bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Worldwide Meta-Analysis on the Use of Zidovudine and Interferon-alpha for the Treatment of Adult T–Cell Leukemia/Lymphoma.
Authors: Bazarbachi Ali , Panelatti Gerard , Ramos Juan Carlos , Tortevoye Patricia , Otrock Zaher , Taylor Graham , Gessain Antoine , Harrington William , Plumelle Yves , Hermine Olivier 
Published: April 2020

Abstract
HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small phase II studies using zidovudine (ZDV) and interferon-alpha (IFN) showed response in ATL patients. However, the impact of this therapy on ATL prognosis remains to be determined. Here, we report a worldwide meta-analysis on the use of ZDV/IFN treatment for ATL in 209 patients treated from 1994 to 2006. Patients were recruited in the USA (27 patients), the UK (13 patients), Martinique (102 patients) and France metropolitaine (67 patients). Collected data included geographic origin, age, sex, type of the disease, clinical presentation, LDH levels, calcemia, and lymphocytes number. Median age was 49 years (range 16 to 95). According to Shimoyama classification, there were 98 acute ATL, 20 chronic ATL, 9 smouldering ATL, 75 ATL lymphoma, and 7 patients with an unknown subtype. Hypercalcemia was present in 60% of patients. The data concerning the course of the disease were also collected, particularly the response status, the length of the response, the duration of ZDV+IFN therapy, as well as previous and post chemotherapy treatments. One hundred patients received first line ZDV+IFN therapy. In these patients, response rate was 66%, including 43% of patients achieving complete remission (CR). Median overall survival and 5 year overall survival rate were 24 months and 50% for patients who received first line ZDV+IFN therapy, versus 7 months and 20% for patients who received first line chemotherapy. When analysis was performed by ATL subtype, patients with acute, chronic, and smouldering ATL significantly benefited from first line ZDV+IFN therapy, whereas no additional benefit was achieved in patients with ATL lymphoma. Achievement of CR with first line ZDV+IFN therapy resulted in prolonged survival of more than 10 years in 70% of the study population, and 75% of the acute ATL subgroup. Finally, first line ZDV+IFN therapy in chronic and smouldering ATL resulted in 100% overall survival at 10 years. In conclusion, these results confirm that treatment of ATL using ZDV and IFN results in a high response and CR rates particularly in acute, chronic and smouldering ATL, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy.
Generation of alpha-Type-1 Polarized Dendritic Cells as a Potent Immunogen in Patients with Chronic Lymphocytic Leukemia.
Authors: Lee Je-Jung , Mailliard Robbie , Muthuswamy Ravikumar , Foon Kenneth A. , Kalinski Pawel 
Published: April 2020

Abstract
We tested the feasibility of generating alpha-type-1 polarized DC (αDC1) from the blood of chronic lymphocytic leukemia (CLL) patients and the in vitro effectiveness of autologous tumor-loaded αDC1s in inducing CTLs against CLL. CD14+ cells were isolated from the peripheral blood of CLL patients and were cultured in rhu GM-CSF and IL-4. On day 6, DC maturation was induced using either a standard cytokine cocktail (in IL-1β, TNFα, IL-6, and PGE2) or αDC1-polarizing cocktail (in IL-1β, TNFα, IFNα, IFNγ, and poly-I:C). In either case, the maturing DCs were loaded with gamma-irradiated autologous CLL cells. αDC1s from CLL patients expressed substantially higher levels of several costimulatory molecules (CD83, CD86, CD80, CD11c and CD40) than standard DCs (sDCs) while CCR7 showed lower expression. Gamma-irradiated CLL cells were more efficienly taken up by DCs compared to UVC-irradiated CLL cells, but the ability of tumor antigen uptake was similar between αDC1 and sDCs. The capacity of IL-12p70 secretion in DCs (baseline and after stimulation with CD40L-transfected J558 cells) was significantly elevated in αDC1s (10–60 times) compared to sDCs. αDC1s also induced significantly higher numbers of functional CD8+ T cells against CLL cells, as determined by IFN-γ ELISPOT, using anti-MHC class I blocking mAb (W6/32) to verify the specificity of CTL responses. Our data demonstrate that αDC1s are a potent alternative to standard DCs as inducers of T cells for adoptive immunotherapy in patients with CLL and a clinical trial will be initiated.
Gene Conversion Is a Late Event in Evolution of High Risk AML.
Authors: Meshinchi Soheil , Pollard Jessica A. , Tsuchiya Karen D. , Stirewalt Derek A. , Bernstein Irwin D. , Radich Jerald 
Published: April 2020

Abstract
Evolution and progression of AML is considered a result of cooperation of multiple genetic and epigenetic alterations. FLT3 internal tandem duplication (ITD) is a common mutation in AML and is considered a secondary, proliferative event in the pathogenesis of AML. We used SNP/CGH microarrays to evaluate the mechanism of disease evolution in FLT3/ITD-positive AML. Diagnostic DNA from patients with FLT3/ITD (N=25), FLT3 activation loop mutation (FLT3/ALM, N=15) or with no FLT3 mutations (FLT3/WT, N=55) was evaluated for copy number and LOH alterations. 12/25 (48%) FLT3/ITD-positive patients had loss of heterozygosity (LOH) of a large segment of 13q arm downstream of the FLT3 gene without an associated chromosome loss, demonstrating a copy neutral LOH (CN-LOH) state. In contrast, CN-LOH was not detected in those with FLT3/ALM or FLT3/WT suggesting that FLT3/ITD is causally associated with evolution of CN-LOH. Single cell analysis of the FACS purified leukemic blasts from FLT3/ITD-positive samples that were heterozygous for 13q (no CN-LOH) by SNP/CGH arrays demonstrated the presence of 3 distinct molecular subtypes that included a subpopulation with CN-LOH, as well as heterozygous ITD and FLT3/WT, demonstrating oligoclonal nature of the leukemic blast population which prevented identification of CN-LOH. In patient samples with CN-LOH, CFU-GM and BFU-E colonies derived from CD34+/CD33- progenitors demonstrated heterozygous ITD, with no LOH or copy number alterations. In contrast, more differentiated, CD33+ leukemic blasts as well as CFU-GM colonies derived from CD34+/CD33+ progenitors had homozygous ITD and CN-LOH. This cumulative data demonstrates that CN-LOH of the 13q, as a result of gene conversion-type event mediates the pathogenesis of FLT3/ITD and is a secondary event in the evolution of high risk FLT3/ITD. Gene conversion, leading to haplo-insufficiency may be an important event in the evolution of AML.
Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14 with Differential Expression of LATS2.
Authors: Malek Sami N. , Erba Harry , Mark Kaminski S. , Kerby Shedden , Peter Ouillette 
Published: April 2020

Abstract
Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness with a variable clinical course. Loss of chromosomal material on chromosome 13 at cytoband 13q14 is the most frequent genetic abnormality in CLL but the molecular aberrations underlying del13q14 in CLL remain incompletely characterized. We analyzed 171 CLL cases for LOH and sub-chromosomal copy loss on chromosome 13 in DNA from FACS-sorted CD19+ cells and paired buccal cells using the Affymetrix XbaI 50K SNP array platform. Comparative analysis of SNP-array-derived detection of del13q14 using copy number analysis compared with clinical FISH results for del13q14 demonstrated strong agreement between both methods: FISH detected 91/171=53% overall del13q14 incidence and 77/171=45% del13q14 cases with greater than 25% of cells involved. SNP-arrays detected 82/171=48% del13q14 incidence. SNP-arrays detected 74/77=96% of all CLL cases that were greater than 25% FISH positive and 82/91=90% of all CLL cases that were FISH positive (% positive range for FISH was 2–97%). Finally, SNP-arrays detected 2 CLL cases not previously known to be del13q14 by FISH. The resulting high-resolution genomic maps, together with array-based measurements of expression levels of RNA in CLL cases with and without del13q14 and Q-PCR-based expression analysis of selected genes, support the following conclusions:
del13q14 is heterogeneous and composed of multiple subtypes (types Ia, Ib and II) with deletion of Rb or the miR15a/16 loci serving as anatomic landmarks, respectively; del13q14 type Ia deletions are relatively uniform in length and extend from breakpoints close to the miR15a/16 cluster to a newly identified telomeric breakpoint cluster at ∼50.2–50.5 Mb physical position; LATS2 RNA levels are ∼2.6–2.8 fold lower in cases with del13q14 type I that do not delete Rb, as opposed to del13q14 type II lesions or all other CLL cases; ∼15% of CLL cases display marked reductions in miR15a/16 expression that are often but not invariably associated with bi-allelic miR15a/16 loss; and Bcl-2 levels and miR16/15a locus loss or miR16/15a expression are not correlated.
This data should aid future investigations into biological differences imparted on CLL by different del13q14 subtypes, including investigations into LATS2 as one of the genes found deregulated as part of del13q14 type I and investigations into additional miR16/15a targets.
Eph Receptor Tyrosine Kinases and Ephrin Ligands Are Epigenetically Inactivated in Acute Lymphoblastic Leukemia and Are Potential New Tumor Suppressor Genes in Human Leukemia.
Authors: Kuang Shao-qing , Fang Zhi-Hong , Lopez Gonzalo , Tong Weigang , Yang Hui , Garcia-Manero Guillermo 
Published: April 2020

Abstract
The Eph (erythroprotein-producing hepatoma amplified sequence) family receptor tyrosine kinases and their ephrin ligands (ephrins) are involved in a variety of functions in normal cell development and cancer. We have identified several members of this family as potential targets of aberrant DNA methylation using Methylated CpG Island Amplification (MCA) / DNA promoter microarray technology. This is of importance as there are no prior reports of potential Eph receptor or Ephrin epigenetic inactivation in human leukemia. To further investigate the role of Eph receptor and ephrin family genes in leukemia, we have analyzed their DNA methylation status in a panel of 23 leukemia cell lines and 65 primary ALL patient samples. Aberrant DNA methylation of 9 of these genes (EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3) was detected in multiple leukemia cell lines but not in normal samples by bisulfite pyrosequencing. In ALL patient samples, the frequencies of DNA methylation detected in the promoter regions of these genes ranged from 23% to 87% for EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3. Expression analysis of 3 of these genes (EPHA5, EPHB4 and Ephrin B2) in leukemia cell lines by real-time PCR further confirmed methylation associated gene silencing. Treatment of methylated/silenced cell lines with DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine resulted in gene re-expression. Forced overexpression of EPHB4 using a lentivirus transduction system in Raji cell lines resulted in decreased cell proliferation and adhesion-independent cell growth, as well as in an increase in staurosporine induction of apoptosis. In addition, EPHB4 overexpression resulted in a significant downregulation of phosphorylated Akt pathway but had no effect on mitogen-activated protein kinase pathway. In summary, we describe for the first time the epigenetic suppression of Ephrin receptors and their ligands in human leukemia, indicating that these genes may be potential tumor suppressors in leukemia. Targeting of these pathways may result in the development of new potential therapies and biomarkers for patients with ALL.
Hazard of Subsequent Hematological Cancer in Patients with Incident Venous Thromboembolism (VTE): A Population-Based Cohort Study.
Authors: Gangat Naseema , Ashrani Aneel A. , Petterson Tanya M. , Schmoll Jeffery , Heit John A. 
Published: April 2020

Abstract
Background: While currently-diagnosable hematological cancer is a potent VTE risk factor (RR range =12–32), whether undiagnosable hematological cancer is a risk factor is uncertain.
Objective: To estimate the hazard of subsequent hematological cancer among incident VTE patients with no apparent active hematological cancer within ± 3 months of the VTE event.
Methods: In a population-based cohort study, we followed Olmsted County, MN residents with incident VTE over the 27-year period, 1973–1999, and previously matched Olmsted County residents without VTE, who survived with no apparent active hematological cancer within ± 3 months of the VTE event or a routine medical visit date, respectively, forward in time through their complete medical records in the community for hematological cancer. Data were abstracted on baseline demographic and clinical characteristics, type and stage of hematological cancer, and any prior solid tumor treatments. For cases and controls, hematological cancer-free survival from the event date was estimated by the Kaplan Meier method, and the homogeneity of survival curves was examined by the log-rank test. Cox proportional hazards regression was used to adjust for covariates.
Results: 1860 VTE cases (56% females) and 1890 controls (53% females) were followed for 16,497 and 15,320 person-years, respectively, conditional on surviving 3-months free of hematological cancer. 43 VTE cases and 24 controls developed hematological cancer at a median of 63.5 months (range 0.7 – 334 months). The median age for cases was 63.2 years compared to 67.8 years for the controls (p&lt;0.001). Hematological cancer types included non-Hodgkin’s lymphoma (n=19), chronic lymphocytic leukemia (n=11), acute myeloid leukemia (n=1), multiple myeloma (n=9), myeloproliferative disorders (n=10), and myelodysplastic syndromes (n=14). Case status was not univariately associated with subsequent hematologic cancer (HR=1.42; 95% CI: 0.85, 2.39; p=0.18). After adjusting for age, also associated with cancer, case status was significantly associated with hematological cancer (HR=1.90; 95% CI: 1.13, 3.20; p=0.015).
Conclusions: Incident VTE patients have nearly a two-fold increased risk of subsequent hematological cancer. We hypothesize that VTE can be the initial manifestation of an occult hematological cancer clone.
Phosphorylation of AML1/Runx1 Is Essential for T Cell Differentiation and Early Hematopoietic Development.
Authors: Yoshimi Mayumi , Goyama Susumu , Nakagawa Masahiro , Asai Takashi , Ichikawa Motoshi , Kurokawa Mineo 
Published: April 2020

Abstract
AML1/Runx1 is one of the most frequent targets of gene aberrations associated with human acute myelogenous leukemia and myelodysplastic syndrome. Furthermore, gene-targeting studies in mice demonstrated that AML1 is a critical regulator for T-cell differentiation and early development of definitive hematopoiesis. It has been shown that phosphorylation of AML1 at specific serine/threonine residues (276, 293, 300, 303) controls both transcriptional activity and rate of degradation. However, the biological consequences of phosphorylation with respect to AML1 function are unclear. In this study, we evaluated hematopoietic activities of AML1 mutants which harbor serine/threonine-to-alanine (A) or serine/threonine-to-asparatic acid (D) mutations at these phosphorylation sites using primary culture systems. We first evaluated the biologic effects of AML1 phosphorylation on T-cell differentiation using the fetal liver (FL)/OP9-DL1 coculture system. In this system, AML1-excised FL cells failed to undergo normal T-cell differentiation, which is successfully restored by the reintroduction of wild-type AML1. AML1-4A, which cannot be phosphorylated at any of the four serine/threonine residues, showed a severely impaired capacity to rescue the defective T-cell differentiation of AML1-deficient cells. We also demonstrate that blocking the ERK-mediated phosphorylation of AML1 by the MEK inhibitor significantly suppressed the AML1-induced T-cell differentiation. Next, we assessed the effect of AML1 phosphorylation on early hematopoietic development using para-aortic splanchnopleural (P-Sp) region/OP9 coculture system. In this system, AML1-deficient P-Sp cells failed to produce any hematopoietic cells and this hematopoietic defect can be rescued by retrovirally transferred AML1. AML1–4A could rescue the hematopoietic defect of AML1-deficient P-Sp cells, but the emergence of hematopoietic cells in cultures infected with AML1–4A was reproducibly delayed two or more days compared with those infected with wild-type AML1. Because it was shown that serine 462 is phosphorylated upon phorbol ester treatment together with the four phosphorylation sites, we then generated AML1 mutants in which serine 462 is substituted with alanine (A) or aspartic acid (D) in AML1–4A or AML1–4D respectively (AML1–5A or AML1-5D). Interestingly, introduction of AML1–5A into AML1-deficient P-Sp cells did not generate any hematopoietic cells. Moreover, AML1–5A completely lost its T-cell differentiation activity. In contrast, the phospho-mimic protein, AML1–5D rescued the hematopoietic defects of AML1-deficient cells as efficiently as wild-type AML1. Taken together, these results suggest that phosphorylation of AML1 at the five serine/threonine residues (276, 293, 300, 303 and 462) is essential for T cell differentiation and early hematopoietic development.
Indian Hedgehog Is Essential for Definitive Haematopoiesis in the Fetal Liver.
Authors: Perkins Andrew C. , Cridland Simon 
Published: April 2020

Abstract
Indian hedgehog (Ihh) is a member of the hedgehog family of secreted proteins which play diverse roles in development. Members of this family have established roles in craniofacial development, long bone formation and spermatogenesis. Mammals have three hedgehog proteins which all act through the Patched receptor to activate smoothened and downstream zinc finger transcription factors of the Gli family. Ihh can induce differentiation of primitive red blood cells during primitive streak formation, and definitive red blood cells from CD34+ cord blood stem cells. Both Ihh and the Patched receptor are expressed in the fetal liver. In this report we show Ihh knockout mice display a partially penetrant defect in fetal liver haematopoiesis characterised by severe anaemia and apoptosis of the fetal liver erythroid compartment. Primitive haematopoiesis is normal, so mutant embryos survive until ∼E14. Components of the hedgehog signalling pathway are expressed in stromal, stem cell and progenitor cell components of the haematopoietic system. Lastly, fetal liver progenitor cells (CFU-e, BFU-e, and myeloid CFUs) are normal in Ihh null mice, suggesting a critical requirement for Ihh in the fetal liver stem cell niche.
Mechanism for γ-Globin Induction by SCF Is Via PKCα/ERK1/2/Nrf2 Dependent Signal Pathway To Regulate Down-Stream Transcriptional Regulators NF-Y and COUP-TFII.
Authors: Aerbajinai Wulin , Zhu Jianqiong , Gao Peter , Chin Kyung , Rodgers Griffin P. 
Published: April 2020

Abstract
Increased fetal hemoglobin has been identified to be associated with stress erythropoiesis. However, the mechanisms underlying γ-globin induction during the rapid expansion of erythroid progenitor cells have not been fully elucidated. Here we examined how intracellular signaling pathway modification of specific transcriptional regulators induced γ-globin expression in vitro cultured erythroid progenitor cells in the presence of erythropoietin and stem cell factor (SCF). We find that γ-globin induced by SCF is through a PKCα-dependent Ras/Raf/Erk1/2 signaling pathway involving activation of the transcription factor NF-Ya and inhibition of the repressor Coup-TFII. Specific inhibition of PKCα with Go6976 blocked both activation of Erk1/2 and p38 MAPK induced by SCF, and abrogated the SCF increased γ-globin gene expression. Activation of Erk1/2 plays a critical role in SCF modulated down-stream transcriptional regulators, involving regulation of γ-globin gene induction. SCF induced nuclear translocation of NF-Ya is required to activate Erk1/2 increased phosphorylation of endogenous Nrf2, which involves up-regulation of thioredoxin, and down-regulation of Coup-TFII. Inhibition of either PKCα or Erk1/2 prevented SCF induced recruitment of NF-Ya, RNA polymerase II and displacement of Coup-TFII repressor from γ-globin-promoter, indicating that the PKCα-Erk1/2 MAPK pathway contributes to SCF induced the γ-globin gene induction in adult erythropoiesis. Furthermore, consistent with this concept, SCF induced the γ-globin gene induction attenuated by inhibition of PKCα or Erk1/2 MAPK. Our data suggest that SCF stimulates the PKCα-Erk1/2 MAPK signaling pathway which regulate the downstream transcriptional activator NF-Ya and repressor Coup-TFII resulting in γ-globin reactivation in adult erythropoiesis. These observations provide the molecular pathways that take part in γ-globin augmentation during “stress erythropoiesis”.
Interferon-α2b-Induced Thrombocytopenia Is Caused by Inhibition of Cytoplasmic Maturation and Platelet Production, but Not Proliferation and Endomitosis in Human Megakaryocytes.
Authors: Yamane Akiko , Nakamura Takanori , Ito Mamoru , Ohnishi Yasuyuki , Ikeda Yasuo , Miyakawa Yoshitaka 
Published: April 2020

Abstract
Human interferon (IFN)-α is a standard treatment for the patients with chronic hepatitis C. It is well known that chronic hepatitis C can transform into liver cirrhosis and hepatocellular carcinoma, and the risk of progression to liver cirrhosis is around 40% in 5 years. Thus, it is important for chronic hepatitis C patients to receive IFN-α treatment to prevent its malignant transformation. Thrombocytopenia is one of the major adverse effects of IFN-α and often leads to a dose reduction or discontinuation of IFN-α therapy. However, there is little information how IFN-α inhibits human megakaryopoiesis. In this study, we demonstrated that IFN-α does not inhibit colony formation of megakaryocytes (CFU-MK) from human CD34-positive hematopoietic stem cells. IFN-α also does not inhibit endomitosis (DNA duplication without cytokinesis), but inhibits cytoplasmic maturation of megakaryocytes and platelet production in vitro. The inhibitory effects of IFN-α on the development of demarcation membrane in human megakaryocytes were visualized by staining primary megakaryocytes with di-8-ANEPPS dye under a confocal laser microscope. Loss of platelet production by IFN-α was analyzed by measuring proplatelet formation (PPF) and counting the human platelets produced in the supernatant of human primary megakaryocytes by flow cytometry. The expression of transcription factors regulating late stage megakaryopoiesis such as GATA-1, p45 NF-E2 and MafG was suppressed by IFN-α. To confirm these in vitro observations in vivo system, we transplanted human CD34-positive hematopoietic cells into the immunodeficient NOD/Shi-scid/IL-2Rγnull (NOG) mice (hu-NOG) after 2.4 Gy irradiation. Recombinant human(rh) IFN-α significantly reduced the number of human platelets but did not decrease the number of human megakaryocytes in hu-NOG mice. rhIFN-α did not change murine platelet counts in hu-NOG mice, as IFN-α has species specificity. The DNA ploidy of human megakaryocytes in the bone marrow of hu-NOG mice was not altered after treatement with rhIFN-α. We also confirmed the life time of human platelets was not shortend by rhIFN-α in hu-NOG mice, indicating IFN-α does not promote the clearance of human platelets. We have also confirmed that a novel thrombopoietin mimetics, NIP-004, prevented rhIFN-α-induced thrombotytopenia and increased the number of polyploid human megakaryocytes in hu-NOG mice, suggesting NIP-004 might be useful for the patients with hepatitis C to avoid IFN-α-induced thrombocytopenia. In conclusion, these results clarified that IFN-α induces thrombocytopenia by inhibiting the cytoplasmic maturation of megakaryocytes but not proliferation and endomitosis in human megakaryocytes.