Background: The conventional, or standard, treatment of chronic myeloid leukaemia (CML) with hydroxyurea and busulfan has no marked influence on its course or duration. Interferon (IFN) alpha administration has, on the other hand, been... more
Background: The conventional, or standard, treatment of chronic myeloid leukaemia (CML) with hydroxyurea and busulfan has no marked influence on its course or duration. Interferon (IFN) alpha administration has, on the other hand, been shown to induce not only a haematological but also cytogenetic response, i.e. partial or complete bone marrow repopulation by Ph-negative cells. This has triggered studies comparing IFN and conventional chemotherapy. The present work had the purpose to gain experience with IFN alpha treatment and compare the results with hydroxyurea and busulfan treatment, in the chronic phase of CML. Methods and results: Therapeutic results obtained in 30 patients given IFN alpha and 30 others given conventional chemotherapy were evaluated retrospectively. In spite of the short time of IFN administration (4-27 months), significantly more complete haematological responses (83%) were observed in this than the conventional chemotherapy group (57%). Cytogenetic responses were achieved in 36%, complete cytogenetic remission in 20% of IFN-treated patients. Conventional chemotherapy produced no cytogenetic effect. Conclusion: The results obtained confirm the value and efficacy of IFN-alpha treatment in CML patients, especially if it is started early and the dose is effective. Regular cytogenetic monitoring is necessary. Longer follow-up of the patients will be necessary for evaluation of the IFN effect on the length of their survival.
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Abstract 2788 Poster Board II-764 Introduction. Patients with MDS-5q- syndrome have macrocytic anemia often with hypoplastic erythropoiesis and on the contrary thrombocythemia with effective though dysplastic megakaryopoiesis.... more
Abstract 2788 Poster Board II-764 Introduction. Patients with MDS-5q- syndrome have macrocytic anemia often with hypoplastic erythropoiesis and on the contrary thrombocythemia with effective though dysplastic megakaryopoiesis. Megakaryocytes and erythroid cells are thought to share a common progenitor MEP (T.P.McDonald et al., Exp. Hematology 1993). There are two key transcription factors which together with other transcription factors and relevant cytokines and receptors determine the hemopoietic differentiation of the common stem cell: erythroid Krüppel-like factor (EKLF) for erythroid lineage and Friend leukemia virus integration 1 (FLi-1) for megakaryopoiesis (Pilar Frontelo et al., Blood 2007; G.A.Blobel, Blood 2007; F.Bouilloux et al., Blood 2008). There is functional cross antagonism between FLi-1 and EKLF (J.Starck et al., Mol. Cel. Biology 2003). FLi-1 is active only if dephosphorylated (H.Huang et al., ASH Abstracts 2008). The question is whether both factors play any role in 5q- syndrome. Methods. FLi-1 and EKLF gene expressions were determined in mononuclear cells isolated from the whole blood or bone marrow using Ficoll-Paque PLUS. Expression of both factors was measured by quantitative real-time PCR. RT-PCR products were verified by electrophoresis and direct sequencing. The assays were performed for sample in duplicate. Glyceraldehyd-3-phosphate dehydrogenase (GAPDH), FLi-1 and EKLF were amplified in 25 μl reaction mixture containing 12.5 μl SYBR Green JumpStart Taq Ready Mix, 2.5 μl 2 μM FLi-1 or EKLF forward and reverse primers, 0,25 μl internal reference dye and 1 μl cDNA. Relative levels of FLi-1 and EKLF mRNAs were calculated to the level of housekeeping GAPDH mRNA. Results. FLi-1 and EKLF were measured in blood mononuclear cells of 8 patients fulfilling all criterias of 5q- syndrome. FLi1mRNA/GAPDHmRNA was higher in all samples, average value was 0.0930 (0.0242-0.4274) compared to control value 0.0194. FLi1mRNA/GAPDHmRNA in bone marrow mononuclear cells of 7 patients with 5q- syndrome was higher in all samples but one. The average value was 0.0827 (0.0070-0.2554) compared to healthy controls 0.0044. EKLF gives very low values in the majority of patients′ blood and bone marrow samples as well as in healthy controls. The evaluation is therefore less reliable then FLi-1 assessment. EKLFmRNA/GAPDHmRNA in blood was 0.0004 (0.0-0.0023) compared to the control 0.0222. The results of EKLF in 5 bone marrow samples are inconsistent. Three are lower than the control (0.0068), 1 of remaining 2 samples is extremely high (0.3491). It is interesting that this patient is the only one who responded to erythropoietin and is transfusion independent. Summary. Our preliminary results with FLi-1 and EKLF gene expression measurement are in agreement with expected findings: increased FLi-1 expression corresponds to thrombocytemia in 5q- syndrome patients and expression of EKLF, lower than in controls would correspond to anemia in these patients. However, EKLF values are less reliable because of very low values in patients as well as in controls and because of inconsistent results in bone marrow samples. We prepare to follow both factors in 5q- patients after the treatment with lenalidomide. Lenalidomide improves anemia in 5q- syndrome patients and temporarily causes decrease of thrombocytes (A.List et al., N.Engl.J.Med. 2005, 2006). Inhibition of phosphatases by lenalidomide (S.Wei et al., Proc.Natl.Acad.Sci.USA 2009) can stop FLi-1 dephosphorylation which leads to FLi-1 inactivation. Hypotetically inactive FLi-1 would enable EKLF to induce MEP into erythroid lineage. Supported by MSM 0021620808 Disclosures: No relevant conflicts of interest to declare.
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Background: myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder with an incompletely known pathogenesis. Long noncoding RNAs (lncRNAs) play multiple roles in hematopoiesis and represent a new class of biomarkers and... more
Background: myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder with an incompletely known pathogenesis. Long noncoding RNAs (lncRNAs) play multiple roles in hematopoiesis and represent a new class of biomarkers and therapeutic targets, but information on their roles in MDS is limited. Aims: here, we aimed to characterize lncRNAs deregulated in MDS that may function in disease pathogenesis. In particular, we focused on the identification of lncRNAs that could serve as novel potential biomarkers of adverse outcomes in MDS. Methods: we performed microarray expression profiling of lncRNAs and protein-coding genes (PCGs) in the CD34+ bone marrow cells of MDS patients. Expression profiles were analyzed in relation to different aspects of the disease (i.e., diagnosis, disease subtypes, cytogenetic and mutational aberrations, and risk of progression). LncRNA-PCG networks were constructed to link deregulated lncRNAs with regulatory mechanisms associated with MDS. Results: w...
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Karyotype represents one of the most valuable prognostic markers for MDS patients with profound impact on differential diagnosis and therapeutic decisions despite of the fact that it is a heterogenous patient population with diverse... more
Karyotype represents one of the most valuable prognostic markers for MDS patients with profound impact on differential diagnosis and therapeutic decisions despite of the fact that it is a heterogenous patient population with diverse pathogenesis and clinical course. In approximately 10–20% of MDS patients complex chromosomal aberrations (CCA; three or more numerical/structural cytogenetic aberrations) are present at diagnosis and this finding is associated with the treatment resistance and poor outcome. Precise identifications of chromosomal regions involved in CCA could help in detection of cryptic, recurrent, prognostically relevant aberrations and in identification of candidate genes involved in leukemogenesis and progression of the disease. In this study we used various modifications of molecular cytogenetic techniques to specify CCA more precisely and to determine exact localization and frequency of chromosomal breakpoints. During the last seven years we examined bone marrow sa...
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Background and Aims A part of lower-risk myelodysplastic (LR-MDS) patients progress to higher-risk MDS or acute myeloid leukemia (AML). The progression may be predicted in some of these patients by determining mutations associated with... more
Background and Aims A part of lower-risk myelodysplastic (LR-MDS) patients progress to higher-risk MDS or acute myeloid leukemia (AML). The progression may be predicted in some of these patients by determining mutations associated with myeloid malignancies at the time of diagnosis. We focused to find out dysregulated pathways caused by a well-defined mutation associated with disease progression. Methods We examined 158 samples from LR-MDS patients at diagnosis using TruSight Myeloid Sequencing Panel containing 54 genes (Illumina) to identify the mutational profile. We applied RNA-seq (NEB; Illumina) on bone marrow CD34+ cells of 5 LR-MDS patients with RUNX1 mutation and 6 LR-MDS patients without mutations. We performed differential gene expression analysis, gene set enrichment analysis (GSEA), Reactome biological pathway and Gene Ontology (GO) annotations. Results Forty out of 158 patients (25%) progressed during the follow-up period (median: 45.1 months). Mutation in RUNX1 gene was...
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Background and Aims A part of lower-risk myelodysplastic (LR-MDS) patients progress to higher-risk MDS or acute myeloid leukemia. These patients have more aggressive type of disease than is expected based on their classification according... more
Background and Aims A part of lower-risk myelodysplastic (LR-MDS) patients progress to higher-risk MDS or acute myeloid leukemia. These patients have more aggressive type of disease than is expected based on their classification according to the International Prognostic Scoring System. Alongside, recent advances in DNA sequencing have enabled the identification of a large number of mutated genes in more than 80% of MDS patients. We focused on the identification of mutational profile that would be predictive of disease progression in LR-MDS patients. Methods We examined samples from 73 LR-MDS patients by TruSight Myeloid Sequencing Panel containing 54 genes (Illumina) to determinate the mutational profile. In 32 (44%) patients, paired samples processed at the time of diagnosis and during progression were analyzed. The median age of patients was 64.5 years (range, 29-83 years). The median observation period was 33.4 months (range, 4.5-195.9 months) from diagnosis, 36 (49%) patients re...
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5023 A direct effects of lenalidomide on gene expression in 5q- patients was studied using HumanRef-8 v2 Expression BeadChips (Illumina). Expression profiles of 6 patients (before treatment and at the time of the first erytroid response)... more
5023 A direct effects of lenalidomide on gene expression in 5q- patients was studied using HumanRef-8 v2 Expression BeadChips (Illumina). Expression profiles of 6 patients (before treatment and at the time of the first erytroid response) and 6 healthy controls were investigated from CD14+ monocytes of peripheral blood. Differentially expressed genes were identified by Significance Analysis of Microarrays (SAM). Simultaneously, selected genes (TNF, JUN, IL1) were monitored in the course of treatment using Real-Time PCR with Taqman Gene Expression Assays. A comparison of gene expression levels before and during lenalidomide treatment revealed 97 differentially expressed genes (FC >2; p<0.05) related to following biological processes: immune response (16 genes), inflammatory response (11 genes), response to bacteria (8 genes), anti-apoptosis (7 genes), regulation of MAP kinase activity (5 genes), oxygen transport (4 genes), and regulation of cell proliferation (11 genes). An over...
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Introduction Friend leukemia virus integration 1 (Fli1) is one of the factors involved in the differentiation of megakaryocytic and erythroid progenitor (MEP). Fli1 plays an important role in the development of megakaryocytes (MGC) (Doré... more
Introduction Friend leukemia virus integration 1 (Fli1) is one of the factors involved in the differentiation of megakaryocytic and erythroid progenitor (MEP). Fli1 plays an important role in the development of megakaryocytes (MGC) (Doré and Crispino 2011). We demonstrated the increased level of Fli1 mRNA in bone marrow mononuclear cells of MDS patients (pts) with 5q- syndrome (Ann Hematol 2013). Kumar et al. (2011) explained the Fli1 increase as a consequence of miR-145 haploinsufficiency in 5q- syndrome. Fli1 is one of the target genes of miR-145. Our presumption is that the interaction between Fli1, MDM2 and p53 is important for the magakaryopoiesis in 5q- syndrome. Truong et al. (2005) demonstrated that Fli1 activates E3-ubiquitin ligase MDM2, which plays an important role in p53 degradation in proteasome. Therefore Fli1 probably protects MGC against ribosomal stress contrary to erythroid cells in 5q- syndrome pts. However, Fli1 and p53 mRNA levels, analysed by us in these patie...
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Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of oncohematologic diseases, characterized by bone marrow hypercellularity, dysplasia of myeloid lineage cells, peripheral cytopenias, and an increased risk of... more
Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of oncohematologic diseases, characterized by bone marrow hypercellularity, dysplasia of myeloid lineage cells, peripheral cytopenias, and an increased risk of evolution to acute myeloid leukemia (AML). Pathophysiology of MDS is not fully understood, however it has been described that oxidative stress plays an important role in initiation and disease progression. Oxidative stress is defined as an imbalance between prooxidative and antioxidative processes that prefers the production of reactive oxygen species (ROS) over an antioxidant defence. The association between MDS and oxidative stress was discussed in several studies, where functional mitochondrial abnormalities in MDS patients have been demonstrated as one of the possible sources of oxidative stress. Another mechanism could be associated with mitochondrial dysfunction via iron overloading, mitochondrial DNA mutation, systemic inflammation, and bone marrow ...
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The aim of this study was to investigate the rearrangement of MLL gene in bone marrow cells of patients with hematological malignancies with various types of 11q aberrations. These aberrations have been observed in acute lymphoblastic and... more
The aim of this study was to investigate the rearrangement of MLL gene in bone marrow cells of patients with hematological malignancies with various types of 11q aberrations. These aberrations have been observed in acute lymphoblastic and acute myeloid leukemias as well as in myelodysplasias and lymphomas. Correlations of clinical characteristics, type of aberrations, diagnoses and survival of patients were evaluated. Using classical cytogenetic techniques we found 11q aberration in 17 patients with different hematological malignancies. FISH with dual color locus specific probe for MLL gene was used to confirm or exclude the rearrangement of this gene. Whole chromosome painting probes and multicolor FISH were performed for identification of chromosomes involved in complex translocations. Balanced rearrangements of 11q were found in 3 patients, in 14 patients unbalanced aberrations were found with rearrangement (4), deletion (4) and amplification (2) of MLL gene. In 7 patients no rea...
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Telomere length was evaluated by terminal repeat fragment method (TRF) in 50 patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) arising from MDS and in 21 patients with untreated primary AML to ascertain,... more
Telomere length was evaluated by terminal repeat fragment method (TRF) in 50 patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) arising from MDS and in 21 patients with untreated primary AML to ascertain, whether telomere erosion was associated with progression of MDS towards overt leukemia. Heterogeneity of TRF among MDS FAB subgroups (P=0.004) originated from its shortening in increased number of patients during progression of the disease. Chromosomal aberrations were present in 32% MDS patients with more eroded telomeres (P=0.022), nevertheless a difference between mean TRF in the subgroups with normal and abnormal karyotype diminished during progression of MDS. A negative correlation between individual TRF and IPSS value (P=0.039) showed that telomere dynamics might serve as a useful prognostic factor for assessment of an individual MDS patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s risk and for decision of an optimal treatment strategy.
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Research Interests: Biology, Medicine, Cytogenetics, Cancer Genetics, Acute Myeloid Leukemia, and 15 moreHumans, Fluorescence in situ hybridization, Female, Male, Karyotyping, Aged, Middle Aged, Karyotype, Fluorescent in situ hybridization, Chromosomal abnormalities, Chromosome Banding, Acute Disease, Chromosome deletion, Chromosome aberrations, and Hematologic neoplasms
Fluorescence in situ hybridization (FISH) using specific probes for the 5q31-32 region and a whole chromosomal painting (WCP) probe for chromosome 5 were used to corroborate the results of classical cytogenetic examinations performed on... more
Fluorescence in situ hybridization (FISH) using specific probes for the 5q31-32 region and a whole chromosomal painting (WCP) probe for chromosome 5 were used to corroborate the results of classical cytogenetic examinations performed on G-banded chromosomes of 77 patients with hematological malignancies. Using classical cytogenetic methods, we suspected the presence of clones with a deletion 5q in 63 patients, and complex rearrangements with involvement of chromosome 5 in 14 other cases. Fluorescence in situ hybridization proved the occurrence of deletion 5q31 in 23 patients and ascertained translocations of part of the long arms of deleted chromosome 5 with missing region 5q31 in 12 patients. In 2 cases, the 5q31 region was translocated to other chromosomes as a part of complex rearrangements. The combination of classical cytogenetics and FISH with specific probes for the 5q31 band yielded cytogenetic results in 35 cases. Routine FISH detection of deleted regions was possible by commercially available cosmid probes for the 5q31 chromosomal band. The interpretation of small deletions and frequent involvement of the deleted chromosomes 5 in complex translocations were ascertained by WCP probes.
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Research Interests: Biology, International Cooperation, Medicine, Phylogeny, Humans, and 13 moreMyelodysplastic Syndrome, Blood, Karyotyping, Gene, CD, Clinical Sciences, Karyotype, Bone Marrow Cells, Gene expression profiling, reverse transcriptase polymerase chain reaction, Myelodysplastic syndromes, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
The karyotype of bone marrow cells at the time of diagnosis is a strong prognostic parameter for overall survival as well as acute myeloid leukemia (AML) progression in patients with myelodysplastic syndromes (MDS). However, to the... more
The karyotype of bone marrow cells at the time of diagnosis is a strong prognostic parameter for overall survival as well as acute myeloid leukemia (AML) progression in patients with myelodysplastic syndromes (MDS). However, to the authors' knowledge, few data exist regarding the prognostic impact of cytogenetic clonal evolution during the course of MDS. The authors evaluated follow-up karyotype analyses in 549 patients from the Dusseldorf MDS Registry. Clonal evolution was detectable in 24% of the entire cohort and in 18% of 294 patients receiving best supportive care. The authors noted a clear adverse effect of clonal evolution on the risk of leukemic transformation (hazard ratio, 2.233; P = .036) and overall survival (hazard ratio, 3.677; P<.001). The authors also analyzed the prognostic influence of subclones detectable at the time of diagnosis. Again, such a finding was associated with a significantly shorter overall survival and a higher 5-year-probability of acute myel...
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INTRODUCTION Nrf2 (nuclear factor, erythroid-derived 2-like 2 or NF-E2-related factor 2) is a transcription factor involved in antioxidant response by reducing oxidative stress. Erythropoietin (EPO) was described as an inducer of Nrf2 in... more
INTRODUCTION Nrf2 (nuclear factor, erythroid-derived 2-like 2 or NF-E2-related factor 2) is a transcription factor involved in antioxidant response by reducing oxidative stress. Erythropoietin (EPO) was described as an inducer of Nrf2 in the brain. Nrf2 binds to the promoter of gene coding for cereblon (CRBN) and stimulates CRBN expression (Lee et al. Biochem.Biphys Res Commun 2010; 399: 711-715). We showed that the high level of full length CRBN mRNA and CRBN protein is important for the efficacy of lenalidomide (LEN) in lower-risk MDS patients (Jonasova et al. Eur J Haematol 2015; 95: 27-34; Fuchs et al. Leuk Res 2017; 55 S1: S132, abstr. 227). Addition of EPO to LEN restored transfusion independence of MDS patients when their anemia relapsed during the course of LEN treatment (Jonasova et al. Leuk Res 2018; 69: 12-17). LEN inhibits E3 ubiquitin ligase RNF41 (ring finger protein 41), which polyubiquitinates EPO receptor (EPOR) and marks it for degradation in proteasomes. (Basiorka...
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Introduction: Chromothripsis is a recently identified genomic instability phenomenon that plays a role in the genesis and progression of cancer. It is a one-step catastrophic genomic event involving multiple chromosomal breakages and... more
Introduction: Chromothripsis is a recently identified genomic instability phenomenon that plays a role in the genesis and progression of cancer. It is a one-step catastrophic genomic event involving multiple chromosomal breakages and random DNA rejoining. This genetic abnormality can affect an entire chromosome, a chromosomal arm, or a single chromosomal region. Chromothripsis is associated with highly complex karyotypes and a very poor prognosis, and has been detected in a wide range of tumor entities, including hematological malignancies. However, this complex genomic abnormality has not been comprehensively studied in patients with myelodysplastic syndromes (MDS). The aim of the study was to assess the incidence, associated genetic features, and clinical significance of chromothripsis in a large homogeneous cohort of patients newly diagnosed with high-risk MDS and complex karyotypes. Methods: A detailed genome-wide analysis of fixed bone-marrow cells from adults with complex kary...
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3825 Introduction: 5q- syndrome and DBA belong to ribosomopathies. 5q- syndrome patients (pts) have haploinsufficient RPS14 gene and approximately 50% DBA pts have mutated some of genes for ribosomal proteins. These two disorders share... more
3825 Introduction: 5q- syndrome and DBA belong to ribosomopathies. 5q- syndrome patients (pts) have haploinsufficient RPS14 gene and approximately 50% DBA pts have mutated some of genes for ribosomal proteins. These two disorders share similar erythroid and megakaryocytic characteristics: macrocytic anemia, decreased erythropoiesis, normal platelet count and they differ in: frequent neutropenia in 5q- syndrome, rare thrombocytemia and absence of hypolobulated megakaryocytes in DBA. We recently studied two transcription factors Fli1(Friend leukemia virus integration 1) and EKLF (Erythroid Krüppel like factor, also named KLF1) involved in MEP (common megakaryocytic and erythroid progenitor) differentiation in MDS 5q-syndrome pts. Now we present the examination of these factors in DBA pts. There exists cross-antagonism between Fli1 and EKLF with probable dominance of EKLF. Fli1 mRNA is target for microRNA-l45 (miR-145) localized in common deleted region of 5q. Haploinsuffciency of miR...
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Introduction The binding of immunomodulatory drugs (IMiDs), including lenalidomide, to CRBN is associated with cytotoxicity of IMiDs used in the treatment of multiple myeloma, myelodysplastic syndromes (MDS) and lymphomas. Cereblon (CRBN)... more
Introduction The binding of immunomodulatory drugs (IMiDs), including lenalidomide, to CRBN is associated with cytotoxicity of IMiDs used in the treatment of multiple myeloma, myelodysplastic syndromes (MDS) and lymphomas. Cereblon (CRBN) is named for its putative role in cerebral development, especially in memory and learning. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), cullin-4 (CUL4) and regulator of cullin 1 (ROC1). This complex regulates DNA repair, DNA replication and transcription. CRBN is a primary target of thalidomide teratogenicity (Ito et al., Science 2010; 327:1345-1350). Down-regulation of the CRBN expression is associated with the development of marked IMiDs resistance in human multiple myeloma cells (Zhu et al., Blood 2011; 118: 4771-4779; Lopez Girona et al., Leukemia 2012; 26: 2326-2335; Heintel et al., Br J Haematol 2013; 161: 695-700; Broyl et al., Blood 2013; 121: 624-627; Lodé et al., Br J Haematol 2013; Jul 17. doi: 10....
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Introduction In 2009, we published an analysis of 68 patients with isolated del(5q), of which 43 fulfilled the criteria of 5q- syndrome (5q- sy). Among these patients (pts), we found 6 pts who had, in addition to the del(5q) clone an... more
Introduction In 2009, we published an analysis of 68 patients with isolated del(5q), of which 43 fulfilled the criteria of 5q- syndrome (5q- sy). Among these patients (pts), we found 6 pts who had, in addition to the del(5q) clone an unrelated clone with trisomy 8. Since then, we have found another 6 biclonal pts. We present the clinical and cytogenetic data of these 12 pts, which we compare to the findings of typical 5q- sy pts. As a point of interest, we further present the data of 5 pts with the same two chromosomal abberations in one clone. Clinical data The comparison of clinical data between pts with two unrelated clones 5q- and +8 and pts with typical 5q- sy did not reveal fundamental differences. All 12 patients are women. The median age is 57, compared to 65 years in our 5q- sy pts. The patients had macrocytic anemia, normal or elevated platelet counts, typical unlobulated megakaryocytes in all cases, and myeloblasts of less than 3%. Cytogenetic data The patients were repea...
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Introduction: Complex chromosomal aberrations (CCAs) are seen in approximately 20% of patients with newly-diagnosed MDS and are associated with poor prognosis. Bone marrow cells of MDS patients with CCAs are characterized by a high degree... more
Introduction: Complex chromosomal aberrations (CCAs) are seen in approximately 20% of patients with newly-diagnosed MDS and are associated with poor prognosis. Bone marrow cells of MDS patients with CCAs are characterized by a high degree of genomic instability, which is connected with an increased risk of formation of different subclones with additional aberrations. The phenomenon of clonal evolution can be observed either at diagnosis or during the disease progression. At diagnosis it is manifested by the presence of two or more related subclones derived from one founder clone. These subclones can obtain a proliferative advantage leading to the clonal expansion. The aim of the study was to perform detailed genome-wide analyses of bone marrow cells of previously untreated MDS patients with CCAs, to investigate the clonal heterogeneity and to assess the frequency and clinical significance of related cytogenetic subclones with complex karyotypes. Methods: A comprehensive molecular cy...
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Deletion of the long arm of chromosome 20 - del(20q) - is a recurrent abnormality observed in various myeloid disorders, including myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), or acute myeloid leukemia (AML). It... more
Deletion of the long arm of chromosome 20 - del(20q) - is a recurrent abnormality observed in various myeloid disorders, including myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), or acute myeloid leukemia (AML). It is a primary cytogenetic aberration, occurring often as a sole abnormality or the first abnormality in complex karyotypes, therefore it is assumed to play a key role in pathogenesis of myeloid malignancies. The proximal breakpoints of the deletion are consistently located in the 20q11.21 band, and the distal breakpoints span from 20q13.13 to band 20q13.33. In our previous study we showed a fusion of the ASXL1 and TSHZ2 genes resulting from an isochromosome of a deleted 20q in a patient with MDS (Brezinova et al Br J Haematol 2014). The ASXL1 gene is one of the most frequently mutated genes in myeloid disorders, mutations are generally associated with more aggressive course of the disease and poor clinical outcome. The aim of this study was to determ...
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Introduction: Inmyelodysplastic syndromes (MDS) the karyotype is one of the most important predictor of disease advancement, response to the treatment and patients' outcome. Clonal cytogenetic abnormalities are detected in the bone... more
Introduction: Inmyelodysplastic syndromes (MDS) the karyotype is one of the most important predictor of disease advancement, response to the treatment and patients' outcome. Clonal cytogenetic abnormalities are detected in the bone marrow cells in approximately 50% MDS patients. The interstitial deletion of the long arm of chromosome 5-del(5q)-is the most common finding, accounting for roughly 30% of abnormal karyotypes. According to IPSS-R, MDS with isolated del(5q) are associated with a favorable clinical course and are recognized as a specific subtype of MDS. However in some cases, acquisition of additional genetic aberrations may occur during the course of the disease and it has been proved it negatively influences outcome of MDS patients. The aim of the study was: (1) to evaluate the frequency of cytogenetic clonal evolution during the course of the disease in MDS patients with isolated del(5q), (2) to analyze the pattern of acquired cytogenetic abnormalities, and (3) to as...
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BACKGROUND AND AIMS Recent results have indicated that the TP53 mutations had a negative prognostic relevance for lower-risk myelodysplastic syndrome (MDS) patients but the relations between the presence of mutations and treatment has not... more
BACKGROUND AND AIMS Recent results have indicated that the TP53 mutations had a negative prognostic relevance for lower-risk myelodysplastic syndrome (MDS) patients but the relations between the presence of mutations and treatment has not been clarified yet. Therefore, we analyzed the prevalence of TP53 mutations in lower-risk MDS patients and determined the proportion of TP53 mutated bone marrow cells during the disease. We further observed mutual relation of treatment and mutated clones and defined impact of mutations on survival of patients. METHODS TP53 mutations were analyzed in DNA from bone marrow of 141 low risk or intermediate-1 risk MDS patients included into the cohort according to the International Prognostic Scoring System using primers designed within the IRON-II study research consortium (Roche Applied Science) on the GS Junior system. If mutations were detected, we searched for mutations at different timepoints of the disease and overall 210 samples were examined for...
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The high incidence of mutations and cytogenetic abnormalities in patients with myelodysplastic syndrome (MDS) suggests that defects in DNA repair mechanisms. We monitored DNA repair pathways in MDS and their alterations during disease... more
The high incidence of mutations and cytogenetic abnormalities in patients with myelodysplastic syndrome (MDS) suggests that defects in DNA repair mechanisms. We monitored DNA repair pathways in MDS and their alterations during disease progression. Expression profiling of DNA repair genes was performed on CD34+ cells, and paired samples were used for monitoring of RAD51 and XRCC2 gene expression during disease progression. Immunohistochemical staining for RAD51 was done on histology samples. RAD51 and XRCC2 showed differential expression between low-risk and high-risk MDS (P<.0001), whereas RPA3 was generally decreased among the entire cohort (FC=-2.65, P<.0001). We demonstrated that RAD51 and XRCC2 expression gradually decreased during the progression of MDS. Down-regulation of XRCC2 and RAD51 expression was connected with abnormalities on chromosome 7 (P=.0858, P=.0457). Immunohistochemical staining revealed the presence of RAD51 only in the cytoplasm in low-risk MDS, while i...