17 and 13 respectively. 50% of our patients (51 patients) had a score of 4 or more on the HCT-CI index. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%) respectively. 4-week induction mortality in <60, 60-69 and ≥70 years of age groups were 0/30(0%), 1/35(2.8%) and 2/36(5.5%) respectively. Similarly, in above age groups, 8-week induction mortality were 0/29(0%), 2/34(5.8%) and 5/36(13.8%) respectively. The median OS in patients with an HCT-CI score ≤3 was 87 months versus 11.5 months in those with a score >3 (log-rank, p=0.0046, Fig1). 2-yr NRM rate for patients with HCT-CI score ≤3 and >3 was 47% and 71%, respectively (p=0.01, Fig2). Hazard ratio for overall mortality in patients with HCT-CI score >3 is 1.793 with p=0.023, 95% CI = (1.083 - 2.971). HR for 8-week mortality in patients with an HCT-CI score >3 is 2.035 (p=0.412), although not statistically significant due to a low number of events. However, by Cox multivariable regression analysis HCT-CI retained a significant impact on 8-week mortality (HR=1.24, p= 0.03) and overall survival (HR=1.144, p= 0.006).
Conclusion:
An HCT-CI score is a valuable tool in the assessment of the induction mortality in newly diagnosed AML patients and can be used for risk assessment of overall mortality.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Open-Label, Expanded Access Study of Taliglucerase Alfa in Patients with Gaucher Disease Requiring Enzyme Replacement Therapy
Authors: Kuter David J. , Wajnrajch Michael , Hernandez Betina , Wang Rong , Chertkoff Raul , Zimran Ari 
Published: October 2019

Abstract
Taliglucerase alfa, an enzyme replacement therapy (ERT) approved in several countries for the treatment of adult and pediatric patients with Type 1 Gaucher disease, is the first FDA-approved plant cell-expressed recombinant therapeutic protein for humans. PB-06-004 (NCT00962260) was a multicenter, open-label, expanded access study designed to follow the safety of taliglucerase alfa in patients with Gaucher disease who required ERT and who were previously treated with imiglucerase but had a dose reduction or discontinued due to a shortage of imiglucerase. Eligible patients (aged ≥18 years) with Type 1 Gaucher disease received taliglucerase alfa every 2 weeks for ³9 months at a dose equivalent to their previous imiglucerase dose, before it was reduced or discontinued (Part A), and had the option of continuing treatment for up to 33 months (Part B); a later amendment allowed treatment-naïve patients. Fifty-eight patients received treatment (55.2% male, mean age 46.1 years, mean bi-weekly dose 35.2 U/kg, mean duration 17.8 months); 51 patients previously received ERT, 7 were treatment-naïve. Thirty-six patients completed the study. Hemoglobin concentration and platelet counts were also explored. Most adverse events (AEs) were mild or moderate in severity and not related to taliglucerase alfa; treatment-related AEs were mild and transient in nature. In previously treated patients, mean (SE) hemoglobin concentration was 13.0 (0.3) g/dL at baseline, 13.4 (0.2) g/dL at 9 months, and 13.4 (0.2) g/dL at last follow-up; mean (SE) platelet count was 179,242 (15,344)/mm3 at baseline, 209,727 (17,157)/mm3 at 9 months, and 215,242 (17,867)/mm3 at last follow-up. In treatment-naïve patients, mean hemoglobin concentration and platelet counts increased. In conclusion, taliglucerase alfa was well tolerated for up to 33 months of treatment and demonstrated a durable therapeutic effect, as evidenced by stable or improved hemoglobin concentration and platelet counts in this expanded access study.

Disclosures
Kuter: BMS: Research Funding; Bioverativ: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Protalex: Research Funding; Novartis: Consultancy; Principia: Research Funding; Amgen Inc.: Consultancy; Argenx: Consultancy; ONO: Consultancy; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wajnrajch:Pfizer Inc: Employment. Hernandez:Pfizer Inc: Employment. Wang:Pfizer Inc: Employment. Chertkoff:Protalix Biotherapeutics: Employment. Zimran:Pfizer Inc: Honoraria; Shire: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.
A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations
Authors: Sirdesai Shreerang , Weekes Kerryn , Alam Asif , Tran Huyen A , Barnes Christopher , Kaplan Zane 
Published: October 2019

Abstract
Aim:
Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients.
Methods:
Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1.
Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor.
Results:
318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1)
In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA.
20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations.
Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care
Conclusion:
This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally.

Disclosures
No relevant conflicts of interest to declare.
Incidence, Prevalence, Mortality, and Causes of Death in Waldenström Macroglobulinemia in South Korea: A Nationwide, Population-Based Study
Authors: Jeong Seri , Kong Seom Gim , Kim Dajung , Lee Ho Sup 
Published: October 2019

Abstract
Backgroud: Studies investigating the epidemiology of Waldenström macroglobulinemia (WM) in Asia are scarce. The aim of this study was to provide the epidemiological and clinical features of WM in South Korea at a national level, including incidence, prevalence, mortality, survival with competing risks, and causes of death.
Methods: We used a national, population-based database maintained by the Health Insurance Review and Assessment Service, which includes information on all WM patients, diagnosed based on uniform criteria from 2003 to 2016.
Results: The total number of patients newly diagnosed with WM was 429 during study period with a female to-male ratio of 3.2. The incidence from 2003 to 2016 increased from 0.03 to 0.11 per 105, and the prevalence in 2016 was 0.42 per 105. A total of 217 WM patients died during the study period (standardized mortality ratio =22.07) and the overall survival (OS) of WM patients was 47.5%. In the multivariate analysis, a significant factor associated with a worse OS was older age, whereas stem cell transplantation showed a better outcome (hazard ratio = 0.163; P = 0.0109). WM was the most common cause of death (n = 173; 79.7%), followed by other malignant neoplasms (n= 21; 9.7%).
Conclusions: The national incidence of WM in Korea, a racially homogeneous country of Asia, was lower than that in previous reports from other countries, reflecting ethnic disparities. However, the incidence increased and mortality was the highest ever reported. The main cause of death was WM itself and stem cell transplantation was considerably effective. This study reflects the need for greater awareness of WM, particularly in Asian countries.

Disclosures
No relevant conflicts of interest to declare.
Albumin Improves Stratification in the Low IPI Risk Patients with Diffuse Large B-Cell Lymphoma
Authors: Wei Xiaolei , Wei Yongqiang , Huang Weimin , Song Jialin , Zeng Hong , Zheng Jingxia , Wei Qi , Feng Ru 
Published: October 2019

Abstract
Our previous study showed albumin at diagnosis can be used to predict survival in diffuse large B-cell lymphoma (DLBCL) patients, but whether albumin could improve the international prognostic index (IPI) risk stratification in DLBCL remains unknown. Herein, we retrospectively analyzed 440 de novo DLBCL patients treated with R-CHOP in this study. The cutoff value of albumin for survival analysis was 34.4 g/L with an area under the curve value of 0.642±0.0037 (p<0.001) by receiver operating characteristic curve. Patients with low serum albumin showed worse overall survival (OS) and event-free survival (EFS) (p<0.001 and p=0.002, respectively). Multivariate analysis revealed that low serum albumin, independent of IPI, indicated different survival in both OS(relative ratio [RR] .0481; 95% confidence interval [CI], 0.294 - 0.789, p=0.004) and EFS (RR, 0.617; 95% CI, 0.419 - 907, p=0.014) in DLBCL patients.According to IPI, there were 170 patients (40.2%) in low risk group, 101patients (23%) in low-intermediate risk group, 97(22.0%) patients in high-intermediate risk group and 65 patients (14.8%) in high-risk group. Low IPI risk patients showed favorable survival (p<0.05). However, there were no significant survival difference in low-intermediate, high-intermediate and high-risk group (p>0.05). Especially low albumin could identify a subgroup of patients with poorer overall survival in low/ low-intermediate IPI risk patients (p = 0.003). In conclusion, our study suggests that albumin at diagnosis is a simple and effective prognostic factor in DLBCL patients,allowing the identification of an inferior outcome subgroup in low/ low-intermediate DLBCL patients, which may help to guide treatment.

Disclosures
No relevant conflicts of interest to declare.
Incidence of Thromboembolic Disease in Hereditary Hemorrhagic Telangiectasia (Osler Weber Rendu Syndrome)
Authors: Serra Marcelo Martin , Elizondo Cristina Maria , Alonso Marina , Peuchot Veronica , Vazquez Fernando Javier 
Published: October 2019

Abstract

The Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia that affects 1-5000 individuals worldwide. Is characterized by fragile mucocutaneous telangiectasia and vascular malformations in organs such as brain, lungs, liver and the gastrointestinal tract. Nose and gastrointestinal bleeding are remarkable, leading to frequent iron deficiency anemia (IDA) or life threatening bleeding episodes. Venous thromboembolic events (VTE) in HHT are probably more frequent than general population due to high plasmatic levels of FVIII specially in clinical conditions like long time immobilization due to brain abscesses or severe anemia. Additionally, in those patients with pulmonary fistula, the thromboembolic events can produce paradoxal strokes. On the other hand, almost all HHT medical treatments usually used to treat HHT related bleeding could produce thromboembolic disease. Anticoagulation (ACO) in this bleeding condition is a challenge, nevertheless, almost 50% can tolerate it well.
Objective: To report the incidence of VTE in the HHT population.
Methods: Ambispective cohort of adult based on the Institutional Registry of HHT. VTE was defined as the first episode of pulmonary embolism (PE), deep venous thrombosis (VTE) or thrombosis in the fistula sac or the progression of a prior event after its first 48 hs despite anticoagulation.
Result: Over 524 patients 394 adults with HHT confirmed by Curazao criteria or positive genetic test and complete data were included. There were 18 VTE events 4.6% (CI95% 2.7-6.8%), 9 DVT (2.3% IC95% 1.2-4.4%) and 3 PE (0.7% IC95% 0.13-2%). The female gender represents 72%. The median age at the event was 67 years (IIQ 25-75% 56-73).
Five patients (27%) were on ACO prior to the event, mainly for atrial fibrillation, and 3(18%) suffered a previous VTE.
The most frequent risk factors were recent hospitalization (44%) and iron deficiency anemia (44%), immobility (33%), recent surgery (18%), as well as cancer (5%) and recent travel (5%) patient each.Fifteen (83%) patients received ACO, 10(55%) received LMH followed by acenocumarol, 3(30%) of which had to be stopped due to nose or gastrointestinal bleeding.In 5 (27%) a cava vein filter were inserted, of which 3 are under anticoagulation therapy.
Conclusion: VTE incidence in our study was significantly higher than reported in general population at similar age. However, the inclusion of more symptomatic and serious HHT patients could be selection bias. The low number of patients, may influence the results. IDA and hospitalization were the most important associated conditions. Most patients tolerated well the anticoagulation therapy.

Disclosures
No relevant conflicts of interest to declare.
Elevated FANCA Expression Marks a Worse Prognosis in Chronic Lymphocytic Leukemia. Evidence of a New Role of FANCA in the Stability of p53 By a Neddylation-Related Mechanism
Authors: Pipaon Carlos , Bravo Navas Sara , Romon Iñigo , Conde Eulogio , Yanez San Segundo Lucrecia 
Published: October 2019

Abstract
Background: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in western countries. It is characterized by a failure in the mechanisms of apoptosis that leads to an accumulation of mature B cells in peripheral blood, bone marrow and lymphoid organs. With exceptions, CLL is considered incurable and some patients show a worse prognosis related to the expression of certain cytogenetic or molecular markers such as p53 dysfunction (17p13 deletion or TP53 inactivation), 11q23 deletion, unmutated IgVH and the presence of a complex karyotype. FANC proteins have been related to chromosomal instability and alterations in the mechanisms of p53 activation, control of cell cycle and apoptosis. Germline mutations in any of the 20 FANC genes known so far generates Fanconi Anemia, a syndrome characterized by a extraordinary proneness to cell apoptosis leading to a progressive bone marrow aplasia and pancytopenia. Some FANCA proteins aggregate in response to DNA damage forming the FANCcore complex that mediates the monoubiquitination of FANCD2 and FANCI, thus activating the mechanism to repair stalled replication forks. In addition, individual FANC proteins have been involved in functions out of the FANCcore. This is the case of FANCA, that has recently been involved in the neddylation of CXCR5 and beta-2-microglobulin, processes reported to be altered in CLL.
Hypothesis: Given the fragmentary information connecting FANC proteins with cellular processes altered in CLL, like apoptosis, cell cycle or neddylation, we hypothesize a role of these proteins in the diagnosis or prognosis of CLL.
Methods: We analyzed the expression of 5 FANC genes in a cohort of 160 patients of CLL by quantitative RT-PCR. Statistical analysis were carried out to establish relations between FANC genes deregulation and clinical manifestations. We also investigated the role of the FANCA gene in primary circulating B-lymphocytes from CLL patients by either gain- or loss-of-function approaches.
Results: Our data identified a group of CLL patients with high expression of FANCA in peripheral B-CLL cells, and we stablished its relationship with the deletion of 11q23 and a worse prognosis. When we investigated the molecular mechanisms of this bad prognosis, we observed a reduction in the mRNA expression of two p53 target genes, p21 and ∆Np73, in CLL primary cells transfected with FANCA. Luciferase studies demonstrated an impairment of p53 function by FANCA. Moreover, we obtained evidence of a cooperation between FANCA and the NEDD8-interacting protein NUB1L in the destabilization of p53.
Conclusion: These results point to FANCA as a bad prognosis marker in CLL and unveils a new role of this protein aside from its role in the FA-BRCA DNA repair pathway.

Disclosures
No relevant conflicts of interest to declare.