Gene/Protein Disease Symptom Drug Enzyme Compound
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The relationship between plasma lipid levels and mortality from cardiovascular diseases has been shown in many studies, but there has been far less investigation into their relationship to non-cardiovascular diseases. The aim of this study was to investigate the lipid profile of individuals with hematological malignancies and its relationship to disease activity. 238 patients were included in the study: 84 with acute leukemia, 62 with non-Hodgkin lymphoma, 35 with Hodgkin's lymphoma, 32 with multiple myeloma, and 25 with myeloproliferative syndrome. The HDL cholesterol level of the patients differed to that of the individuals in the control group in the active disease period for all the analyzed disorders, but only remained statistically significant in the acute leukemia and non-Hodgkin lymphoma groups during the remission period. Smaller differences were observed for the remaining lipid fractions, except for the triglyceride level, which increased in the active disease period in all the analyzed disorders except non-Hodgkin lymphoma. The most pronounced changes in the lipid fractions occurred in the HDL cholesterol level, and were the most remarkable for acute leukemia.
Cell Mol Biol Lett 2008
PMID:Lipid changes occuring in the course of hematological cancers. 1846 97

It is known that presence of xenobiotic-metabolizing gene polymorphisms in some cases correlates with hereditary predisposition to the oncological diseases. In the present work the frequencies of xenobiotic-metabolizing gene polymorphisms in 332 children with the diagnosis acute lymphoblastic leukemia (ALL), 71 children with the diagnosis acute myeloblastic leukemia (AML) and 490 healthy donors have been determined using allele-specific hybridization on the biochip. Statistically significant increase in the frequency of GSTT1 "null" genotype (OR = 1.9, p = 4.7E-5) and GSTT1/GSTM1 double "null" genotype (OR = 3.1, p = 2.5E-8) in children with acute leukemia relative to healthy donors group has been revealed. Also 1.8-fold increase in the frequency of NAT2 genotype 341T/T, 481C/C, 590G/G in children with acute leukemia relative to healthy donors group (p = 0.026) has been recognized. Analysis of gene-gene interactions has showed that in patients with acute leukemia genotype NAT2 341T/T, 481C/C, 590G/G in combination with GSTT1 "null" and/or GSTM1 "null" genotype is significantly more frequent than in population control. Besides the reduction of MTRR genotype 66G/G frequency in girls with acute leukemia relative to female healthy donors has been found (OR = 0.50, p = 0.0015). Analysis of gene-gene interactions has shown that the presence of GSTT1 "null" and/or GSTM1 "null" genotype in combination with MTRR genotype 66A/- may consider as risk factor of acute leukemia in girls. Thus, the studied polymorphic variants of genes GSTT1, GSTM1, NAT2 and MTRR can modulate the risk of childhood acute leukemia, residents of European part of Russia.
Mol Biol (Mosk)
PMID:[Genetic polymorphism in GST, NAT2, and MTRR and susceptibility to childhood acute leukemia]. 1861 Aug 29

The specificity and sensitivity of CD19, CD20, CD79a, and PAX5 for detection of B-cell lineage lymphoma/leukemia derivation was determined on tissue microarrays containing 148 Hodgkin lymphomas, 358 B-cell and 16 T-cell lymphomas, 50 myelomas, and 69 acute leukemias. In mature lymphoid neoplasms, receiver-operating characteristic curve analysis showed CD20 to be the most sensitive, and CD20 and CD79a the most specific markers for B-lineage derivation. CD19 had the weakest specificity, because it was expressed in 3 T-cell lymphomas, but its sensitivity was better than CD79a. In Hodgkin lymphoma cases, the presence of B-cell markers in Hodgkin and Reed-Sternberg cells decreased in the following order: PAX5>CD20>CD79a>CD19. CD19 and PAX5 were not detectable in myelomas. In acute leukemia, CD20 turned to be the most specific, and PAX5 and CD19 the most sensitive markers for B-lineage derivation. In conclusion, an optimal B-cell lineage panel for daily routine on paraffin-embedded tissues should consist of CD20 and CD79a, and eventually, PAX5 for mature lymphoid neoplasms and PAX5 and CD19, and eventually, CD20 in (acute) precursor cell leukemias, because they cover most of the sensitivity and specificity needed.
Appl Immunohistochem Mol Morphol 2009 Mar
PMID:Diagnostic utility of the B-cell lineage markers CD20, CD79a, PAX5, and CD19 in paraffin-embedded tissues from lymphoid neoplasms. 1883 17

The aim of this study was to evaluate the phospholipid concentration in acute leukemia (AL) blast cells from peripheral blood (PBMC) and bone marrow (BMMC). In vitro 31P Nuclear Magnetic Resonance Spectroscopy (31P MRS) was used. The integral intensities of the resonant peaks and the phospholipid concentrations in PBMC and BMMC were analyzed. Differences in the phospholipid concentrations in cells from myeloblastic or lymphoblastic lines were also evaluated. This investigation was carried out on phospholipid extracts from PBMC and BMMC from 15 healthy volunteers and 77 patients with AL (samples taken at the moment of diagnosis). A significant decrease in sphingomyelin (SM) and phosphtidylserine (PS) was observed in the PBMC of patients with AL relative to the results for the healthy volunteers. For ALL, we found a significant decrease in the concentration of phosphatidylcholine plasmalogen (CPLAS), SM, PI+PE (phosphatidylinositol + phosphatidylethanolamine) and PS in comparison with the results for healthy volunteers and patients with AML. Experiments with BMMC cells revealed a significant decrease in the concentration of CPLAS, SM, PI+PE, and PS in ALL relative to AML. Additionally, a significant decrease in phosphatidylcholine (PC) concentration was observed in ALL compared to AML. If the phospholipid extracts were taken simultaneously from the same patient, there were no significant differences in the integral intensities and phospholipid concentrations between PBMC and BMMC.
Cell Mol Biol Lett 2009
PMID:31P MRS analysis of the phospholipid composition of the peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) of patients with acute leukemia (AL). 1883 72

In this concise report, we describe the history and evolution of childhood acute leukemia studies in Brazil, and the application if key biomarkers for clinical trials and epidemiological studies over the past 8 years. Highlights of each ongoing study are summarized. A Brazilian network integrating hospitals and scientific institutions from all country regions has been established. This organization is made possible through informatics and computer networking, and the standardization of pathological reviews including immunophenotyping and molecular characterization of childhood leukemias. The unique characteristics of the Brazilian population combined with a large clinical and epidemiologic framework for patient ascertainment has enabled large-scale epidemiological studies on childhood leukemia in Brazil.
Blood Cells Mol Dis
PMID:Development and perspective of current Brazilian studies on the epidemiology of childhood leukemia. 1906 27

One of the main problems in treating cancer patients is that cancer cells can develop drug resistance. Resistance to multiple anticancer drugs, so called multidrug resistance (MDR), most likely involves a nonspecific mode of resistance, through drug-efflux transporters. One of the most extensively studied genes involved in MDR is multidrug resistance protein 1 (MRP1). We investigated a possible association between the expression level of MRP1 and the occurrence of MDR in leukemic patients, and we tested the hypothesis that MRP1 polymorphisms are predictive of MDR in patients with acute leukemia. The mRNA level of MRP1 was determined in 111 patients with acute leukemia (including 52 patients with acute myeloid leukemia and 59 patients with acute lymphoblastic leukemia), by quantitative real-time PCR, to determine how it affected the response to chemotherapy. We typed T2684C, C2007T, C2012T, and C2665T MRP1 polymorphisms in 111 patients classified as either drug-resistant or drug-responsive. We found that high expression of MRP1 was associated with the MDR phenotype in both acute myeloid leukemia and acute lymphoblastic leukemia patients. There was no effect of a particular genotype on the expression level of the MRP1 gene. We found no significant differences in chemosensitivity among any of these genotypes.
Genet Mol Res 2008
PMID:MRP1 polymorphisms (T2684C, C2007T, C2012T, and C2665T) are not associated with multidrug resistance in leukemic patients. 1906 72

The human MLL gene is one of the most promiscuous recombination hot spots of our genome with regard to the onset of malignant diseases. With the exception of gene internal partial-tandem duplications involving several exons located in the 5'-end of MLL, all recombination events occur in a small genomic region flanked by MLL exons 8-14, designated as the MLL breakpoint cluster region. Efforts from different laboratories, including our own, have led to the identification of more than 50 MLL fusion partners that were characterized at the molecular level. The common theme of recombination events involving the human MLL gene is the creation of "functional" fusion genes that are translated into oncoproteins. Many different labs have already demonstrated that these MLL fusion proteins have the capability to instruct hematopoietic stem/precursor cells to convert into a preleukemic state, which finally leads to the onset of leukemia in experimental model systems.Here we have focused on the identification of MLL fusion partners by using the genomic DNA of acute leukemia patients. After initial screening using for example split signal FISH experiments (as an example for technologies to identify MLL rearrangements), genomic DNA from leukemia patients is analyzed by long-distance-inverse (LDI)-PCR. LDI-PCR is based on the hydrolysis of patient DNA using distinct combinations of restriction enzymes, self-ligation of the resulting DNA fragments and a subsequent PCR reaction using a specific set of oligonucleotides. This strategy allows in principle any investigator to identify known and unknown MLL fusion partner genes. Furthermore, the genomic fusion site in MLL rearrangements represent a unique and reliable molecular marker that allows the tracing of minimal residual disease (MRD) in these patients before, during, and after therapy.
Methods Mol Biol 2009
PMID:LDI-PCR: identification of known and unknown gene fusions of the human MLL gene. 1927 76

Acute leukemia is an aggressive form of hematological malignancy, which is characterized and classified into different subtypes according to the morphology and immunophenotype of the leukemic blasts. However in the past decade, it became clear that it is the genetic makeup and probably the origin of leukemic stem cells, which determine the phenotype, aggressiveness, and prognosis of the disease. To further advance our knowledge, various molecular and cellular methodologies have been developed by clinical and basic researchers to not only identify and monitor these genetic changes in patients, but also model and dissect the underlying transformation mechanisms of the disease. In this chapter, I will summarize some of the key developments and latest technologies that have been instrumental to modern leukemia research.
Methods Mol Biol 2009
PMID:An overview: from discovery of candidate mutations to disease modeling and transformation mechanisms of acute leukemia. 1927 92

We present an update of our results regarding related HLA-haploidentical and HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in patients with leukemia. We compared the outcomes of 107 patients with leukemia undergoing HLA-identical sibling (n=51) or related HLA-haploidentical (n=56) HSCT performed during the same time period. Patients received BU-CY/CY-TBI in HLA-identical sibling HSCT or TBI+Ara-C+CY+ATG/CCNU+Ara-C+Bu+CY+ATG in haploidentical HSCT as conditioning regimens, followed by unmanipulated marrow and/or peripheral blood (PB) transplantation. All patients achieved full engraftment. The cumulative incidence of grades II through IV acute graft-versus-host disease (aGvHD) in the matched and haploidentical cohorts was 13.7% and 26.8% (P<0.05), respectively. The risk of developing cGvHD was not different between HLA-matched and haploidentical patients (P>0.05). The two-year incidence of treatment-related mortality for matched and haploidentical patients was 7.8% and 12.5%, respectively, with P>0.05, and the incidence of relapse was 17% and 22%, respectively, with P>0.05. The two-year adjusted leukemia-free survival for matched versus haploidentical patients was 76% and 68%, respectively, with P>0.05, and the overall survival for matched versus haploidentical patients was 80% and 70%, respectively, with P>0.05. Multivariate analyses showed that only advanced disease stage and a diagnosis of acute leukemia were related to increased risk of relapse, treatment failure, and overall mortality. In summary, HSCT performed with related HLA-haploidentical donors is a feasible approach with acceptable outcomes.
Blood Cells Mol Dis
PMID:HLA-haploidentical blood and bone marrow transplantation with anti-thymocyte globulin: long-term comparison with HLA-identical sibling transplantation. 1935 56

The c-myb proto-oncogene is a key regulator of hematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in, and is required for the proliferation of, most human myeloid and acute lymphoid leukemias. Recently, chromosomal translocation and genomic duplications of c-MYB have been identified in human T-cell acute leukemia. The present work focuses on the effects of mutations in different domains of the murine c-Myb protein on its transforming ability as defined by suppression of myelomonocytic differentiation and continued proliferation. Using both a novel myeloid cell line-based assay and a primary hematopoietic cell assay, we have shown that mutation of single residues in the transactivation domain important for CBP/p300 binding leads to complete loss of transforming ability. We also simultaneously mutated residues in the DNA-binding domain and the negative regulatory domain of the protein. These double mutants, but not the corresponding single mutants, show a complete loss of transforming activity. Surprisingly, these double mutants show severely impaired transactivation and are also defective for CBP/p300 binding. Our results imply that multiple Myb domains influence its interaction with CBP/p300, highlight the importance of this interaction for myeloid transformation, and suggest an approach for molecular targeting of Myb in leukemia.
Mol Cancer Res 2009 Sep
PMID:Mutations in multiple domains of c-Myb disrupt interaction with CBP/p300 and abrogate myeloid transforming ability. 1973 67


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