bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling from the Oncogenic Fusion Protein BCR/ABL1 Leads to Expression of Wilms’ Tumor Gene 1 Protein (WT1), Which Induces Transcriptional Repression of Interferon Consensus Sequence Binding Protein (ICSBP) in Human Cells.
Authors: Vidovic Karina , Svensson Emelie , Borg Ake , Vallon-Christersson Johan , Lassen Carin , Hakansson Petra , Richter Johan , Olofsson Tor , Fioretos Thoas , Gullberg Urban 
Published: October 2019

Abstract
The Wilms’ tumor gene 1 (WT1) encodes a transcription factor highly expressed in most leukemias. Overexpression of WT1 and the fusion protein AML1-ETO in transgenic mice rapidly induces acute myeloid leukemia (AML), indicating an oncogenic effect by WT1. However, mechanisms behind expression of WT1 in leukemic cells, as well as mechanisms downstream of WT1, are largely unknown. Here, we report that the fusion protein BCR/ABL1, associated with chronic myeloid leukemia (CML), increases expression of WT1 mRNA and protein, which induces transcriptional represssion of ICSBP. Inhibition of BCR/ABL1 signaling by imatinib mesylate reduced WT1 mRNA levels in five different human CML cell lines, confirming previous reports (Cilloni D et al. Cancer 101:979, 2004). In extended investigations, we show that signaling via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway is critical for BCR/ABL1 induced WT1 expression, while independent of JAK-STAT signaling. BCR/ABL1 signaling did not affect half-life of WT1 mRNA, but inhibition of BCR/ABL1 or PI3K strongly suppressed the transcriptional activity of WT1 promoter/enhancer reporters, indicating that BCR/ABL1 signaling increases transcription of the WT1 gene. Downstream of WT1, we report the interferon consensus sequence binding protein (ICSBP) gene as a new target gene of WT1. Increased levels of WT1 reduced the amount of ICSBP mRNA in both normal progenitors and in U937 leukemic cells. Moreover, WT1 repressed transcription from the ICSBP-promoter. Finally, we report that forced expression of BCR/ABL1 in human CD34+ bone marrow progenitor cells resulted in increased expression of WT1 mRNA and protein and repressed levels of ICSBP mRNA and protein, indicating that WT1 can repress expression of ICSBP. In contrast to the almost ubiquitously high expression of WT1 in leukemia, expression of ICSBP is very low or absent in most leukemias, consistent with the notion of WT1 as a repressor of ICSBP in vivo. Moreover, several reports point out ICSBP as an important suppressor gene in CML. Our results provide a mechanistic explanation for BCR/ABL1 induced repression of ICSBP via induction of WT1, and a general mechanism by which high expression of WT1 could contribute to repression of ICSBP also in other leukemias.
Enhancement of Imatinib-Induced Apoptosis through Catalase Activity Modulation in Imatinib-Resistant Chronic Myelogenous Leukemia Blastic Phase Cells.
Authors: Kwee Jolie Kiemlian , Ferreira Ana Carolina dos Santos , Luque Diogo Gomes , da Cunha Vasconcelos Flavia , Silva Karina Lani , Klumb Claudete Esteves , Maia Raquel Ciuvalschi 
Published: October 2019

Abstract
Therapeutic selectivity and drug resistance are two major issues in cancer chemotherapy. Strategies to improve therapeutic selectivity largely rely on our understanding of the biological difference between cancer and normal cells, and on the availability of therapeutic agents that target biological events critical for cancer cells but not essential for normal cells. Imatinib is a selective inhibitor of the BCR-ABL tyrosine kinase activity in chronic myelogenous leukemia (CML). Resistance to imatinib is a major problem in CML patients especially in blast phase (BP). Recently, it was also described that reactive oxygen species (ROS) is another mechanism through which imatinib induces apoptosis. To evaluate the possible role of catalase (a well known ROS enzyme scavenger) in imatinib resistant cells, we studied through apoptosis/necrosis analysis, K562 cells in presence or absence of 3-amino-1,2,4-triazole (AT), an inhibitor of catalase activity. Cell apoptosis index was tested in cells labeled with Annexin V-FITC/PI and analysed by flow cytometry. In order to examine the efficacy of imatinib apoptosis induction we evaluated firstly the apoptosis index in K562 cells after 24 hours of incubation with imatinib at the less cytotoxic concentrations of 0.5, 1.0 and 5.0 μM. Induced imatinib early apoptosis, was significantly higher, (25%, p < 0.05) than control in all concentrations tested. After that, we conducted the same assay in K562 cells previously treated with aminotriazole (AT-K562) and, to address the question of whether the resistance to imatinib could also be counteracted by glutathione modulation, another ROS scavenger, K562 cells previously treated with buthionine S,R-sulphoximine (BSO) a specific inhibitor of g-glutamylcysteine synthetase the rate limiting enzyme in glutathione synthesis, were also analysed. Untreated K562 cells and those previously treated with AT or BSO were incubated with imatinib (0.5, 1.0 and 5.0 μM) and hydrogen peroxide (H2O2) 1.0 μM, a well known apoptosis inductor inhibited by catalase. Only AT-K562 cells had their apoptosis significantly enhanced when compared with non treated cells (p < 0.05). Indeed, we showed that inhibition of catalase activity in K562 cells overcame imatinib resistance in 35% of these cells in the final concentration of 0.5 μM which is equivalent to the half mean plasma concentration used in clinical practice. The present findings suggest that combination of catalase inhibitors with imatinib in lower dosage represent an emerging therapeutic concept for preventing or overcoming resistance formation in CML. Therefore, further studies with drugs clinically available that inhibit catalase activity should be explored.
Ferrocenyl Nucleoside Analogs, a New Class of Cytostatic Drugs, Overcome Multiple Drug Resistance in Acute Lymphoplastic Leukemia Ex Vivo.
Authors: Prokop Aram , Eissmann Moritz , Jesse Patrick , Henze Guenter , James Philippe , Neudoerfl Joerg , Schmalz Hans-Guenther 
Published: October 2019

Abstract
In spite of the relatively good prognosis for de novo acute lymphoplastic leukemia (ALL), the survival rate for relapsed ALL is only 40%. The therapy of relapsed ALL and secondary leukemias with the common cytostatic drugs often show a poor response. Therefore new substances are required to lead multiple drug resistant leukemia cells into cell death. Nucleoside analogs play a very important role in anti-leukemic therapy. Here we present a new, own-synthesized class of Ferrocenyl Nucleosides, a type of organometallic sandwich compounds, where two cyclopentadenyl rings bind to a central Fe2+ ion. We could show anti-leukemic and anti-cancer activity in different leukemia and tumor cell lines and primary cells from children with primary ALL and AML. The apoptosis induction was efficient in low micro molar concentrations (LC50 = 10–20μM). The DNA fragmentation has been extraordinary high (LC90 = 30–50μM). Ex vivo experiments showed that some Ferrocenyl Nucleoside Analogs, like PJ184, are able to overcome resistance against anthracyclines like Doxorubicin (p<0,001), Daunorubicin (p<0,001) and Idarubicin (p<0,001) or alkaloids like Vincristin (p<0,001). Furthermore Ferrocenyl Cytosin Analog (PJ184) mediated apoptosis induction is significant higher than apoptosis induced by the clinical used nucleoside analogs like Fludarabin (p<0,001), Cytarabine (p<0,001) and Cladribine (p<0,001; all p-values by ANOVA test). These results have been achieved by testing primary lymphoblasts of seven primary ALL patients after incubation for 60h with LC50 determined in leukemic cell lines. The testing of one AML revealed similar results. Apoptosis induction has been investigated by flowcytometric measurement of DNA-fragmentation, mitochondrial membrane potential reduction and phosphatedylserin-staining on cell membrane surface. The cell death by necrosis could be excluded by a lactatdehydrogenase-release assay. In order to characterize the Ferrocenyl Nucleoside apoptosis pathway we used cellular model systems with deficiencies in different molecular parts of the apoptosis cascade. Apoptosis reveals to be independent of CD95 receptor and the pro-apoptotic factor SMAC, but shows a dependency of the apoptosis inhibitor Bcl-2. We also investigated a loss of mitochondrial membrane potential, which indicates the involvement of the mitochondrial apoptosis machinery. Taken together, these new class of Ferrocenyl Nucleoside Analogs revealed very promising in vitro and ex vivo results and may lead to a new approach in antileukemic therapy. In vivo experiments will be performed soon.
Potential Application of Differential Glycosylation in Childhood Acute Lymphoblastic Leukemia.
Authors: Chowdhury Suchandra , Mandal Chandan , Chandra Sarmila , Mandal Chitra 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is a malignant transformation of lymphoblasts representing the commonest type of cancer in pediatric population. We have earlier demonstrated the differential expression of 9-O-acetylated sialoglycoproteins (9-OAcGP) [Pal et.al.2004,] as disease-associated molecules on these lymphoblasts. These are functionally active signaling molecules [Ghosh et.al.2005] capable of inducing disease-specific anti-9-OAcGP antibodies [6–8]. Subclass switching of anti-9-OAcGP from IgG1 to IgG2, alteration in their glycosylation profile along with impairment of effector functions hint toward imbalanced homeostasis thereby circumventing host defense [Bandyopadhyay et.al 2005]. Aim of the present study was to explore the expression of 9-OAcGP during chemotherapy (MCP841 protocol) and establish it as a universal marker for minimal residual disease (MRD) detection. Along with B/T- lineage-specific CD antigens, the status of 9-OAcGP have been investigated by flow cytometry in paired-samples of bone marrow (BM, 11-times from each patient) and peripheral blood (PB, 18-times from each patient) during the treatment protocol in a longitudinal follow-up study. 89 patients were monitored throughout the study period, of which the number of B-ALL and T-ALL are n =75 and n= 14 respectively. The special templates used for MRD detection, 9-OAcGP+CD10+CD19+/9-OAcGP+CD34+CD19+/9-OAcGP+CD7+CD3+ increased the sensitivity to 0.01% (i.e. one cancer cell could be detected in 10,000 normal cells during clinical remission)while those with high MRD followed by relapse. The number of patients having a clinical relapse during the two years treatment were n = 2. The MRD in BM correlated well with PB both in B and T- ALL. We propose that close monitoring of patients, irrespective of lineage, even in PB, may provide an efficient and reliable index for the MRD detection, enabling more long-term management of these children.
Therapy-Related Acute Lymphoblastic Leukemia (t-ALL).
Authors: Escobar Carolina , McLarty Jerry , Ballester Oscar 
Published: October 2019

Abstract
Introduction: Myelodysplasia and Acute Myeloid Leukemia are recognized and well characterized complications of cancer therapy. Much less is known about t-ALL, but an increasing number of cases are being reported.
Materials and Methods: We conducted a MEDLINE search to identify patients with ALL diagnosed after exposure to chemotherapy and/or radiotherapy. Data extracted included: latency period, radiation and type of chemotherapy drug exposure, phenotype, cytogenetics and survival.
Results: 74 patients were identified with a median age at the time of t-ALL of 33 years, (range 2 to 90; 16 cases age ≤ 10 and 9 cases age ≥60). History of a prior malignancy, including solid tumors in 45 (sarcomas 12, breast cancer 11, others 22) and hematological malignancies in 25 (Hodgkin’s lymphoma 17, others 8), was documeted in all patients with the exception of 4, who received chemotherapy or radiation for a non-malignant disorder. Exposure to radiotherapy was documented in 65% of patients (4 cases had exposure only to radiotherapy), 64% had recieved topoisomerase II inhibitors and 84% other chemotherapy drugs. Median time to t-ALL was 38 months. Follow up data was available in 56/74 (75.6%), 20 were reported alive (27%), 3 to 132 months from t-ALL diagnosis. Twelve patients received stem cell transplants, 7 of them were survivors (8 to 79 months). Based on phenotype and/or cytogenetics, 5 subsets of patients were identified. Group A: 32 patients (43%) with 11q23 translocations and/or MLL rearrangements: 23 of these patients (72%) presented with pro-B cell phenotype (CD19+, CD10−)(2 pre-B cell, 2 T cell, 5 unknown); 90% had history of exposure to topoisomerase II inhibitors; median time to t-ALL was 21 months in Group A, significanlty shorter (p<.0001) when compared to all other patients (median 60 months). Median overall survival was 8 months, 5 year survival 27%. Group B: 11 patients (14.8%), with L3/Burkitt’s leukemia; all with t(8;14), t(8;22) or t(2;8) abnormalities. None of them are long term survivors. Group C: 4 patients with t(9;22) (5.4%). Group D: 4 patients with T cell phenotype (5.4%). Group E: the remaining 23 patients (31%) with primarily a pre-B cell phenotype (CD19+, CD10+) with normal (21.7%), complex (21.7%) or unknown cytogenetics (56%). Of the 18 patients who received induction therapy in Group E, 9 (50%) are survivors (median 60 months from diagnosis).
Conclusions: Various subsets of t-ALL can be recognized, resembling the pattern seen in patients with de novo ALL. However, high-risk subtypes such as 11q23/MLL + cases are overrepresented. Patients with t-ALL not identified by 11q23 or t(9;22) abnormalities, L3/Burkitt’s or T cell phenotype (Group E) appear to have a better prognosis: survival at 5 years 45% compared to 24% for all other patients.
Non-Hodgkin Lymphoma Involving the Bone (NHLB): Report of Ten Cases.
Authors: Vigliotti Maria Luigia , Fazioli Flavio , De Chiara Anna , D’Arena Giovanni , Villani Oreste , Pinto Antonio 
Published: October 2019

Abstract
Background: NHLB is an unusual entity. Primary NHL of the bone comprising approximately 5–12 % of all bone cancer and less than 12% of all extra-nodal lymphomas; surgery resection does not have a therapeutic role and diagnosis is usually established by bone biopsy.
Aim of the study: To demonstrate the clinical features of bone lesion in order to optimize diagnostic approaches and to evaluate prognostic factors and treatment.
Patients and Methods: Ten pts with NHLB were diagnosed with surgical bone biopsy in the last 5 years. Pain and soft tissue swelling were the commonest symptoms. Two pts showed a unique bone lesion which was classified as primary lymphoma of the bone (PLB). In 8 cases, dissemination of the disease with multiple bone and/or visceral involvement was apparent (dNHL). The characteristics of pts were: median age 58,4 years (range 39–82 yrs), male: 70%; female: 30%; CS I, 20%, and CS IV, 80%, BM+ vs BM− (20% vs 80%); IPI was: low, 0–2, in 50%, vs high, 3–5 in 50%; bulky disease in 20%. All pts had B-phenotype; DLBCL in 8 pts, lymphoplasmocitoid lymphoma in 1 pt and follicular lymphoma, grading 2, in 1 pt, according to REAL-classification. Nine pts received CT with CHOP- like regimens (6 courses) to be repeated every 2 or 3 weeks. Only one pt received HDT with PBSCT. Three pts received CT + local irradiation (30 Gy).
Results: CR was achieved in 80% of cases; all these pts were alive and disease free. Only the pt with unique bone lesion and lymphoplasmocitoid features, received only surgery therapy and is alive and disease free. Two pts died for PD at +1 and +6 months at initial sites of disease. Median OS was 19.6 months (range 1–62) and DFS was 20 months (range 2–58).
Conclusions: The long-term survival of these pts is favourable but dependent on histology and clinical stage and appears to parallel that of pts with lymphoma of similar histology involving other sites.
Vinblastine Based Short-Pulse B-Non-Hodgkin’s Lymphoma Type Chemotherapy (CT) with Maintenance Therapy Is Highly Efficacious Treatment for Anaplastic Large Cell Lymphoma (ALCL).
Authors: Banavali Shripad D. , Goyal Lovenish , Bhagwat Roshni V. , Narayan Prasad , Mandhaniya Sushil , Arora Brijesh , Vora Amish , Pai Suresh K. , Gujral Sumeet , Kurkure Purna A. , Adde Melissa , Magrath Ian , Parikh Purvish M. 
Published: October 2019

Abstract
OBJECTIVE: ALCL is a rare but biologically well characterized disorder. Though ALCLs are highly chemo-sensitive, 20% to 40% of patients develop recurrent disease. No standard therapeutic regimen exists for the treatment of ALCL. The objective of the present study is to characterize the clinical features and treatment response of children and young adults with ALCL in India
Methods: 30 patients of ALCL who were previously untreated were enrolled between Jan 1991 and July 2006. Treatment consisted of eight alternating cycles of two regimens A and B. Regimen A included Cyclophosphamide, Adriamycin, Vincristine and Cytosine-arabinoside. Regimen B included Etoposide, Vincristine, Methotrexate (standard dose), and Ifosfamide with Mesna. Intrathecal Methotrexate and Cytosine Arabinoside were administered in the first 4 cycles (MCP 842. Ann. Oncol.1997; 8: 893). No high dose chemotherapy or radiotherapy was given. Since Jan. 2004, Vincristine was replaced with Vinblastine and patients received 6 months (Stg. I and II) or 12 months (Stg. III and IV), of oral maintenance therapy with 6-MP and Methotrexate (11 patients).
Results: The median age was 14 years (range 2.6 to 31 years). The male to female ratio was 2.8:1. Common predominant disease sites included: Abdomen-27%; Nodes-33%; Bones-17%, Head and Neck-10%; and Mediastinum-13%. Four patients (13%) presented with stage I disease, 7 (23%) with stage II, 14 (47%) with stage III and 5 (17%) with stage IV. The response rate was 93% for the 29 evaluable patients (1 still on second cycle), with complete response in 86%. There were 6 relapses (20.7%) with majority (83%) of relapses showing newer sites of involvement. For the whole group, the projected 10 year EFS was 52.7% and OS was 73.3%. The EFS analyzed stage wise was 66.7% and 44.1% for localized Stages (I and II) and advanced Stages (III and IV) respectively. For the 20 post-2000 patients, the probability of 5 yr. OS is 100% (Stg I and II) and 84.4% (Stg III and IV) (3 relapsed patients have received Vinblastine based chemotherapy and are in subsequent remission). Most importantly, the EFS so far is 100% for all 11 patients treated with Vinblastine and maintenance therapy.
Conclusions: Most Indian patients with ALCL present in advanced stages with abdomen and nodes as the dominant primary sites of disease. Although, in the past, initial treatment responses were good, long term survival was suboptimal due to relapses. Simple addition of Vinblastine and oral maintenance may improve EFS in ALCL without the need of adding high dose or more aggressive CT. This protocol would be especially useful to treat both children and adults with ALCL in countries with limited resources & supportive care.
b2a2 Type bcr-abl Transcript Chronic Myelogenous Leukemia (CML) Patients in Chronic Phase (CP) on Glivec Achieve Complete Cytogenetic Remission (CCyR) Earlier Than Those with b3a2.
Authors: Lomaia Elza G. , Martinkevich Irina S. , Ogorodnikova Yulia S. , Lyschov Anton A. , Bogdanov Konstantin V. , Zaritskey Andrey Yu 
Published: October 2019

Abstract
There are few data on different biological significance of b2a2 and b3a2 transcripts. The main one is thrombocytosis in b3a2 CML patients (R.A.Perego e.a.,2000), probably associated with coexpression of m-bcr-abl (T.Liu e.a.,2006). Noteworthy that the level of transcripts in primary CML patients did not differ(Rodrigues J. e.a.,2005). That was the reason for evaluating Glivec efficacy in CP CML patients with bcr-abl trabscripts- b2a2 and b3a2.
Patients and Methods. 97 Ph+, CP CML patients were studied. They received Glivec either as front line therapy or after resistance to preceeding therapy. Analysis of b3a2 and b2a2 transcripts was performed in 27 of them. Cytogenetics was performed routine technology with G-banding. Statitics: Kaplan-Meier survival analysis and Cox regression model were used.
Results. The median time to CCyR in whole cohort of patients was 320 days. Of 27 bcr-abl studied patients, 9 had b2a2 and 18 b3a3 transcripts. They did not differ in age, duration of the disease and Sokal Score. Median time to CCyR in b2a2 patients was 172 days and 362 in b3a2 patients(p=.0001). Time to CCyR was shorter in b2a2 patients(p=.003) and insignificantly longer in b3a2 patients when compared to the whole cohort of studied patients. Cox analysis revealed that type of transcripts is independant prognostic factor, including platelet level and spleen size. Difference was more pronounced in patients with front line Glivec therapy.
Conclusion. b2a2 transcript is independent prognostic marker for early achievement of CCyR on Glivec therapy.
Evaluation of the Clinical Significance of Immunophenotyping in Myelodysplastic Syndrome.
Authors: Liu Dan D. , Jiao Xue L. , Geng Mei J. , Zhu Ming Q. , Gong Jing X. , Wu Wei L. , Ma Qin F. , Xue Yong Q. , Chen Zi X. 
Published: October 2019

Abstract
The myelodysplastic syndrome (MDS) is a clonal hematologic disorder with extremely heterogeneous cell component. Diagnosis is currently depending on the dysplastic morphology of bone marrow cells and the presence of specific cytogenetic abnormalities. Since no specific marker could be identified in MDS, it is sometimes hard to distinguish from other anemias, such as aplastic anemia (AA). The cell immunotype may be helpful in differential diagnosis and predicting the disease progress. To evaluate the clinical usage of immunotyping in MDS patients, we have compared the immunotypes between 36 MDS patients, 18 patients with AA and 11 healthy controls by using flow cytometry. Moreover, in combination with karyotype analysis and prognosis indicator IPSS, the value of immunotyping was further analyzed and discussed.
Our results demonstrated:
In MDS-RA patients, the distribution of surface antigen on BM cells had no preferential difference between lymphoid and myeloid lineages. In RAEB patients, expressions of CD13, CD33 and CD34 were prevailing, significantly higher than others(P<0.05). In contrast, in AA patients, expressions of CD2, CD7, CD19, CD20 were significantly higher than other surface antigens(P<0.05). In high risk MDS (RAEB/RAEB-t) patients, the cells expressing B cell lineage antigens (CD19,CD20) are markedly less than that in healthy people(P<0.05)while percentage of myeloid lineage antigen (CD13,CD33) are much higher than that in health control(P<0.05), However, in low risk MDS patients (RA) the frequency of expression of all myeloid, T and B lymphoid lineage antigens were not different from that in health controls. The distribution pattern of these three lineage antigens in high risk MDS patients was remarkably different with those of AA patients(P<0.05). Comparing with low-risk MDS, high-risk MDS expressed more myeloid lineage antigens (P<0.05)while expressed less B lineage antigens(P<0.05). In MDS patients, expression of CD14 was correlated with special chromosomal abnormalities defined by IPSS
Our results suggested:
The pattern of immunotype distribution in MDS cells are highly heterogenous. Expressions of myeloid antigens was predominant in MDS patients. Immunotyping can be helpful for discriminating MDS from AA and for monitoring the disease progression from low risk to high risk MDS. Expressions of certain immunotype are correlated with prognosis of MDS.