bluuebunny/crossref_metadata_2025_split huggingface dataset:
GATA-2 L359V Mutation Is Solely Associated with Cml progression but Not Other Hematological Malignancies.
Authors: Zhang Su-Jiang , Shi Jing-Yi 
Published: April 2020

Abstract
Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell disease with distinct biology and clinical features. According to clinical and biology process, CML can be divided as two different phase: the initial chronic phase (CP) and progression phase including accelerated phase (AP) followed by blast crisis (BC). In a previous study, we have identified the transcription factor GATA-2 L359V mutation in CML BC patients but not CP and its pivotal role in CML progression (PNAS 2008 105:2076–2081). Here, we continued to explore the occurrence of GATA-2 L359V mutation in other hematological malignancies using Mass-ARRAY assay and sequence analysis. A total of 652 patient samples were included in our study. These patients were referred to 270 Acute Myeloid Leukemia (AML) including M1–M7, 30 Myelodysplastic Syndrome (MDS), 50 Acute Lymphoblastic Leukemia (ALL), 12 Chronic Lymphocytic Leukemia (CLL), 40 CML CP and 250 BCR/ABL negative Myeloproliferative Disorder (MPD) patients. 5 ml bone marrow sample before therapy was collected with informed consent and genomic DNA was isolated. The diagnosis of AML, ALL, CML, CLL, MDS and MPD was established according to the 2001 WHO diagnostic criteria. In addition, 8 samples of CML BC harboring GATA-2 L359V were supplied into our study as positive control and 100 peripheral blood samples of healthy adult as normal control. As a result, no L359V mutation was detected in AML, ALL, MDS, CLL, BCR/ABL negative MPD and CML CP. Our data strongly suggested that GATA-2 L359V is solely associated with CML progression but not other hematological malignancies. Therefore, we favored this idea, i.e., BCR/ABL underlies the pathogenic basis of CML CP; However, subsequent genomic instabilities contribute to mutation of key transcription factor such as GATA-2 which ultimately trigger the blastic transformation of CML.
Generation of T Cells from Human Embryonic Stem Cells.
Authors: Timmermans Frank , Velghe Imke , Van Walleghem Lieve , De Smedt Magda , Van Coppernolle Stefanie , Leclercq Georges , Taghon Tom , Moore Harry , Langerak Anton W , Kerre Tessa C. C. , Plum Jean , Vandekerckhove Bart 
Published: April 2020

Abstract
Background: Human embryonic stem cells (hESC) are derived from early stage blastocysts and are characterized by the ability to both self-renew and to generate differentiated functional cell types. One of the major challenges in the field of hESC research, is to set up a culture system that drives hESC down a particular lineage fate. To date, studies reporting hematopoietic development have not provided evidence on the differentiation capacity of hESC into T lineage cells in vitro. Material and
Methods: hESC line H1 (National Institutes of Health [NIH] code: WA01), Wisconson, Madison, USA) was used (Passage 30–60) in all experiments. The hESC line was kept in an undifferentiated state on MEFs as previously described. OP9 cells and OP9 cells that express high levels of the Notch ligand Delta-like 1 (OP9-DLL1, a gift from J. C. Zuniga-Pflücker, University of Toronto, Canada) were cultured as previously described in MEM-α with 20 % FCS.
Results: Our data show that T cells can be generated in vitro from hESC in a robust and highly reproducible manner using the sequential exposure of hESC to the murine OP9 cell line and OP9-DLL1. On OP9 stromal layers, a CD34highCD43dim hematopoietic precursor population is generated that is confined to vascular-like structures, reminiscent of blood islands that emerge during in vivo embryonic development. This precursor population becomes T lineage committed when exposed to OP9-DLL1 monolayers, passing sequentially through a CD34+CD7+ phenotype, a CD4+CD8+ double positive intermediate stage and eventually differentiates into a mature T cells. Polyclonal T cells are generated, cell receptor (TCR) alpha-beta and TCRgamma-delta which are functional based on proliferative capacity and production of cytokines after TCR crosslinking.
Conclusion: We show that mature and functional T cells can be generated from hESC using well defined in vitro conditions. This protocol in combination with the recently described induced pluripotent cells may find clinical applicability in tumor immunology.
Tec Kinase Inhibits the Expression of IL-2 Receptor Alpha (CD25) in Human T-Lymphocyte.
Authors: Susaki Kentaro , Kitanaka Akira , Dobashi Hiroaki , Kittaka Katsuharu , Mano Hiroyuki , Kubota Yoshitsugu , Tanaka Terukazu 
Published: April 2020

Abstract
Activation and development of lymphocytes is regulated by the engagement of cell surface immune cell antigen receptors. Following receptor engagement, these receptors transmit signals by the activation of cytoplasmic protein tyrosine kinases (PTKs). The Tec PTK belongs to a group of structurally related nonreceptor PTKs that also includes Btk, Itk (Emt), Rlk (Txk), and Bmx (Etk). We have found the contribution of Tec in the antigen receptor signaling in B-lymphoid cells in the previous studies. Despite the presence of evidences suggesting the involvement of Tec in T-lymphocyte activation pathway via T-cell receptor (TCR) and CD28, the role of Tec in T-lymphocyte still remains unclear because of the lack of apparent defects in T-lymphocyte function in Tec-deficient mice. In this study, we investigated the role of Tec in T-lymphocyte using Jurkat human T-lymphoid cell line stably transfected with a cDNA encoding Tec. We found that the expression of wild type Tec but not kinase-deleted Tec inhibited the expression of IL-2 receptor alpha (CD25) induced by TCR cross-linking. The percentage of CD25 expressing cells after TCR cross-linking was 41.7% in mock-transfected cells, 18.3% in the wild type Tec expressing cells and 41.3% in the kinase-deleted Tec expressing cells. Second, the selective inhibitor of Tec family PTK, LFM-A13, rescued the suppression of TCR-induced CD25 expression observed in the wild type Tec-expressing Jurkat cells. We conclude that Tec PTK mediates signals that negatively regulate CD25 expression induced by TCR cross-linking, implying that this PTK plays a role in the attenuation of the IL-2 activity in human T-lymphocytes.
Results of a Phase 2 NCI Multicenter Study of Romidepsin in Patients with Relapsed Peripheral T-Cell Lymphoma (PTCL).
Authors: Piekarz Richard , Wright John , Frye Robin , Allen Steven L. , Craig Michael , Geskin Larisa , Hutchins Laura , Joske David , Kirschbaum Mark , Leonard John P , Prince Miles , Reeder Craig B. , Jaffe Elaine , Bates Susan 
Published: April 2020

Abstract
Background: The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel, HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with T-cell lymphoma in a phase 1 NCI study.
Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and cutaneous T-cell lymphoma (CTCL).
Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 43 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. The clinical results for pts with PTCL are presented here; the clinical results for the pts with CTCL and the biomarker analyses for both PTCL and CTCL are presented elsewhere. This study is now closed to accrual. Pts with relapsed or refractory PTCL or primary cutaneous anaplastic large cell lymphoma were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease.
Results: 43 pts (23[53%] men and 20 [47%] women) with a mean age of 58.1 (range: 27 to 84) years were treated with romidepsin. 31 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 3.9 (range 1 to 12). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1–37) and the overall median duration of response was 8.3 months (range 1.6 months to 4.8+ yrs) for all pts. The median duration of response for the 7 pts who achieved CR was 8.5 months (range 4.6 months to 4.8+yrs). The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (86%; 0% ≥grade 3), fatigue (79%; 0% ≥grade 3), decreased platelets (70%; 7% ≥grade 3), and decreased AGC (63%; 5% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment.
Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 39% and median duration of response of 8.3 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with progressive or relapsed PTCL is ongoing at multiple international centers.
All Pts N=43 Pts ≥ 2 cycles N=31 ORR (CR+PR), n (%) 17 (39%) 17 (55%) PR, n (%) 10 (23%) 10 (32%) CR, n (%) 7 (16%) 7 (23%)
Interim Results of the RiPAD+C Regimen Including Velcade in Front Line Therapy for Elderly Patients with Mantle Cell Lymphoma. A Phase II Prospective Study of the GOELAMS Group.
Authors: Gressin Remy , Maugendre Sylvie caulet , Le Gouill Steven , Uribe Mario ojeda , Vigier Magda Alexis , Bouabdallah Krimo , Mounier Christiane , Tournilhac Olivier , Rodon Philippe , Yamani Abderrazak El , Sutton Laurent , Senecal Delphine , Lioure Bruno , Assouline David , Le Mevel Annie , Villemagne Bruno , Dauriac Charles , Gardembas Martine , Park Sophie , Lamy Thierry 
Published: April 2020

Abstract
Elderly patients with mantle cell lymphoma (MCL) do not take benefit from dose-intensive chemotherapy such as HyperCVAD because of its high toxicity (Romaguera JCO 2005). Prior Goelams clinical trials using the VAD plus Chlorambucil regimen with or without Rituximab have demonstrated a good efficacy/toxicity ratio in front line therapy (EHA 2008, a0259). Proteasome inhibitors are among the most promising new agents for relapsing patients (Fisher, JCO 2006). Therefore, the GOELAMS conducted a phase II clinical trial including Velcade plus R-AD and Chlorambucil (RiPAD + Chlorambucil) for elderly MCL patients upfront.
Aims: To evaluate toxicity and overall response rate after 4 cycles of RiPAD + Chlorambucil regimen.
Protocol: RiPAD + C: Rituximab 375 mg/sqm, D1 (and D8 for cycle 1); PS 341, Velcade 1.3 mg/sqm D1, 4, 8 and 11; Adriblastine 9mg/sqm/D in a 4 days continuous infusion; Dexamethasone 20 mgx2/D for D1 to D4; Chlorambucil 12 mg/D, D20 to D29. One cycles every 35 D. The patients received a maximum of 6 cycles.
Inclusion criteria: Untreated MCL patients (from 65 to 80 years) with a stage II to IV disease, and good PS (Ecog &lt; 3). Response criteria is evaluated according to the 1999 Cheson’s criteria, all patients were also evaluated by FDG-PETscan.
Results: since June 2007, 27 patients have been included. Thirteen have been evaluable after 4 cycles. Median age is 71 years (66–80 y). After 4 cycles, disease Status was: 10 patients in response (3 in CR with negative FDG-PETscan and 7 in PR including 3 with a negative PETscan) and 3 patients progressed on therapy. The 3 non responding patients had the highest Ki67 value over 30%. Toxicity evaluation has been evaluated based on 59 cycles. Grade 3–4 toxicities have been reported in 5 cases (2 neurologic, 1 hepatic, 1 cardiac and 1 pulmonary). Only 3 cycles were delayed because of toxic reasons.
Conclusion: this intermediaire analysis shows an ORR of 77% (10/13) including 6 patients with a negative FDG-PET after only 4 cycles. Our study demonstrates that the RiPAD+C regimen has a good efficacy/toxicity ratio and is a promising therapeutic option for MCL elderly patients. The study is ongoing and additional results on response rate and toxicity will be updated for presentation in the ASH meeting.
NPM-ALK Mutants in Kinase Domain Exhibit Altered Kinase Activity and Various Sensitivity to ALK Inhibitors.
Authors: Lu Lihui , Ghose Arup , Quail Matt , Ruggeri Bruce , Cheng Mangeng 
Published: April 2020

Abstract
Abnormal expression of constitutively active anaplastic lymphoma kinase chimeric proteins (NPM-ALK) in the pathogenesis of anaplastic large-cell lymphoma (ALCL) is well defined. Recently, small molecule inhibitors have been reported that provide solid proof-of-concept validation that inhibition of ALK is sufficient to attenuate the growth and proliferation of ALK+ALCL cells. Although robust clinical response of ALCL patients to the ALK inhibitors is expected, some of those patients are also anticipated to develop resistance to an ALK inhibitor, most likely associated with single point mutations in the kinase domain of ALK. In this study, the nonsense mutants of NPM-ALK on the phosphate anchor region and the gatekeeper region were generated by site-directed mutagenesis and their kinase activity was measured in cells. NPM-ALK/L182M, L182V and L256M mutants displayed comparable or higher kinase activity in cells relative to NPM-ALK wt, and were able to render BaF3 cells into growth factor-independent growth, while NPM-ALK/L182R, L256R, L256V, L256P and L256Q displayed much weaker or little kinase activity in cells and failed to transform BaF3 cells. While NPM-ALK/L182M and L182V displayed comparable sensitivity to a fused pyrrolocarbazole (FP)-derived ALK inhibitor as NPM-ALK wt, they were &gt;30-fold less sensitive to a diaminopyrimidine (DAP)-derived ALK inhibitor. On the other hand, NPM-ALK/L256M displayed &gt;30-fold less sensitivity to both the FP-derived and the DAP-derived ALK inhibitors. Consistent with NPM-ALK autophosphorylation inhibition, the FP-ALK inhibitor induced growth inhibition and cytotoxicity of BaF3/NPM-ALK/L182M and L182V cells but not L256M cells, and the DAP ALK inhibitor failed to induce growth inhibition and cytotoxicity of all three BaF3/NPM-ALK mutant cell lines in culture. In the absence of an ALK inhibitor, BaF3 cells harboring NPM-ALK mutants did not display growth advantage in culture with 10% serum and in mice over the NPM-ALK wt cells. However, the BaF3/NPM-ALK mutants displayed significant growth advantage in culture with low serum (2%) over the BaF3/NPM-ALKwt cells, suggesting the BAF3/NPM-ALK mutant cells may proliferate better in the stressed conditions. Analyses of binding of ALK inhibitors to ALK wt and mutants in ALK homology models are in progress and the results will be discussed.
Identification of Core Gene Signature Associated with Synergism Between ABT-869, a FLT3 Inhibitor and SAHA, a HDAC Inhibitor in AML with FLT3-ITD Mutation.
Authors: Zhou Jianbiao , Bi Chonglei , Liu Shaw-Cheng , Chng Wee-Joo , Tay Kian-Ghee , Yu Hanry , Glaser Keith , Albert Daniel , Davidsen Steven K , Chen Chien-Shing 
Published: April 2020

Abstract
Internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation occurs in about 25% of acute myeloid leukemia (AML) patients and is associated with poor prognosis. Various FLT3 inhibitors of different chemical structure are under clinical investigation for the treatment of AML patients with FLT3 mutations. In contrast to their impressive potency in cell culture systems, FLT3 inhibitors as single agents in clinical trials only induce transient reduction of peripheral blasts, but not bone marrow blasts. Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. Small molecule HDAC inhibitors (HDACi) have proven to be a promising new class of anticancer drugs against hematological malignancies, as well as solid tumors. The HDACi, suberoylanilide hydroxamic acid (SAHA, Vorinostat) has been examined in a combinatory fashion with other classes of anticancer agents in acute leukemias, including cyclin-dependent kinase (CDK) inhibitors (flavopiridol), HSP 90 antagonists (17-allylamino- 17-demethoxygeldanamycin, 17-AAG), and estradiol analogs (2-methoxyestradiol, 2-ME). ABT-869, a multi-targeted receptor tyrosine kinase inhibitor, inhibits FLT3 phosphorylation and signaling and now is in active clinical development. In the current study, cell proliferation and apoptosis assays revealed that combining ABT-869 with SAHA led to synergistic killing of AML cells with FLT3 mutations in conventional cell culture and human stromal cell coculture models. To elucidate the molecular mechanism of the synergistic lethality between ABT-869 and SAHA, we compared the gene expression profiles of cells from FLT3 mutated leukemia cell lines, MV4-11 and MOLM-14, treated with DMSO control, ABT-869, SAHA and combination therapy using the Affymetrix microarray platform. Here, we focused on delineating a core gene signature unique to combination therapy and common to both MV4-11 and MOLM-14 cell lines, which could be crucial for the positive cooperation we observed. The core gene signature differentially induced more than two-fold by combination therapy in both cell lines included upregulation of FRY, LMO4, IFI16, ACADSB, and S100A8, and downregulation of PTP4A3 (PRL-3), ORC1L, MND1, ZNF85, DENND3, FAM119A, ACAT2, HMGCS1, DCS2, GSPG4, CBS, TUBE1. Overexpression of PRL-3, a metastasis-associated gene, has been found in different types of solid tumors and multiple myeloma. Modulation of PRL-3 expression level using genetic approaches demonstrated that PRL-3 played an essential role in the synergism in the therapeutic effect of ABT-869 and SAHA.
The CXCR4 Antagonist AMD3100 Impairs Survival of AML Cells and Induces Their Differentiation.
Authors: Tavor Sigal , Eisenbach Manny , Jacob-Hirsch Jasmine , Golan Tammar , Petit Isabelle , Ben-Zion Katz , Kay Sigi , Baron Shoshana , Amariglio Ninette , Deutsch Varda , Naparstek Elizabeth , Rechavi Gideon 
Published: April 2020

Abstract
The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, participate in the retention of AML cells within the bone marrow microenvironment and their release into the circulation. We previously showed that the expression of cell surface elastase in AML cells is dependent on the SDF-1/CXCR4 axis, giving a first evidence for the association between the SDF-1 and elastase pathways. In the present study, we hypothesized that inhibition of the SDF-1/CXCR4 axis or elastase may regulate similar pathways and genes in AML cells. In order to test our hypothesis, we compared gene expression profiles of U937 AML cells that express high level of membrane CXCR4, treated with neutralizing CXCR4 mAb or elastase inhibitor (EI), with non-treated cells, by employing gene-array technology. Unsupervised hierarchical clustering analysis demonstrated similar gene expression profiles of anti-CXCR4 antibody or EI treated cells, as compared to control. Analysis of the 364 genes that were differentially expressed in both anti CXCR4 mAb or EI treated cells under both treatment agents identified genes that correspond to the transcriptional profiles of differentiated myeloid cells in a significantly high prevalence. Quantitative Real-time RT-PCR for 4 selected genes C/EBPe, FLT3, HOXA9 and G-CSFR, demonstrated gene expression profiles identical to the microarray expression profiles. Given thus, we further analyzed the effect of CXCR4 inhibition on AML cell growth and differentiation using the antagonist AMD3100. AMD3100 arrested proliferation in five AML cell lines as was suggested by proliferation assay, cell cycle and caspase 3 activity analyses. Moreover, cell differentiation was demonstrated by:
Modifications in cell morphology, Increased expression of myeloid differentiation antigens Acquisition of the ability to produce oxidative bursts An increase in DNA ploidy in megakaryoblasts. Our study defines a new role for the SDF-1/CXCR4 axis in the regulation of leukemic cell survival and differentiation.
Novel Small Molecule Pim Protein Kinase Inhibitors Induce Cell Cycle Arrest and Apoptosis in Human Leukemias: A Potential Therapeutic Approach.
Authors: Lin Yingwei , Song Jin H. , Zhang Zhenhua , Aplan Peter D. , Smith Charles D , Kraft Andrew , Beharry Zanna M 
Published: April 2020

Abstract
The Pim protein kinases, first identified as a proviral integration site in c-Myc overexpressor mice, are increased in multiple human hematopoietic neoplasms including myeloid leukemia, diffuse large B-cell lymphoma, and T-cell lymphoma. In culture these protein kinases have been associated with the signaling pathways that control Flt3-ITD and BCR/ABL driven leukemias. To examine the role of Pim as a target for anticancer chemotherapy, we have screened a 50,000 compound small molecule library and identified and synthesized novel benzylidene-thiazolidine-2,4-diones, D5 and F801, that inhibit the activity of this enzyme with IC50 in the nanomolar range. Screening of 60 serine/threonine and tyrosine kinases demonstrated high specificity of these molecules for Pim kinase. Incubation of these compounds with myeloid leukemias, U937, K562 and MV4;11, inhibited cell growth by inducing a relative cell cycle block in G1. This cell cycle block at G1 phase was associated with a decrease in Cdk2 activity and a translocation of p27Kip1 to the nucleus, suggesting an important role for Pim in controlling the cell cycle. In contrast, we find that in two T-ALL cell lines, Jurkat and 6812, which was established from a double transgenic mouse overexpressing the SCL and LMO1 genes, 70–80% of the cells were killed after 48 hours of treatment with the inhibitors at the concentration of 10 μM. Cell cycle analysis revealed a two-to three-fold increase in sub-G1 population (10.8% in control, 21.2% in D5, and 29.67% in F801), which suggested an increase in apoptosis. Cleavage and activation of the proapopotic protease Caspase 3 was identified by Western blot after 24-hour treatment of exposure to the Pim inhibitors. We further examined the toxicity of D5 and F801 in wild type FVB mice and found that when mice were treated with either 15 mg/kg D5 or 30 mg/kg F801 for 5 days they had no remarkable hematologic toxicity. The antileukemic activity of these agents in vivo is currently under examination. Thus, the Pim protein kinase appears to be a potential target for leukemia therapy using these novel benzylidene-thiazolidine-2,4-diones.