- Complete sequence of human T cell leukemia virus type 1 in ATLL patients from Northeast Iran, Mashhad revealed a prematurely terminated protease and an elongated pX open reading frame III. [Journal Article]
- IGInfect Genet Evol 2019 May 15
- To gain insight into the origin, evolution, dissemination and viral factors affecting HTLV-1-associated diseases, knowing the complete viral genome sequences is important. So far, no full-length HTLV…
To gain insight into the origin, evolution, dissemination and viral factors affecting HTLV-1-associated diseases, knowing the complete viral genome sequences is important. So far, no full-length HTLV-1 genome sequence has been reported from Iran. Here we report the complete nucleotide sequence of HTLV-1 viruses isolated from adult T cell leukemia/lymphoma (ATLL) patients from this region. The genome size of HTLV-1-MhD (Mashhad) was found to be 9036 bp and sequence analysis of the LTR region showed that it belongs to cosmopolitan subtype A. Comparing the sequences with isolates from another endemic area (HTLV-1ATK) revealed variations in the U3 region (~3.4%), while there was 99.1% and 97.0% similarity in R and U5 regions, respectively. The nucleotide sequences of HTLV-1 gag, pro and pol genes had a difference of 1.1% compared with HTLV-1 ATK with 16 nucleotides replaced in the gag and 27 in the pol regions. There was no variability in the amino acid sequences in the p24gag, however three residues were different in the p19gag and one in the p15gag. The nucleotide sequence of env showed a divergence of 1.5% compared to ATK with 22-nucleotide variation. The HTLV-1-MhD Tax, p13, p30, and p12 had 99.1, 100, 98.8, and 98%, respectively similarity with the prototype strain. Four amino acid changes were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. The nucleotide identity between the isolates of Mashhad and those isolated from France, Germany, China, Canada and Brazil was 99.1%, 99.2%, 97.9%, 99% and 99.3%, respectively. Four amino acid changes compared with HTLV-1ATK from Japan were detected in ORF1 and ORF2 products p12 and p30, respectively, while the p13 region showed 100% conservation. This data could provide information regarding the evolutionary history, phylogeny, origin of the virus and vaccine design.
- Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. [Review]
- DDDrug Discov Today 2019 May 15
- Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm the hallmark of which, the breakpoint cluster region-Abelson (BCR-ABL) oncogene, has been the target of tyrosine kinase inhibitors (TKI…
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm the hallmark of which, the breakpoint cluster region-Abelson (BCR-ABL) oncogene, has been the target of tyrosine kinase inhibitors (TKIs), which have significantly improved the survival of patients with CML. However, because of an increase in TKI resistance, it is becoming imperative to identify resistance mechanisms so that drug therapies can be better prescribed and new agents developed. In this review, we discuss the various BCR-ABL-dependent and -independent mechanisms of resistance observed in CML, and the range of therapeutic solutions available to overcome such resistance and to ultimately improve the survival of patients with CML.
- Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children. [Journal Article]
- GCGenes Chromosomes Cancer 2019 May 18
- High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer s…
High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study (CCLS) via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional 6 patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P=4.4x10-3), an observation that was replicated in ALL patients from the TARGET project (P=0.034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene. This article is protected by copyright. All rights reserved.
- Decitabine treatment for an unusual case of atypical chronic myeloid leukemia (aCML) with a concomitant chronic lymphocytic leukemia (CLL). [Letter]
- HOHematol Oncol 2019 May 18
- Atypical chronic myeloid leukemia (aCML) is a rare hematological malignancy with dismal prognosis, usually being reported as isolated disease or in association with other myeloid neoplasms. Treatment…
Atypical chronic myeloid leukemia (aCML) is a rare hematological malignancy with dismal prognosis, usually being reported as isolated disease or in association with other myeloid neoplasms. Treatment strategies used for MDS and MPN, as hypomethylating agents (HMA) or kinase inhibitors, may be considered although experience is limited. We biologically studied an old patient affected by aCML unusually mutated for both SETBP1 and CSF3R, with concomitant chronic lymphocytic leukemia (CLL). Decitabine (DCA) therapy carried complete response after fourth cycle and was complicated by hematological toxicities and infections mainly due to the old age and the CLL-related immune deficit. Our case confirms DCA effectiveness in aCML and shows for the first time its safety even in older patients with concomitant lymphoproliferative disorders.
- [Expression of WT1 gene and its prognostic value in patients with acute myeloid leukemia]. [Journal Article]
- ZDZhejiang Da Xue Xue Bao Yi Xue Ban 2019 May 25; 48(1):50-57
- CONCLUSIONS: WT1 gene overexpression indicated poor prognosis of AML patients; the patients with decreased WT1 gene expression ≥ 1 log after the first induction therapy show better prognosis than those with<1 log. The WT1 gene expression level at diagnosis can be used as an unfavorable prognostic factor for AML patients with NPM1 or FLT3-ITD wild types.
- Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positve AML. [Journal Article]
- INInvest New Drugs 2019 May 17
- Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro a…
Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.
- Direct adjusted survival and cumulative incidence curves for observational studies. [Journal Article]
- BMBone Marrow Transplant 2019 May 17
- Large randomized clinical trials testing the impact of subject-, disease- and transplant-related co-variates on outcomes amongst recipients of haematopoietic cell transplants are uncommon. For exampl…
Large randomized clinical trials testing the impact of subject-, disease- and transplant-related co-variates on outcomes amongst recipients of haematopoietic cell transplants are uncommon. For example, who is the best donor, which is the best pretransplant conditioning regimen or the best regimen to prevent or treat acute and/or chronic graft-versus-host disease. To answer these questions we often rely on analyses of data from large observational datasets such as those of the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation (EBMT). Such analyses have proved extremely important in advancing the field. However, in contrast to randomized trials, we cannot be certain potentially important prognostic or predictive co-variates are balanced between cohorts selected for comparison from an observational dataset, a limitation which can lead to incorrect conclusions. In the typescript which follows the authours describe a method to adjust for known imbalances in co-variates and get a closer approximation of the truth. They give two examples, the impact of a new pretransplant conditioning regimen on disease-free survival (DFS) in subjects with Ewing sarcoma and the impact of donor-type on treatment-related mortality (TRM) and leukaemia relapse in subjects with acute leukaemia. Direct adjusted survival and cumulative incidence function (CIF) analyses are an important step forward. These analyses can be done using available statistical packages and we encourage readers to use them rather than reporting unadjusted analyses. Finally, we must emphasize direct adjustment can only be done for know prognostic or predictive co-variates, not unknown co-variates. Unknown co-variates will be balanced in randomized trials which is why we do them. So direct adjustment is an important step forward but not a perfect substitute for randomized trials. But any step forward is important. To quote Laozi: (A journey of a thousand miles begins with a single step).
- Surmounting Cytarabine-resistance in acute myeloblastic leukemia cells and specimens with a synergistic combination of hydroxyurea and azidothymidine. [Journal Article]
- CDCell Death Dis 2019 May 17; 10(6):390
- Acute myeloid leukemia (AML) patients display dismal prognosis due to high prevalence of refractory and relapsed disease resulting from chemoresistance. Treatment protocols, primarily based on the an…
Acute myeloid leukemia (AML) patients display dismal prognosis due to high prevalence of refractory and relapsed disease resulting from chemoresistance. Treatment protocols, primarily based on the anchor drug Cytarabine, remained chiefly unchanged in the past 50 years with no standardized salvage regimens. Herein we aimed at exploring potential pre-clinical treatment strategies to surmount Cytarabine resistance in human AML cells. We established Cytarabine-resistant sublines derived from human leukemia K562 and Kasumi cells, and characterized the expression of Cytarabine-related genes using real-time PCR and Western blot analyses to uncover the mechanisms underlying their Cytarabine resistance. This was followed by growth inhibition assays and isobologram analyses testing the sublines' sensitivity to the clinically approved drugs hydroxyurea (HU) and azidothymidine (AZT), compared to their parental cells. All Cytarabine-resistant sublines lost deoxycytidine kinase (dCK) expression, rendering them refractory to Cytarabine. Loss of dCK function involved dCK gene deletions and/or a novel frameshift mutation leading to dCK transcript degradation via nonsense-mediated decay. Cytarabine-resistant sublines displayed hypersensitivity to HU and AZT compared to parental cells; HU and AZT combinations exhibited a marked synergistic growth inhibition effect on leukemic cells, which was intensified upon acquisition of Cytarabine-resistance. In contrast, HU and AZT combination showed an antagonistic effect in non-malignant cells. Finally, HU and AZT synergism was demonstrated on peripheral blood specimens from AML patients. These findings identify a promising HU and AZT combination for the possible future treatment of relapsed and refractory AML, while sparing normal tissues from untoward toxicity.
- [SELECTIVE EFFICACY OF GEORGIAN LEGUME EXTRACTS ON JURKAT AND MDCK CELLS]. [Journal Article]
- GMGeorgian Med News 2019; (288):158-162
- The goal of our study was to establish the anti- proapoptotic activity of the common in Georgia crops on the Jurkat and MDCK cells. Extracts of various varieties of beans (Tirkmela, Batumi meadow, Sh…
The goal of our study was to establish the anti- proapoptotic activity of the common in Georgia crops on the Jurkat and MDCK cells. Extracts of various varieties of beans (Tirkmela, Batumi meadow, Shulavera, Udelebi, as well as green peas, Lens Culinaris lentils, soy beans) were added to the intact or incubated under oxidative stress conditions Jurkat and MDCK cells. Cell viability (apoptosis intensity) was determined by a cell proliferative activity test (MTT test). Correlation and statistical analysis of ANOVA was performed using the package (SPSS version 11.0). In the presented study the selective effectiveness of extracts with different antioxidant activity on intact and incubated under oxidative stress Jurkat and MDCK cells was revealed, related with different sensitivity of cells to the oxidative stress. In normal MDCK epithelial cells, resistant to redox-active factors (H2O2), inverse relationship between the intensity of apoptosis and the antiradical potential of the extract was found; in leukemia transformated Jurkat cells, characterized by high sensitivity to oxidants (H2O2), a violation of the redox-dependent anti-apoptotic cell protection mechanisms was revealed, which is manifested by the absence of regularity of the cytoprotective / cytotoxic effects of the extracts on intact and incubated cells under oxidative stress conditions. These results can be used in the development of schemes of anti-tumor and anti-inflammatory therapy.
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- THE FORECAST OF LETHAL OUTCOME IN CHRONIC LEUKEMIA PATIENTS WITH PNEUMONIA. [Journal Article]
- GMGeorgian Med News 2019; (288):91-97
- The aim of the study - to create a mathematical model for forecasting of poor pneumonia outcome in patients with chronic leukemia in order to optimize treatment. Study included 323 patients with pneu…
The aim of the study - to create a mathematical model for forecasting of poor pneumonia outcome in patients with chronic leukemia in order to optimize treatment. Study included 323 patients with pneumonia and chronic leukemia. All indicators obtained in the study were entered into electronic database of formalized medical histories like a table "object-feature". These results were subjected to stepwise multidimensional statistical processing using non-parametric dispersive analysis by Kruskal-Wallis, correlation analysis with Spearman's rank correlation coefficient, and ROC - analysis. The statistically significant level was p <0,05 (5%). We determined that the forecast of pneumonia poor outcome in patients with chronic leukemia is associated with: leukocytes, lymphocytes, neutrophils, platelets, erythrocytes, hemoglobin and immunity: B (CD19+) (G/L), T (CD4+) (%), immunoregulatory index (CD4+/СD8+) and IgG (g/l). A mathematical model for predicting the pneumonia poor outcome in patients with chronic leukemia was created in our study: PPO=exp (-0.073-0.994*(leukocytes)+4.842*(P.aeroginosa))/[1+exp (-0.073-0.994*(leukocytes)+4.842*(R. aeroginosa)]. Using in clinical practice the proposed mathematical model of prediction pneumonia poor outcome in patients with chronic leukemia will allow determining the treatment place and timely optimizing the treatment program.