bluuebunny/crossref_metadata_2025_split huggingface dataset:
FHL2 Interacts with Iaspp and Impacts the Biological Functions of Leukemia Cells
Authors: Lu Wenting , Yu Tengteng , Liu Shuang , Li Saisai , Li Shouyun , Liu Jia , Xing Haiyan , Tian Zheng , Tang Kejing , Rao Qing , Wang Jianxiang , Wang Min 
Published: October 2019

Abstract
Introduction iASPP played an important role in leukemogenesis in our previous study. In order to clarify its mechanism, a yeast two-hybrid screen was performed to find the binding partner of iASPP. In this study, we reported FHL2 as a novel binding partner of iASPP. The biological functions of the communication between FHL2 and iASPP were detected, and its possible mechanisms were investigated in human leukemia cell lines.
Methods A yeast two-hybrid screen was performed to identify FHL2 as a novel binding partner of iASPP. Immunofluorescence, Co-IP and Western blot analysis were used to confirm the communication between FHL2 and iASPP. After FHL2 or iASPP was knocked down in K562 and Kasumi-1 cells by lentiviral, MTT assay and flow cytometry were performed to detect the proliferation, cell cycle distribution and apoptosis rate of leukemic cells, meanwhile Western blot analysis was used to analyze the level of cell cycle- and apoptotic-related proteins. Dual luciferase assay was conducted to investigate the transcriptional activity of p53 on Bax when iASPP and FHL2 were overexpressed or FHL2 was knocked down.
Results FHL2 was highly expressed in K562 and Kasumi-1 cells. FHL2 and iASPP interacted with each other and co-localized in both nucleus and cytoplasm. Either FHL2 or iASPP silenced could reduce cell proliferation, induce cell cycle arrest at G0/G1 phases, and increase cell apoptosis. Western blot analysis showed that the level of p21 increased and anti-apoptotic protein Bcl-2 was reduced. Interestingly, when FHL2 was knocked down, the protein expression level of iASPP also decreased. Similarly, the expression of FHL2 would reduce when iASPP was silenced. Dual luciferase assay suggested that iASPP could reduce the transcriptional activity of p53 on Bax, furthermore, when FHL2 was knocked down at the same time, the transcriptional activity of p53 was rescued.
Conclusions The interaction between FHL2 and iASPP in AML was observed for the first time. Cell proliferation reducing, cell cycle arresting at G0/G1 phases, and cell apoptosis increasing occurred in either FHL2 knockdown or iASPP knockdown. Moreover, iASPP and FHL2 participated in the regulation of the transcriptional activation function of p53. These results indicated that FHL2 might be a novel potential target for AML treatment.

Disclosures
No relevant conflicts of interest to declare.
Abnormal Expression of the Chemokine (C-C Motif) Ligand 17 Gene in Adult B-Cell Acute Lymphoblastic Leukemia
Authors: Feng Yong-Huai , Wang Wei-Min , Lu Wen-Yi , Wang Shu-Juan , Yao Qiu-Mei , Zhou Jiao , Zhang Jia-Min , Huan Xiao-Jun , Liu Kai-Yan , Ruan Guo-Rui 
Published: October 2019

Abstract
Abstract
Background: Chemokine (C-C Motif) Ligand 17 is a protein coding gene. This chemokine plays important roles in T cell development in thymus as well as in trafficking and activation of mature T cells. Diseases associated with CCL17 include mycosis fungoides, paragonimiasis and some hematologic malignancies such as Hodgkin¡¯s lymphoma, B cell lymphoma, and Nasal natural killer/T cell lymphoma (NNKTL). However, our knowledge of the expression levels of CCL17 in B-cell acute lymphoblastic leukemia (ALL) remains limited.
Aims: The purpose of this study was to investigate the expression levels of human CCL17 messenger RNA in adult B-cell ALL.
Methods: A real-time quantitative reverse transcription-polymerase chain reaction assay based on TaqMan fluorescence methodology was used to quantify the CCL17 mRNA copy number in the bone marrow cells from patients with adult leukemia and in 16 human hematologic malignant cell lines. Normal marrow samples from the allogeneic stem cell transplantation donors were served as control. Informed consent was obtained for every marrow sample.
Results:
Expression levels of the CCL17 gene in leukemic cell lines, leukemia patients and normal donor marrow are shown in Figure 1. These results showed that the relative levels of CCL17 gene expression in marrow from 189 newly diagnosed B-cell ALL(median 0.23%; range 0%¡«69000%) was significantly higher than those of bone marrow from the 43 healthy donors (median 0.05%; range 0%¡«6.87%;P =0.0007). Significant CCL17 mRNA overexpression was found in the de novo B-cell ALL patients compared with 102 treated B-cell ALL patients(median 0.02%; range 0%¡«3339%) who achieved complete remission or 70 de novo AML (median 0.02%; range 0%¡«9.132%;P¡¯s <0.0001). The expression levels of CCL17 was higher in 21 refractory/relapsed B-cell ALL patients (median 0.68%; range 0.003%¡«13490%) than that newly diagnosed B-cell ALL, but no statistical significant difference was observed (P=0.34). Besides, no statistical significant difference was observed in 16 newly diagnosed T-cell ALL(median 0.06%, range 0%¡«9.947%), 70 AML and 43 healthy donors (P¡¯s > 0.05), but it was higher in SupB15 and Nalm-6 cells from B-cell ALL cell lines than in other cells from AML or T-cell ALL cell lines.
Conclusion: These results suggest that abnormal expression of CCL17 in leukemia may be involved in the pathomechanism of B-cell ALL.
Figure 1 A: CCL17 expression levels in B-cell ALL and healthy donors( ** represent P< 0.01). B: CCL17 expression levels in human hematologic malignant cell lines. Figure 1. A: CCL17 expression levels in B-cell ALL and healthy donors( ** represent P< 0.01). / B: CCL17 expression levels in human hematologic malignant cell lines.

Disclosures
No relevant conflicts of interest to declare.
Clinical and Pathological Features and Differential Diagnosis of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): a Series of Cases
Authors: Cesarman-Maus Gabriela , Lome Carmen , Espinosa Karla Adriana , Quezada-Fiallos Carmen Marcela , Rivas Silvia , Quezda Roxana 
Published: October 2019

Abstract
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is a recently recognized highly aggressive malignant proliferation of plasmacytoid dendritic-cell (PDC) precursors which consistently express CD4, CD56 and CD123. Mortality is high despite transplant and the response to treatment is poor, except for preliminary results with conjugated anti-CD123. Clinically, cutaneous involvement is the most common feature with or without the presence of initial bone marrow infiltration, however patients may present with bone marrow-only disease. BPDCN is underdiagnosed, and can be confused with several entities, including acute myeloid leukemia. We describe our experience with 7 cases of BPDCN, their clinical and pathological presentation, and describe possible misdiagnosis and the antibodies that may help in corroborating BPDCN. See table for clinical characteristics at diagnosis. Diagnosis of BPDCN must take into account clinical, morphological and immunohistochemical analysis (IHC), since these tumors variably express markers that may be shared with other neoplasias including CD56 and TCL-1. When IHC is not categorical for BPDCN, the WHO recommends reporting the cases as AML of ambiguous lineage. The typical IHC includes CD4, CD43, CD45RA, CD56, CD123, TCL1, CLA and CD68. The absence of CD56 does not exclude the diagnosis. Markers shared with other hematological tumors include: CD7, CD33, CD2,CD36 and CD38 and TdT. Thus differential diagnosis should be done primarily with A) Skin infiltration by acute myeloid leukemia (myeloperoxidase +, 7- lysozyme +, CD34 +, CD117 +/-) B) Skin Infiltration by T / NK extra nodal lymphoma ( CD8 , cytotoxic cytoplasmic granules [CCG] , granzyme B, perforin, TIA1 and EBER) C) cutaneous peripheral T lymphoma ( +/- CD8, CD2 +/-, +/- CD5, CD7 +/- and variably positive CCG´s). D) Other histiocytic and dendritic cell-neoplasms may also be considered in the differential diagnosis however the histological appearance is usually characteristic. BPDCN is a poorly known entity that should be suspected by both clinician and pathologist in order to make a correct diagnosis.
Table Table.

Disclosures
No relevant conflicts of interest to declare.
The Combination Effect of Homoharringtonine and Ibrutinib on FLT3-ITD Mutant Acute Myeloid Leukemia
Authors: Li Xia , Yin Xiufeng , Wang Huafeng , Huang Jiansong , Yu Mengxia , Ma Zhixin , Li Chenying , Zhou Yile , Yan Xiao , Huang Shujuan , Jin Jie 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a highly heterogenous disease and the patients with an internal tandem duplication mutation in FMS-liketyrosine-kinase-3 (FLT3-ITD) have a negative impact on outcome. Finding effective treatment regimens is desperately needed. In this study, we explored the inhibitory effects and mechanism of homoharringtonine (HHT) in combination with ibrutinib on FLT3-ITD mutant AML cells. Consequently, we observed a synergistic inhibitory effect when ibrutinib was combined with HHT to inhibit cell proliferation, induce apoptosis and arrest cell cycle at G0/G1 phase in MV4-11 and MOLM-13 leukemia cells. Our results indicate that the mechanisms of the combination effect are mainly via regulating the STAT5/Pim-2/C-Myc pathway, AKT pathway and Bcl-2 family, activation p21WAF1/CIP1 and inhibiting CCND/CDK complex protein. Interestingly, synergistic cytotoxicity of ibrutinib and HHT was both dependent of FLT3 and BTK. Here we provide a novel effective therapeutic approach for the treatment of AML patients with FLT3-ITD mutation.

Disclosures
No relevant conflicts of interest to declare.
Remodeling Ca2+ Flux By ORP4L Is Essential for Leukemia Stem Cells (LSCs) Survival
Authors: Zhong Wenbin , Olkkonen Vesa , Bing Xu , Zhu Biying , Li Guoping , Li Jian , Yi Qing , Yan Daoguang 
Published: October 2019

Abstract
Acute myelogenous leukemia (AML) is one of the deadliest hematological malignancies and there is at present no efficient strategy to defeat it. New detailed insight into AML leukemia stem cells (LSCs) survival will facilitate the identification of targets for the development of new therapeutic approaches. Recent work has provided evidence that LSCs are defective in their ability to employ glycolysis, but are highly reliant on oxidative phosphorylation, and the maintenance of mitochondrial function is essential for LSCs survival. It is increasingly clear that Ca2+ released constitutively from endoplasmic reticulum (ER) is taken up by mitochondria to sustain optimal bioenergetics and cell survival. Here we report three striking findings: 1) oxysterol-binding protein (OSBP)-related protein 4 (ORP4L) is expressed in LSCs but not in normal hematopoietic stem cells (HSCs). 2) ORP4L is essential for LSC bioenergetics; It forms a complex with PLCβ3 and IP3 receptor 1 (ITPR1) to control Ca2+ release from the ER and subsequent cytosolic and mitochondrial parallel Ca2+ spike oscillations that sustain pyruvate dehydrogenase (PDH) activation and oxidative phosphorylation. 3) ORP4L inhibition eradicates LSCs in vitro and in vivo through impairment of Ca2+-dependent bioenergetics. These results suggest a novel role of ORP4L in governing Ca2+ release to sustain mitochondrial function and survival of LSCs and identify ORP4L as a putative new oncoprotein and therapeutic target for LSCs elimination.

Disclosures
No relevant conflicts of interest to declare.
Clinical Research and Genomic Analysis on Relapsed or Refractory Angioimmunoblastic T Cell Lymphoma with Chidamide Monotherapy
Authors: Wu Yu , Xu Juan , Tang Yuan , Jia Yongqian 
Published: October 2019

Abstract
BACKGROUND: This study was to evaluate the efficacy and safety of chidamide monotherapy, which is a new histone deacetylase inhibitor (HDAci) of the benzamide class, in relapsed or refractory Angioimmunoblastic T cell lymphoma (AITL), to investigate its genomic expression signatures as well as the mechanisms of chidamide's anti-lymphoma effect and its resistance.
METHODS: Two cases with relapsed or refractory AITL were treated with chidamide. We performed a repeated biopsy on relapsed lymphomas and did whole genome next-generation sequencing (NGS) testing on drug -resistant tumor samples.
RESULTS: The first patient is a 54-year-old man presented with stage Ⅳ AITL. He underwent autologous stem cell transplantation in his first complete remission (CR) but relapsed 7 months later. In view of resistance to multiple lines of chemotherapy and poor performance status, chidamide was adaministered orally at a standard dose of 30mg twice a week. Pulmonary lesions regressed quickly and a second CR was achieved. Adverse events included grade 2 cytopenias, diarrhea, and reversible QT interval prolongation. The disease free survival was 6 months and AITL relapsed again 4 months ago. He responded to low-dose chidamide combined with lenalidomide and dexamethasone and remains well. Formalin-fixed, paraffin-embeded tumor tissues collected at first relapse were tackled for whole-genome sequencing. The other patient is a 62-year-old woman who had stage Ⅲ AITL. Disease progressed after two cycles of combined chemotherapy, thereafter a standard dose of chidamide monotherapy was initiated. With well tolerability, an unconfirmed CR was achieved and lasted for nearly 3 months. She is still alive but remains refractory to various salvage therapeutics, including chemotherapies, arsenic trioxide, thalidomide, and pralatrexate. A rebiopsy was perferomed and the histopathological findings confirmed the relapse of AITL, associated with Epstein-barr virus infection. Fresh tumor tissues were sent for whole-genome sequencing. In both cases, NGS testing identified mutations of RHOA gene, epigenetic regulators TET2, IDH1, and DNMT3A, as well as CD28.
CONCLUSIONS: Chidamide, a low nanomolar inhibitor of HDAC1, 2, 3, and 10, was approved in China for the management of relapsed and/or refractory peripheral T cell lymphoma. It's reported that patients with AITL tended to have higher response rates and more durable responses to chidamide treatment. Our report showed single-agent chidamide is a reasonable approach to treat the formidable disease but seemed difficult to achieve a sustained remission. Various genetic, epigenetic, and immune alterations involve in the pathogensis of AITL, which provide targets for chidamide therapy. High-throughput sequencing approach is very helpful to clarify the mechanisms.

Disclosures
No relevant conflicts of interest to declare.
Kidney Damage in the Manifestation of Lymphoproliferative Diseases
Authors: Boldukyz Dzhumabaeva Tolgonbaevna , Ludmila Birjukova Semenovna , Hunan Julhakyan , Saliya Maryna , Ludmila Roshchina Sergeevna 
Published: October 2019

Abstract
Objectives:
Kidney lesions at lymphoproliferative diseases mainly described with disease progression or relapse. Renal involvement in the manifestation of lymphoproliferative diseases were observed rarely. Pathogenesis of renal damage is obscure.
Aim: To determine especially renal damage in the manifestation of lymphoproliferative diseases.
Subjects and methods. The study included 19 patients (13 males, and 6 females, age 63.3±8.8 years) with lymphoproliferative diseases accompanied by renal failure: chronic lymphocytic leukemia (n=12), marginal zone lymphoma (n=4), follicular lymphoma (n=1), Waldenstrom's macroglobulinemia (n=1), diffuse large B-cell lymphoma (n=1). Nephrotic syndrome was observed in 3 patients and renal failure in 18 ones. The average creatinine level was 330.9±152.3 μmol/l, glomerular filtration rate was 25.7±12.9 ml/min. The presence of monoclonal IgMk secretion (n=6), Bence Jones protein kappa (n=9), increased level of free light chains (n=4), cryoglobulin (n=4). The renal biopsy was studied by histological, immunohistochemical, immunofluorescence, and electron microscopy.
Results:Glomerulonephritises were revealed in 10 cases (52.6%): membranoproliferative glomerulonephritis (n=2), membranous (n=2), mesangiocapillary (n=3), fibrillary (n=1), immunotactoid glomerulonephritis (n=1), minimal-change disease (n=1). Neoplastic lymphoid infiltration of renal parenchyma was detected in 10 (52.6%) cases. The massive diffuse small cell lymphoid proliferation was determined in 1 case, focal infiltration in 9 ones. Neoplastic lymphoid infiltration was associated with glomerulonephritis in 3 cases and with carcinoma of the kidney in 4 cases. Large focal lymphoid proliferation was found in 1 case in a patient with diffuse large B-cell lymphoma. AL - amyloidosis was identified in 2 cases and the thrombotic microangiopathies in 2 ones.
Conclusion. Glomerular disease, lymphoid tumor infiltration, sometimes AL - amyloidosis, thrombotic microangiopathy were detected in the manifestation of lymphatic tumor. In all cases examined, there was a secretion of monoclonal immunoglobulin, protein Bence Jones, free light chains and cryoglobulin, pathogenetic value in the development of glomerulopathy should be clarified.

Disclosures
No relevant conflicts of interest to declare.
The Clinical Features and Prognosis of Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia: A Large Series Analysis from a Single Center
Authors: Xiong Wenjie , Yi Shuhua , Li Heng , Li Zengjun , Lv Rui , Liu Wei , Xu Yan , Zou Dehui , Hao Mu , Qiu Lugui 
Published: October 2019

Abstract
Background: Lymphoplasmacytic Lymphoma/Waldenströmmacroglobulinemia (LPL/WM) is a rare B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and /or bone marrow infiltration by lymphocyte, lymphoplasmacytic and/or plasma cells. The clinical features and prognosis of WM/LPL have less been investigated in Chinese patients. Moreover, few studies had reported the prognostic value of cytogenetic aberrations in Chinese WM/LPL patients.
Methods: We systematically reviewed the records of 233 LPL/WM patients, who had been diagnosed at institute of Hematology&Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College.
Results: The median age of 233 patients was 62 years (range 32-87) and the male to female ratio was 2.76 (171/62). The most common symptoms at diagnosis were fatigue (59.1%) and bleeding (11.2%). The patients in low, intermediate and higher risk group of the international prognostic scoring system for WM (ISSWM) occupied 14.9%, 32.6% and 52.6%, respectively. 90.4% and 16% patients showed an elevated serum β2-microglobulinand LDH. The percentages of hepatomegaly, splenomegaly, peripheral lymphadenopathy, B symptom were 14.9%, 34.5%, 43% and 29.3%, respectively. The degree of splenomegaly was always mild or moderate, only 19.1% patients with giant spleen. The karyotypes abnormalities were not common in LPL/WM patients. Only 8.9% (14/157) patients had abnormal chromosome karyotypes. The most common cytogenetic aberration detected by fluorescence in situ hybridization (FISH) were deletion of 17q13 (9/120, 7.5%), trisomy 12(5/58, 8.6%). Other aberrations include 13q14 deletion in 3 of 128 patients (2.3%), 11q22 deletion in2 of 90 patients (2.2%). Univariate analysis showed that age>62 years, leukocytopenia, thrombocytopenia, anemia, cytopenias ≥ 2, elevated LDH, abnormal chromosome karyotypes, P53 deletion and high risk of ISSWM were adverse risk factors for OS. But only clinical effect not reaching partial response (p=0.006), elevated LDH (p=0.049) and leukocytopenia (p=0.048) were the independent prognostic factors at multivariate analysis.
Conclusion: Distinct characteristics exist in WM in China compared with the Western country. Elevated LDH and leukocytopenia were the independent adviser factors for OS in this series patient.

Disclosures
No relevant conflicts of interest to declare.
Failure Pattern of Treatment of Hodgkin Lymphoma -- Retrospective from a Single Institution
Authors: Tan Tran-Der , Chiou Lun-Wei 
Published: October 2019

Backgound:
Hodgkin lymphoma is a highly curable malignant disease by chemotherapy or chemoradiation. However, there is still small percentage of patients can not achieved complete remission or relapsed later then died of disease refractoriness. We investigated the treatment failure pattern in those relapsed and refractory patients.
Method:
This is a retrospective study of patients treated at our institute in ten years with ABVD +/- RT. For relapsed patients, the salvage chemotherapy includes DHAP, ICE, or GDP, and patients may undergo high dose chemotherapy plus hematopoietic stem cell transplantation when second remission achieved.
Results:
Between 2002 and 2012, we have treated 108 patients of Hodgkin lymphom and the ten-year overall survival was 92% with stage I and II (N=63) versus III and IV (N=45) were 100% and 80%, respectively. Twenty patients got disease relapsed after ABVD +/- RT with 6 patients died of disease refractoriess and 14 patients achieved second remission after salvage chemotherapy then underwent hematopoietic stem cell transplantation with 11 survived over ten years. In these 20 relapsed patients, the initial involved sites include lung (n=8), bone (n=5),bone marrow (n=5), liver (n=3), mediastinal bulky (n=2), nodal only (n=2).
Conclusion:
Stage IV with extramedullary involvement over lung, bone, bone marrow and liver are high risk for treatment failure and earlier intensive treatment is warranted.

Disclosures
No relevant conflicts of interest to declare.
Everolimus Is Active in Pretreated Hodgkin Lymphoma after Failure of Brentuximab Vedotin: Single Institute Experience
Authors: Dada Reyad , Yassin Fawwaz 
Published: October 2019

Abstract
Introduction: Patients with Hodgkin lymphoma (HL) relapsing after ASCT and those not eligible for myeloablative therapy can be salvaged with conventional chemotherapy or new novel agents such the immunotoxin brentuximab vedotin and the recently FDA approved anti-PD-1 inhibitor nivolumab. Other options include the mTOR inhibitor everolimus (1) for which, the data in literature is scarce. Moreover, there is no data on the efficacy of everolimus after failure of brentuximab vedotin.
Patients and methods: In this study, we retrospectively analyzed the outcome of patients with relapsed/ refractory HL treated with single agent everolimus at our center between July 2015 and July 2016. All patients were started on everolimus 10 mg daily. Response to treatment was assessed every 2 months. Primary endpoint was the response rate of everolimus as single agent in patients with relapsed/refractory HL.
Results: We identified 5 patients with heavily pretreated HL who received single agent everolimus. Mean age was 24.4 years (range, 20-30). Mean lines of previous treatment was 6.4 (range, 5-8). All patients failed brentuximab vedotin. Two patients failed previous autologous stem cell transplantation. Prior treatments included ABVD, radiation, ICE, ESHAP, miniBEAM, GVD, brentuximab vedotin, gemzar plus brentuximab vedotin, bendamustine, and ASCT.
Mean duration of everolimus treatment was 5 months (range 4-7). One patient showed complete metabolic remission after 5 months of treatment. This remarkable response was achieved after failure of 6 lines. Partial remission and stable disease each were documented in 40%. Grade 1 neutropenia was reported in 80%. Grade 2 anemia, thrombocytopenia, fatigue and stomatitis were observed in 60%, 80%, 20% and 20% respectively. Everolimus dose reduction (5 mg) was required in two cases (one patient had grade 2 thrombocytopenia and other one had grade 3 fatigue). The latter discontinued the treatment after 4 months and is still in complete remission 5 months after discontinuation. No pulmonary toxicity was observed.
Conclusion:The presented data suggest that everolimus is effective in heavily pretreated HL patients who failed conventional treatment including ASCT and new novel agents with 60% ORR. This result is the first of its kind showing efficacy of everolimus after failure of brentuximab vedotin.
Literature: Johnston PB et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010 May;85(5):320-4.

Disclosures
No relevant conflicts of interest to declare.