bluuebunny/crossref_metadata_2025_split huggingface dataset:
Set7 Is Highly Expressed in B-Lineage Acute Lymphoblastic Leukemia Cells and Overexpression of Set7 Exhibits Antileukemia Effect
Authors: Ma Xiao-Tong , Mou Ya-Kun , Zhao Yang-Yang , Wang Nan , Liu Xiao-Yan , Yin Jing , Ma Yan-Ping , Guo Dan 
Published: October 2019

Abstract
Set7 is a member of protein lysine methyltransferase family that is highly conserved in vertebrates. Set7 can regulate the maintenance of chromosome structure, cell cycle and apoptosis, and plays an important role in many kinds of cancer, metabolism and inflammatory process. However, studies concerning its pathogenic role in leukemia are scarce. We analyzed the expression of Set7 in different types of leukemia and healthy human bone marrow cells or peripheral blood from the Oncomine databases (http://www.oncomine.org), and showed that Set7 was highly expressed in acute lymphoid leukemia (ALL) patients, especially in patients with B-ALL. In this study, we examined the expression of Set7 in various hematopoietic tumor cell lines, bone marrow samples from patients and healthy volunteers. We found that Set7 was highly expressed in B-ALL cell lines Nalm6 and REH compared with other hematopoietic malignant cell lines. Furthermore, Set7 was overexpressed in bone marrow mononuclear cells of adult and pediatric patients with B-ALL than in healthy human bone marrow samples, and sorted CD19+ cells, as well (P<0.001). To investigate Set7 gene function, retroviral-mediated overexpression or removal experiments were performed. Gain-of-function and loss-of-function analyses in Nalm6 and REH cells demonstrated that Set7 inhibited cell growth, colony formation and enhanced the chemosensitivity of B-ALL cells to Vincristine (VCR), Arabinocytidine (Ara) and Daunorubicin (DNR). Protein sequence analysis showed that Ebf1 might be a potential substrate for Set7. The expression of Rad51 and Tnsf11, the downstream target genes of Ebf1, were changed as expected when Set7 was overexpressed in Nalm6 and REH. Our study shows for the first time that overexpression of Set7 has an inhibitory effect on B-ALL. These findings suggest that Set7 may be a promising molecular therapy target for B-ALL treatment and provide new clues for understanding the molecular mechanisms of the leukemogenesis of B-ALL.

Disclosures
No relevant conflicts of interest to declare.
Mir-130a Is Aberrantly Overexpressed in Adult Acute Myeloid Leukemia with t(8;21) and Its Suppression Induces AML Cell Death
Authors: Dai Haiping , Ding Chao , Chen Suning , MacLeod Roderick A. F. , Ehrentraut Stefan , Drexler Hans G. , Nagel Stefan , Wu Depei , Sun Aining 
Published: October 2019

Abstract
Emerging evidence has revealed that miRNAs can function as oncogenes or tumor suppressor genes in leukemia. By profiling miRNA expression across a cohort (n=156) with de novo acute myeloid leukemia (AML), we identified miR-130a as significantly overexpressed in AML with t(8;21). Expression of miR-130a decreased significantly once patients with t(8;21) achieved complete remission, but increased sharply at the time of relapse. In patients with t(8;21) AML, KIT mutational status was associated with miR-130a expression - with higher expression associated with KIT activating mutations. Increased miR-130a expression in t(8;21) AML was associated with worse event-free survival, however no impact on overall survival was observed. Knockdown of RUNX1/RUNX1T1 (AML1/ETO) protein in the SKNO-1 cell line resulted in decrease of expression of miR-130a. Direct binding of RUNX1/RUNX1T1 fusion protein with the promoter sequence of miR-130a was detected with luciferase reporter gene assay. Following miR-130a knockdown, SKNO-1 demonstrated increased sensitivity to etoposide. Taken together, our data suggest that miR-130a is directly activated by RUNX1/RUNX1T1, and can be used to predict leukemia burden, event-free survival and chemotherapy sensitivity in AML with t(8;21).

Disclosures
No relevant conflicts of interest to declare.
Internal Tandem Duplication (ITD) in the Tyrosine Kinase Domain of FLT3 Displays Higher Oncogenic Potential in Acute Myeloid Leukemia
Authors: Marhäll Alissa , Fischer Thomas , Heidel Florian H. , Kazi Julhash U. , Rönnstrand Lars 
Published: October 2019

Abstract
Up to 30% of patients with acute myeloid leukemia (AML) harbor a mutation in FMS like tyrosine kinase 3 (FLT3). This mutation is not only the most frequent, but also the most clinically challenging, because it is associated with increased risk of relapse and poor overall survival. The most common oncogenic FLT3 mutation is the internal tandem duplication (ITD) in the juxtamembrane domain (ITD-JM). Other less frequently occurring mutations include ITD mutations in the tyrosine kinase domain (ITD-TDK) and point mutations in the TKD (e. g. D835Y-TKD). Use of FLT3 inhibitors has shown initial promise, though an acquired resistance remains a problem. A need therefore remains for additional therapeutic targets, and in order to identify these we need to have a better understanding of the mechanisms by which the FLT3 mutations drive leukemogenesis. Although ITD-JM and D835Y-TKD mutations have been studied extensively, the role of the recently identified ITD-TKD remains poorly understood. In this study we compared the ITD-TKD domain mutations with other well-studied FLT3 mutations. We observed that transfection of cytokine-dependent Ba/F3 cells with ITD-TKD is sufficient to induce formation of colonies in semisolid medium in the absence of cytokines. Number and size of colonies were comparable to that of ITD-JM, while D835Y-TKD transfected cells failed to form colonies suggesting that the ITD-TKD mutations have stronger transforming potential than other TKD mutations. Similar to colony formation assays, proliferation and cell survival was significantly higher in ITD-TKD transfected cells compared to cells transfected with D835Y-TKD. ITD-TKD selectively enhanced STAT5 and AKT phosphorylation while ERK1/2 and p38 phosphorylation remained unchanged. Collectively our data suggest that ITD-TKD is a more potent oncogenic mutant compared to the TKD mutants.

Disclosures
Fischer: Novartis: Consultancy, Honoraria.
Sequential Induction of Cell Cycle Arrest and Mitotic Catastrophe Followed By Apoptosis Via Activation of PTEN By GL-V9 in Human T-Cell Malignancies
Authors: Hui Hui , Xu Jingyan 
Published: October 2019

Abstract
GL-V9, a newly synthetic flavonoid derivative, is an active cytotoxic component and exhibits anticancer activities. Here, we demonstrated the sequence of death reponses to different concentration of GL-V9 in human T-cell malignancies cell Jurkat and HuT78. Responses included transient accumulation of cells at the G2/M border followed by also transient rise in several mitotic markers and mitotic attempts were largely abnormal, resulting in numerous micronucleated and multinucleated cells in low drug concentration (2 μM), as shown by flow cytometre analyses and Giemsa staining. These events, indicative of mitotic catastrophe, were not associated with immediate cell death. However, MTT assay showed that high concentration of GL-V9 (4, 8, 16 μM) causes near complete cell growth inhibition at 12 h. Also, the classical manifestations of apoptosis (including phosphatidylserine externalization, mitochondrial dysfunction, and caspase activation) were marginal at 24 h, as shown by Annexin V-PI staining, JC-1, and western blot assay. The mechanism research reveals that low dose of GL-V9 induced mitotic catastrophe via decreasing EEA1, which is required for cytokinesis, and increasing the expression of PTEN. Besides, high concentration of GL-V9 induced cell apoptosis by up-regulating the expression of apoptosis-related proteins caspase 3 and Bim in lymphoid tumor cell lines and primary ALL cells. Collectively, these findings show that different concentrations of GL-V9 can induce mitotic catastrophe and ultimate cell death event of human T-cell malignancies respectively, which would be a potential therapeutical compound for treating human lymphoid tumor.

Disclosures
No relevant conflicts of interest to declare.
Micafungin As Antifungal Prophylaxis during Induction Phase of Chemotherapy in Pediatric Acute Lymphoblastic Leukemia
Authors: Khalil Sahar A , Mahmoud Afaf m , Shalaby Lobna m , el-Mahallawy Hadir A , Elhaddad Alaa M 
Published: October 2019

Abstract
Background:
Invasive fungal infection (IFI) comprises a major cause of infection related morbidity and mortality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation (HSCT). Micafungin exhibits broad antifungal activity against both Aspergillus and Candida species.
Objective :
We performed a prospective study to determine the efficacy, safety, and tolerability of prophylactic micafungin against IFI in pediatric neutropenic patients during induction chemotherapy for acute lymphoblastic leukemia (ALL). Patients and methods:
The study included 70 patients randomized in to two groups: Intervention group: 35 patients were given micafungin daily at a dose of (1 mg/kg/day) with maximum of 50mg/day from day one to the end of induction with close follow up for toxicity, tolerability, and efficacy. In case of failure of prophylaxis (defined as development of proven, probable, or possible fungal infection according to revised definitions of EORTC/MSG consensus group), we shifted to either voriconazole or liposomal ampho-B. Control group: 35 patients were treated according to empirical antifungal approach. Follow up of patients by clinical examination, routine work up, serum galactomannan, blood cultures, and CT chest together with paranasal sinuses. Results:
Treatment success rate, defined as absence of proven, probable, or possible IFIs was 75%; in the control group 8/35 (22.8%) developed IFIs, while in the intervention group 2/35 (5.7%). No adverse events were observed that could be related to micafungin prophylaxis. Conclusions:
These results suggest that prophylactic micafungin is well tolerated and may prevent IFIs in pediatric patients with neutropenia receiving chemotherapy.
Keywords: Pediatric, ALL, induction chemotherapy, IFI, micafungin prophylaxis.

Disclosures
No relevant conflicts of interest to declare.
Acute Promyelocytic Leukemia Relapse in a Large Medical Center of China over a 9-Year Period: Evolving Treatment Strategies and Lessons for This Highly Curable Disease
Authors: Wang Huaiyu , Zhang Huiyun , Li Dengzhe , Zhang Xinxin , Chen Limei 
Published: October 2019

Abstract
All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination based therapy has become recommended first line treatment for de novo diagnosed low- to intermediate-risk acute promyelocytic leukemia (APL) patients. Though highly curable, relapses of APL could happen due to various reasons. In this research, we retrospectively analyzed data from patients who were diagnosed and treated APL between 2007 and 2015 in a tertiary hospital in northwest China. 123 APL patients were included, among which, 13 patients experienced relapse despite intensive treatment of ATRA plus ATO or ATRA plus chemotherapy or ATRA plus ATO plus chemotherapy. Although they all achieved complete remission after first induction therapy, 2 patients relapsed during maintenance therapy, 3 patients discontinued treatment then relapsed, 6 patients relapsed during consolidation therapy. Relevant data were subsequently compared with guidelines and multi-centre clinical researches to find out possible reasons of relapse. The results showed, all 13 relapsed patients received less than recommended dose of ATRA and ATO. 6 patients had longer than 4 months' treatment intervals, 4 patients received more than 5 courses of chemotherapy as consolidation or maintenance therapy, among which 2 patients relapsed during maintenance therapy till received chemotherapy 12 and 16 courses respectively. Risk assessment: 5 patients with low-risk, 4 patients with intermediate-risk, 4 patients with high-risk. Conclusion: It is highly possible that the relapse of APL is related to insufficient prescription of ATRA and ATO, and too many courses of chemotherapy may exert negative effects on outcome.

Disclosures
Wang: National Natural Science Foundation of China: Research Funding. Zhang:National Natural Science Foundation of China: Research Funding. Li:National Natural Science Foundation of China: Research Funding. Zhang:National Natural Science Foundation of China: Research Funding. Chen:National Natural Science Foundation of China: Research Funding.
Acute Promyelocytic Leukemia with FLT3/ITD and RUNX1 Mutation Presenting As Extramedullary Soft Tissue Mass
Authors: Mori Shahram , Yuan Cai , Ahmed Wesam B. , Patel Rushang D. 
Published: October 2019

Abstract
Background: APL formerly known as AML M3 is a variant of myeloid malignancies characterized by recurrent cytogenetic abnormality of PML/RARA translocation, t(15;17). Myeloid sarcoma, also called granulocytic sarcoma or chloroma, is a very rare presentation of extramedullary APL. In rare cases seen, it presents mainly as CNS disease in relapsed or refractory patients. Extramedullary APL on initial presentation is even rarer. As a result no significant information exists on the prognosis of such patients.
Case report: A 50-year-old Caucasian female with no past medical history, presented with 6-month duration of chest pain, which was treated as costochondritis without any improvement. Three months later, a soft tissue mass was identified on her sternum. Complete blood count revealed pancytopenia with white blood cell 3.24 x 103/uL, hemoglobin 10.0 g/dL, platelets 58x 103/uL, absolute neutrophil count 1.13 x103/uL, and monocytes 0.13 x103/uL which indicated "low risk disease". A PET/CT scan revealed a 4.6 cm x 4 cm sternal soft tissue mass. The biopsy of the mass confirmed myeloid sarcoma. Bone marrow biopsy showed acute promyelocytic leukemia, approximately 20% blasts in a hypercellular marrow with 70-80% cellularity. Cytogenesis test was negative. FISH analysis subsequently showed a partial RARA transcript inserted at the PML locus suggestive of a cryptic PML/RARA. This was confirmed by PCR for the fusion transcript PML/RARA from the bone marrow. Next generation genome sequencing identified FLT3/ITD and RUNX1 mutation. The patient was treated as a high risk disease due to the presence of chloroma and immediately started on treatment with Daunorubicin, Arsenic Trioxide (ATO), and All-Trans-Retinoic Acid (ATRA).
Conclusion: We present an extremely rare case of APL initially presenting with concomitant extramedullary sternal soft tissue mass with cryptic t(15;17) and somatic mutations in FLT/ITD as well as RUNX1 mutations. To our knowledge this is the first reported case of extramedullary APL with FLT/ITD and RUNX1 mutations. Early recognition of this rare presentation with timely chemotherapy may improve the outcomes of these patients.

Disclosures
No relevant conflicts of interest to declare.
Chemotherapy Cannot Replace Transplantation in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia
Authors: Li Xiaoyu , Chen Baoan , Cheng Jian , Lin Min , Zhang Xiaoping , Ge Zheng 
Published: October 2019

Abstract
Abstract Text: Objective: The mortality rate of refractory/relapsed acute myeloid leukemia (AML) is very high with poor prognostic. Three are still no standard treatments for these patients nowadays. Our research compared the treatment effect between patients with chemotherapy and transplantation. Method: A retrospective research of 45 patients with refractory/relapsed AML was performed in our center. We analyzed the clinical features including gender, age, classification of AML, performance status (PS), complete remission (CR) duration, cytogenetic and molecular abnormities. Survival analyses were made by using the Kaplan Meier method and took the Log - rank test. Results: The mean survival time of the 45 patients with refractory/relapsed AML was (36.25¡À8.40) months and the median follow up was (9¡À2.58) months. The one year and two years overall survival rate was (40.6¡À7.5)% and (23.7¡À7.0)%. Univariate analysis results demonstrated that age¡Ý60 years and failing to undergo HSCT after relapse had poor influence on OS. Conclusion: Performance of HSCT after relapse can improve the prognosis through the single center study. HSCT is still the effective salvage therapy for patients with refractory/relapsed AML. Our research is benefit for individual therapy and can be applied to improve the survival.

Disclosures
No relevant conflicts of interest to declare.
The Experience in Treating Elders with AML Using High-Dose AraC.
Authors: Rodriguez Cesar , Herzig Roger , Herzig Geoffrey P. 
Published: October 2019

Abstract
Introduction
Cytarabine combined with an anthracycline has long been the basis of therapy for acute myeloid leukemia (AML). Complete remission (CR) with standard therapy in patients > 60 has been reported to be 30 - 50%. Studies to improve remission rates have suggested that induction treatment using high-dose cytarabine (HDAraC) in adults age < 60 is safe and may improve survival in some patients. The use of such an aggressive induction regimen in older (>60) patients has not been extensively studied. The objective of this study was to assess tolerability and efficacy of HDAraC in patients 60 years of age or older compared to those age < 60.
Methods
Chart review of all patients that received induction chemotherapy with HDAraC between 2007 and 2013 at University of Louisville was done evaluating for: disease status and performance status at time of diagnosis, adverse effects during induction treatment, and treatment outcomes. HDAraC treatment in patients > 50 involved cytarabine at 1.5 g/m2 every 12 hours for 12 doses; for patients < 50, the cytarabine dose was 3g/m2 every 12 hours for 12 doses. Cytarabine was combined with 3 daily doses of idarubicin (12 mg/m2) on days 2-4 in all patients. Response was assessed with bone marrow biopsy on day 30 of induction or until neutropenia resolved.
Results
Seventy-seven patients received HDAraC between 2007 and 2013 (42 patients age < 60 and 35 patients age > 60. One patient < 60 and 8 patients > 60 died before day 30 without remission; 35 (83%) patients < 60 achieved CR and 21 (60%) of patients > 60 achieved CR (p=0.038). Adverse events related to induction chemotherapy were statistically significant more common in patients > 60 for respiratory failure (p=0.01), septic shock (p=0.004), bleeding complications (p=0.029), and cardiac toxicity (p=0.001), but not for kidney failure (p=0.302), gastrointestinal complications (p=0.226), neurotoxicity (p=0.105), or neutropenic fever (p=0.205). Overall toxicities, especially death within 30 days, was increased in patients > 60.
Conclusions
HDAraC induction in patients > 60 had a favorable CR rate (60%) compared to reported CR with conventional therapy, but with more toxicity when compared to younger patients. Additional studies involving a larger study group and subset analysis of cytogenetic and molecular markers could identify a specific elder population that may benefit from high-dose treatment. Evaluation of tools like the Comprehensive Geriatric Assessment (CGA) or a modified HCT-CI in this setting are recommended.

Disclosures
No relevant conflicts of interest to declare.
γH2AX Foci Increase Across the Spectrum from Myelodysplastic Syndromes to Acute Myeloid Leukemias and Co-Localize with 53BP1 in Specific Patterns in the Context of an Impaired DNA Damage Response
Authors: Popp Henning D , Brendel Susanne , Naumann Nicole , Henzler Thomas , Hofmann Wolf-Karsten , Fabarius Alice 
Published: October 2019

Abstract
Purpose: Increased DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability presumably implicated in pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML).
Materials and methods: We performed combined γH2AX/53BP1 immunofluorescent focus staining of DNA double-strand breaks (DSB) in MDS and AML cell lines, in CD34+ selected cells of normal and MDS bone marrow (including three cases of chronic myelomonocytic leukemias) and in blasts of AML bone marrow. In addition, we screened for activation of DDR by immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53.
Results: Compared to γH2AX foci levels in normal bone marrow samples (0.18 focus per CD34+ ± 0.6), increased levels of γH2AX foci were detected in 1/1 MDS cell line (6.4 foci per cell ± 0.0), 6/6 AML cell lines (12.0 foci per cell ± 0.6), 12/12 MDS bone marrow samples (2.8 foci per CD34+ ± 0.7) as well as 12/12 AML bone marrow samples (6.0 foci per blast ± 0.6). γH2AX and 53BP1 co-localized in all tested samples forming diffuse, clustered and marginal patterns. DDR proteins were expressed heterogeneously suggesting impairment of DDR.
Conclusions: Our results provide evidence for a continuous increase of constitutive DSB across the spectrum from MDS to AML in the context of an impaired DDR. γH2AX and 53BP1 co-localize in unique patterns in nuclei of MDS and AML presumably owing to a non-random spatial organization of the genome and foci formation implies promotion of ineffective nonhomologous end-joining repair mechanisms at sites of constitutive DSB.

Disclosures
No relevant conflicts of interest to declare.
BM-MSC Hhip Induced Microenvironment Protection from Chemotherapy in AML Via Ptch/Smo/Gli Pathwa
Authors: Jiang Xuejie , Xu Dan , Chen Fang , Jiang Ling , Yu Guopan , Meng Fanyi , Liu Xiaoli , Liu Qifa 
Published: October 2019

Abstract
Introduction. The mechanism of drug resistance is complicated in acute myeloid leukemia (AML), bone microenvironment provides protection niche for leukemia stem cells (LSC), and considered as an internal environment for AML cells to escape from chemotherapeutics cytotoxicity, but mechanism of drug resistance induced by microenvironment mesenchymal stem cell (MSC) isn't completely clear. In prophase study, it was found that Ptch/Smo/Glis pathway was the key in the network of AML drug resistance. Smo inhibition improved the survival of AML-bearing mice. Low expression of HHIP was found in refractory AML MSC and bone morrow liquid, overexpression of Smo and Gli-1 was verified in AML cells, and negatively correlated with prognosis in AML patients. Chemotherapeutic drug sensitivity was decreased in AML cells after co-cultured with AML MSC in vitro.
Methods. Bone morrow samples from AML patients and normal donors were collected to culture MSC cells. HL60/ADM and Kasumi-1 cells as well as HL60、KG-1cells were treated with daunomycin (DNR) or cytosine arabinoside (Ara-C) when cocultured with MSC. Cell cycle and apoptosis were determined by flow cytometry. The expression of HHIP was determined by confocal image and western blotting. Smo and Gli-1 activity was determined by western blotting.
Result. We took advantage of AML cells cocultured with MSC to imitate leukemic microenvironment in vitro. Co-culture with AML BM-MSC decreased the sensitivity to DNR or Ara-C compared with normal BM-MSC in HL60/ADM or Kasumi-1 cells. Flow cytometry analysis showed that cells in S phase and percentage of apoptosis cells were increased after co-culture with AML MSC. Western blotting also determined that low expression of HHIP was detected in refractory AML BM-MSC, Smo and Gli-1 expression were increased in HL60/ADM or Kasumi-1 cells after co-cultured with MSC. Confocal analysis also confirmed that the combination of HHIP and Ptch was decreased in AML MSC co-culture, Smo/Gli-1 pathway was activated through decreased inhibition of Shh in refractory AML cells co-cultured with MSC. Samples from AML patients also demonstrated that HHIP expression in AML BM-MSC was lower than that in normal BM-MSC, especially in refractory AML samples. HHIP expression in BM-MSC was negatively related to Smo and Gli-1 activity. Clinic data also showed that AML patients with overexpression of HHIP had a worse prognosis.
Conclusion. Our study demonstrated expression of BM-MSC HHIP was negatively related to activity of Ptch/Smo/Glis in AML. Low expression of BM-MSC HHIP resulted in activating Ptch/Smo/Gli pathway, and indicated drug resisitance and bad prognosis in AML. This project is connected with basic research and clinic, and provides support for diagnosis and targeted therapy in AML.

Disclosures
No relevant conflicts of interest to declare.