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acute lymphocytic leukemia [keywords]
- Antileukemic Activity and Mechanism of Drug Resistance to the Marine Salinispora Tropica Proteasome Inhibitor Salinosporamide A (marizomib). [JOURNAL ARTICLE]
- Mol Pharmacol 2014 Apr 15.
Salinosporamide A (NPI-0052, marizomib) is a naturally-occurring proteasome inhibitor derived from the marine actinobacterium Salinispora tropica and represents a promising clinical agent in the treatment of hematologic malignancies. Recently, these actinobacteria were shown to harbor self-resistance properties to salinosporamide A by expressing redundant catalytically-active mutants of the 20S proteasome β-subunit, reminiscent of PSMB5 mutations identified in cancer cells with acquired resistance to the founding proteasome inhibitor, bortezomib. Here, we assessed the growth inhibitory potential of salinosporamide A in human acute lymphocytic leukemia CCRF-CEM cells, and its 10-fold (CEM/BTZ7), and 123-fold (CEM/BTZ200) bortezomib-resistant sublines harboring PSMB5 mutations. Parental cells displayed sensitivity to salinosporamide A (IC50= 5.1 nM), whereas their bortezomib-resistant sublines were 9- and 17-fold cross-resistant to salinosporamide A, respectively. Notably, combination experiments of salinosporamide A and bortezomib showed synergistic activity in CEM/BTZ200 cells. CEM cells gradually exposed to 20 nM salinosporamide A (CEM/S20) displayed stable 5-fold acquired resistance to salinosporamide A and were 3-fold cross-resistant to bortezomib. Consistent with the acquisition of a PSMB5 point mutation (Met45Val) in CEM/S20 cells, salinosporamide A displayed a markedly impaired capacity to inhibit β5-associated catalytic activity. Lastly, compared to parental CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulation of constitutive proteasome subunits, while retaining unaltered immunoproteasome subunit expression. In conclusion, salinosporamide A displayed potent antileukemic activity against bortezomib-resistant leukemia cells. β-subunit point mutations as a common feature of acquired resistance to salinosporamide A and bortezomib in hematologic cells and Salinispora tropica suggest an evolutionarily conserved mechanism of resistance to proteasome inhibitors.
- Assessment of Thiopurine-based drugs according to Thiopurine S-methyltransferase genotype in patients with Acute Lymphoblastic Leukemia. [REVIEW]
- Iran J Ped Hematol Oncol 2014; 4(1):32-38.
For the past half century, thiopurines have earned themselves a reputation as effective anti-cancer and immunosuppressive drugs. Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of all thiopurines and is one of the main enzymes that inactivates mercaptopurine. 6-MP is now used as a combination therapies for maintenance therapy of children with acute lymphocytic leukemia (ALL). In all patients receiving mercaptopurine, there is a risk of bone marrow suppression. TPMT activity is inherited as a monogenic, co-dominant trait. More than 25 variants are known. Genetic testing is available for several TPMT variant alleles. Most commonly TPMT*2, *3A, and *3C are tested for, which account for >90% of inactivating alleles. Differences in DNA that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals.Genotyping may become part of routine investigations to help clinicians tailor drug treatment effectively. This success is mainly due to the development of combination therapies and stratification of patients according to risk of treatment failure and relapse, rather than the discovery of new drugs. The aim of this study was to investigate the effect of genotype or methyltransferase enzyme activity before starting therapy in children with ALL. This can prevent the side effect of thiopurine drugs. In fact, the common polymorphism of this enzyme in population could be a prognostic factor in relation to drug use and treatment of patients with ALL.
- Automated Analysis of Bone Marrow Aspirates from Dogs with Haematological Disorders. [JOURNAL ARTICLE]
- J Comp Pathol 2014 Feb 26.
Automated analysis of bone marrow (BM) aspirates is a useful 'pre-microscopical' screen to identify hypocellular samples and those with potentially abnormal cells. In order to determine whether automated analysis could also be used to identify haemopoietic abnormalities, EDTA-anticoagulated BM aspirates from 43 dogs were analysed using the Advia 2120 instrument. Corresponding Wright-stained BM smears were evaluated microscopically to determine smear quality, cell composition and 500-cell differential counts, and correlation to automated analysis parameters was computed. Leucocyte cytograms generated by the automated analyzer were scrutinized and compared with those of 'normal' BM. Twenty-three neoplastic and 20 non-neoplastic samples were analysed, including samples from 10 cases of acute myeloid leukaemia, four cases of acute lymphocytic leukaemia, four cases of chronic lymphocytic leukaemia, one case of chronic neutrophilic leukaemia, three cases of multiple myeloma, one case of myelodysplastic syndrome, five cases of non-regenerative immune-mediated haemolytic anaemia, one case of immune-mediated neutropenia, three cases of immune-mediated thrombocytopenia, six cases of inflammatory disease, three samples with myelotoxicity and two samples analysed for staging of neoplasia. Automated white blood cell (WBC) counts correlated significantly with smear cellularity, particle cellularity and particle number. There was a significant difference in WBC counts of samples with insufficient versus sufficient particles. Significant correlations between Advia percent neutrophils and microscopical determination of marrow segmented neutrophils/neutrophilic granulocyte reserve, Advia percent lymphocytes and microscopical determination of lymphocytes/rubricytes, Advia percent large unstained cells and microscopical determination of myeloblasts/promyelocytes and between Advia percent eosinophils and manual determination of eosinophils were identified. This suggested that Advia WBC counts may be used to approximate BM sample quality and that Advia differential counts may predict marrow granulocyte reserve and lymphocyte/rubricyte stores. Distinct and consistent alterations in cytogram patterns were observed in cases of acute leukaemia, but were less obvious in chronic leukaemia. Complete automated BM analysis was performed in approximately 2 min, while staining and coverslipping of BM slides required approximately 30 min. Hence, although automated analysis should not supplant microscopical evaluation of BM, it can provide useful ancillary information in a short time and flag potentially inadequate or abnormal samples.
- A new pattern of Pulmonary Graft versus Host disease in a hematopoietic stem cell transplant patient. [JOURNAL ARTICLE]
- Clin Respir J 2014 Apr 14.
The primary pulmonary manifestation of chronic graft versus host disease (GvHD) is the development of bronchiolitis obliterans. Other pulmonary manifestations of chronic GvHD that have been reported include diffuse alveolar damage , lymphocytic interstitial pneumonia , bronchiolitis organizing pneumonia and lymphocytic bronchiolitis/bronchitis.We report an unusual case of a 34 year old patient with acute myeloid leukemia status post allogenic hematopoietic stem cell transplant who was a known case of GvHD with skin involvement. The patient developed respiratory failure and on subsequent surgical lung biopsy was found to have non-specific interstitial pneumonia (NSIP).This is the third case of a patient with biopsy proven GvHD who had NSIP pattern on surgical lung biopsy. We believe this may represent a rare manifestation of pulmonary GvHD.
- [Novel therapy for malignant lymphoma: adoptive immuno-gene therapy using chimeric antigen receptor(CAR)-expressing T lymphocytes]. [English Abstract, Journal Article]
- Nihon Rinsho 2014 Mar; 72(3):547-52.
Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3 zeta receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in the clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In this review article, CD19-CAR-T gene therapy for refractory B-cell non-Hodgkin lymphoma is discussed.
- Chlorambucil-induced acute interstitial pneumonitis. [Journal Article]
- Case Rep Hematol 2014.:575417.
Chlorambucil is an alkylating agent commonly used in treatment of chronic lymphocytic leukemia (CLL). We report a case of interstitial pneumonitis developing in an 83-year-old man 1.5 months after completing a six-month course of chlorambucil for CLL. The interstitial pneumonitis responded to therapy with prednisone. We performed a systematic review of literature and identified 13 other case reports of chlorambucil-induced pulmonary toxicity, particularly interstitial pneumonitis. No unifying risk factor could be discerned and the mechanism of injury remains unknown. In contrast, major randomized trials of chlorambucil therapy in CLL have not reported interstitial pneumonitis as an adverse effect, which may be due to the rarity of the phenomenon or due to underreporting of events occurring after completion of treatment. Clinicians should consider drug-induced interstitial pneumonitis in the differential diagnosis of a suggestive syndrome developing even after discontinuation of chlorambucil.
- Bone marrow mesenchymal stromal cells affect the cell cycle arrest effect of genotoxic agents on acute lymphocytic leukemia cells via p21 down-regulation. [JOURNAL ARTICLE]
- Ann Hematol 2014 Apr 6.
The effect of bone marrow microenvironment on the cell cycle of acute lymphocytic leukemia (ALL) and the underlying mechanism has not been elucidated. In this study, we found that in normal condition, bone marrow mesenchymal stromal cells (BM-MSCs) had no significant effect on the cell cycle and apoptosis of ALL; in the condition when the cell cycle of ALL was blocked by genotoxic agents, BM-MSCs could increase the S-phase cell ratio and decrease the G2/M phase ratio of ALL. Besides, BM-MSCs could protect ALL cells from drug-induced apoptosis. Then, we proved that BM-MSCs affect the cell cycle arrest effect of genotoxic agents on ALL cells via p21 down-regulation. Moreover, our results indicated that activation of Wnt/β-catenin and Erk pathways might be involved in the BM-MSC-induced down-regulation of p21 in ALL cells. Targeting microenvironment-related signaling pathway may therefore be a potential novel approach for ALL therapy.
- Acute respiratory viral infections in pediatric cancer patients undergoing chemotherapy. [JOURNAL ARTICLE]
- J Pediatr (Rio J) 2014 Apr 1.
to estimate the prevalence of infection by respiratory viruses in pediatric patients with cancer and acute respiratory infection (ARI) and/or fever.cross-sectional study, from January 2011 to December 2012. The secretions of nasopharyngeal aspirates were analyzed in children younger than 21 years with acute respiratory infections. Patients were treated at the Grupo em Defesa da Criança Com Câncer (Grendacc) and University Hospital (HU), Jundiaí, SP. The rapid test was used for detection of influenza virus (Kit Biotrin, Inc. Ireland), and real-time multiplex polymerase chain reaction (FTD, Respiratory pathogens, multiplex Fast Trade Kit, Malta) for detection of influenza virus (H1N1, B), rhinovirus, parainfluenza virus, adenovirus, respiratory syncytial virus, human parechovirus, bocavirus, metapneumovirus, and human coronavirus. The prevalence of viral infection was estimated and association tests were used (χ(2) or Fisher's exact test).104 samples of nasopharyngeal aspirate and blood were analyzed. The median age was 12 ± 5.2 years, 51% males, 68% whites, 32% had repeated ARIs, 32% prior antibiotic use, 19.8% cough, and 8% contact with ARIs. A total of 94.3% were in good general status. Acute lymphocytic leukemia (42.3%) was the most prevalent neoplasia. Respiratory viruses were detected in 50 samples: rhinoviruses (23.1%), respiratory syncytial virus AB (8.7%), and coronavirus (6.8%). Co-detection occurred in 19% of cases with 2 viruses and in 3% of those with 3 viruses, and was more frequent between rhinovirus and coronavirus 43. Fever in neutropenic patients was observed in 13%, of which four (30.7) were positive for viruses. There were no deaths.the prevalence of respiratory viruses was relevant in the infectious episode, with no increase in morbidity and mortality. Viral co-detection was frequent in patients with cancer and ARIs.
- Selenium inadequacy is not associated with oxidative stress in child and adolescent acute lymphocytic leukemia survivors. [Journal Article]
- Nutrition 2014 May; 30(5):563-8.
Acute lymphocytic leukemia (ALL) and its subsequent treatment may provoke increased oxidative stress. The aim of this study was to investigate the antioxidant status of children and adolescents who had received ALL therapy, and to test the hypothesis that selenium (Se) inadequacy is correlated with reduced defenses against oxidative stress in this population.This case-control study involved 24 patients between ages 5 and 13 y who had been treated successfully for ALL (ALL group) and 60 children of similar age and socioeconomic background with no clinical history of leukemia (control group). Dietary intake of Se was evaluated by the 24-h recall method, and the concentrations of Se in plasma, erythrocytes, and urine determined. Antioxidant status was assessed by analysis of the oxidative stress markers, namely, superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), α-tocopherol, and 8-oxo-deoxyguanosine (8-oxo-dG).There were no between-group differences with respect to plasma (P = 0.122), erythrocyte (P = 0.202), urinary (P = 0.608), or dietary (P = 0.757) levels of Se. GPx activity was significantly (P < 0.001) reduced in the ALL group compared with the control group, whereas SOD activity and MDA concentrations were similar. The concentrations of α-tocopherol and 8-oxo-dG were significantly increased in the ALL group compared with the control group (P < 0.001 and P = 0.031, respectively).All participants were Se inadequate, but such inadequacy was not correlated with reduced defenses against oxidative stress. However, individuals of the ALL group were with increased oxidative stress compared with the control group, possibly due to previous disease and to intensive polychemotherapy.
- Elevated expression of pleiotrophin in lymphocytic leukemia CD19(+) B cells. [JOURNAL ARTICLE]
- APMIS 2014 Apr 3.
Pleiotrophin (PTN) has been demonstrated to be strongly expressed in many fetal tissues, but seldom in healthy adult tissues. While PTN has been reported to be expressed in many types of tumors as well as at high serum concentrations in patients with many types of cancer, to date, there has been no report that PTN is expressed in leukemia, especially in lymphocytic leukemia. We isolated the CD19(+) subset of B cells from peripheral blood from healthy adults, B-cell acute lymphocytic leukemia (B-ALL) patients, and B-cell chronic lymphocytic leukemia (B-CLL) patients and examined these cells for PTN mRNA and protein expression. We used immunocytochemistry, western blotting, and enzyme-linked immunosorbent assay to show that PTN protein is highly expressed in CD19(+) B cells from B-ALL and B-CLL patients, but barely expressed in B cells from healthy adults. We also examined PTN expression at the nucleic acid level using reverse transcription polymerase chain reaction (RT-PCR) and northern blotting and detected a high levels of PTN transcripts in the CD19(+) B cells from both groups of leukemia patients, but very few in the CD19(+) B cells from the healthy controls. Interestingly, the quantity of the PTN transcripts correlated with the severity of disease. Moreover, suppression of PTN activity with an anti-PTN antibody promoted apoptosis of cells from leukemia patients and cell lines SMS-SB and JVM-2. This effect of the anti-PTN antibody suggests that PTN may be a new target for the treatment of lymphocytic leukemia.