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PubMed2002

The myelodysplastic syndromes: analysis of prognostic factors and comparison of prognostic systems in 128 Chinese patients from a single institution.

INTRODUCTION: Although retrospective analysis were frequently undertaken, and many prognostic systems for myelodysplastic syndromes (MDS) have been proposed worldwide, few such studies have been performed and the effectiveness of different scoring systems have not yet been verified in independent patient populations in China. The aim of this single center study was to evaluate the prognostic factors and compare the prognostic scoring systems in Chinese patients with MDS. MATERIALS AND METHODS: One hundred and twenty-eight patients diagnosed as primary MDS in our Institution were studied retrospectively to identify significant prognostic factors and to assess the predictive value of 11 previously described prognostic systems, including French-American-British (FAB) classification, World Health Organization (WHO) classification, Mufti, Sanz, Morra, Aul, Oguma, Toyama, Morel and international prognostic scoring system (IPSS). RESULTS: The median age of the patients was 50 years (range 13-82). The 2- and 5-year survival rate of the patients were 55.22+/-4.90% and 26.09+/-6.36% respectively, with a median survival of 31 months (range 1-127 months). Fifty patients (39.1%) had progressed to acute leukemia (AL) with a median time of 8 months (range 1-43 months). Major independent variables indicated by multivariate analysis were the percentage of bone marrow (BM) blast cells and complex karyotype aberrations for survival (P=0.042 and 0.042, respectively) and only the percentage of BM blast cells for AL transformation (P=0.023). All the systems except Mufti scores successfully discriminated risk groups concerning both survival and AL evolution, especially in the high risk group, ranging from 10 to 20 months and from 4 to 7 months, respectively. The FAB and WHO classification, as well as Sanz, Oguma, Morel and IPSS possessed lower P value (P<0.0001) than that of the rest scoring systems. CONCLUSION: The patients in our study were younger than these of the Western population, whereas the survival and AL transformation ratio were comparable to these previous studies. The BM blast proportion and complex chromosomal defects were highly significant for predicting outcome in MDS patients. Most investigated systems effectively stratified patients into groups with different life expectancies and identified a subset of patients with poor clinical outcome. The FAB, WHO classification, as well as Sanz, Oguma, Morel and IPSS scoring systems were more applicable for predicting survival and leukemia progression.

Adolescent↗
PubMed2006

Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.

BACKGROUND AND OBJECTIVES: The aim of this study was a prospective validation of the World Health Organization (WHO) proposals for the classification of myelodysplastic syndromes (MDS) with respect to their prognostic relevance. DESIGN AND METHODS: We classified 1095 patients with MDS diagnosed at our institution between November 1999 and December 2004 according to French-American-British (FAB) and WHO criteria by central morphologic review. The study was not population-based, but included all newly diagnosed patients from different regions in Germany. Patients were followed for survival and disease evolution to acute myeloid leukemia (AML) through December 31th, 2005. RESULTS: According to the WHO classification, there were 89 cases of refractory anemia (RA), 293 of refractory cytopenias with multilineage dysplasia (RCMD), 31 RA with ringed sideroblasts (RARS), 139 RCMD with ringed sideroblasts (RCMD-RS), 142 RA with excess blasts (RAEB) I and 149 RAEB II and 52 patients with 5q- syndrome. The median survival of patients with RA or RARS was not reached, the median survival of patients with RCMD was 31 months, that of patients with RCMD-RS was 28 months, that of 5q- patients was 40 months, of RAEB I 27 months and of RAEB II 12 months. The cumulative risk of AML evolution 2 years after diagnosis was 0% in RA and RARS, 8% in 5q-, 9% in RCMD, 12% in RCMD-RS, 13% in RAEB I and 40% in RAEB II. The number of high-risk karyotypes was lower in patients with RA/RARS than in those with RCMD/RCMD-RS and RAEB I/RAEB II. Karyotype findings were major prognostic variables. INTERPRETATION AND CONCLUSIONS: The WHO classification is feasible and provides valuable prognostic information, even in a short-term prospective study. Together with cytogenetic data and other prognostic parameters, the WHO classification is very useful for clinical decision making.

Adolescent↗
PubMed1993

[The usefulness of the bcr/abl rearrangement in the diagnosis and evolution of chronic myeloid leukemia].

BACKGROUND: The rearrangement of the bcr/abl gene constitutes the molecular substrate of the Philadelphia chromosome (Ph'). The aim of this study was to analyze the usefulness of bcr/abl rearrangement in the diagnosis and evolution of chronic myeloid leukemia (CML). METHODS: The rearrangement of the bcr/abl gene was studied in 81 cases of which 34 corresponded to patients with CML (29 Ph' positive chromosome, 2 Ph' negative chromosome and 3 without karyotype), 2 patients with Ph' positive acute lymphoblastic leukemia, 15 patients with chronic myeloproliferative syndromes different from CML and 30 controls. Of the patients with CML, 6 were reevaluated when a blastic crisis was developed, 2 after receiving interferon treatment and 1 following allogeneic bone marrow transplantation. The technique used was that of Southern blotting using the restriction enzymes Bgl II and BamHI and the transprobe. RESULTS: Rearrangement of the bcr/abl gene was observed in all the patients with CML except in one with Ph' negative chromosome. In the remaining cases bcr/abl rearrangement was not observed. CONCLUSIONS: The Southern blotting technique for the study of the bcr/abl gene rearrangement is a sensitive and specific method in the diagnosis of chronic myeloid leukemia constituting a valid alternative to chromosomic study when this cannot be carried out or is not conclusive. It may also be used for the control of treatment in chronic myeloid leukemia.

Adult↗
PubMed2002

Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres.

Carcinomas of the head and neck typically exhibit complex chromosome aberrations but the underlying mutational mechanisms remain obscure. Evaluation of cell division dynamics in low-passage cell lines from three benign and five malignant head and neck tumours revealed a strong positive correlation between multipolarity of the mitotic spindle and the formation of bridges at anaphase in both benign and malignant tumours. Cells exhibiting a high rate of mitotic abnormalities also showed several chromosome termini lacking TTAGGG repeats and a high frequency of dicentric chromosomes. Multicolour karyotyping demonstrated a preferential involvement in structural rearrangements of chromosomes with deficient telomeres. The majority of malignant, mitotically unstable tumours expressed the reverse transcriptase subunit of telomerase. These data indicate that some of the genomic instability in head and neck tumours is initiated by telomere dysfunction, leading to the formation of dicentric chromosomes. These form chromosome bridges at mitosis that could prevent the normal anaphase-telophase transition. In turn, this may cause an accumulation of centrosomes and mitotic multipolarity. Telomerase expression does not confer total stability to the tumour genome but could be crucial for moderating the rate of chromosomal evolution.

Adenoma, Pleomorphic↗
PubMed2003

Aberrant p15 gene promoter methylation in therapy-related myelodysplastic syndrome and acute myeloid leukaemia: clinicopathological and karyotypic associations.

Seventeen patients with therapy-related myelodysplastic syndrome/acute myeloid leukaemia (t-MDS/AML) were examined for aberrant p15 gene methylation by methylation-specific polymerase chain reaction. Ten patients (58%) showed p15 methylation, which was significantly related to monosomy/deletion of chromosome 7q, but not to antecedent chemotherapy, blast count, leukaemic evolution or survival. In three of six patients with marrow samples obtained prior to the diagnosis of t-MDS/AML, p15 methylation predated disease development by up to 2 years. Bone marrow transplantation led to the disappearance of p15 methylation in one patient. These results showed that p15 methylation was an early event in the evolution of some t-MDS/AML patients.

Acute Disease↗
PubMed1993

Ph+ acute myelogenous leukemia with t(7;11)(p15;p15) and clonal evolution in relapse after bone marrow transplantation.

A 20-year-old female with Ph+ acute myelogenous leukemia (M2) associated with t(7;11)(p15;p15) is reported. Bone marrow aspirates were hypercellular with leukemic cells including Auer rods. Chromosome analysis showed t(7;11) and the Ph chromosome. After complete remission, normal karyotype was restored. Normal male karyotypic cells replaced the bone marrow following allogeneic bone marrow transplantation from her brother. On day 358, cytogenetic study at relapse revealed 14q+ as an additional change and clearly showed that the abnormal clone was derived from the patient, because metaphases with XX were all of abnormal karyotype and those with XY were normal.

Adult↗
PubMed1992

Clonal characteristics of acute lymphoblastic cells derived from BCR/ABL p190 transgenic mice.

The clonal and immunophenotypic characteristics of blood leukemic cells from BCR/ABL p190 transgenic mice were investigated. All cell populations evaluated in vivo and in vitro had B-lymphocyte progenitor immunophenotypes. Immunoglobulin (JH) rearrangement patterns provided evidence for clonal diversification at different sites in vivo. Multiple clones were established in vitro from two of these mice (nos. 730 and 753). These cells expressed BCR/ABL p190 protein tyrosine kinase (PTK) and were highly malignant on transfer to secondary recipients. Cells independently cloned in vitro shared identical immunophenotypes and clonal IgH rearrangements, but these were distinct from those of the dominant clones in the mouse from which they were derived. Nevertheless, in vitro clones from mouse no. 753 had an abnormal karyotype (chromosome 14 trisomy) in common with the dominant clone in blood, providing evidence for a hierarchy or clonal selection in vivo and in vitro. Two sets of in vitro clones proliferated independently of exogenous growth factors and stroma and released autocrine interleukin 7 growth factor activity. These data provide evidence for rapid divergent clonal evolution and selection of B-cell progenitors initiated by BCR/ABL p190, followed by other, secondary genetic events mirroring similar changes in the equivalent, highly malignant human leukemia Philadelphia (Ph)-positive/B-precursor acute lymphoblastic leukemia (ALL).

Animals↗
PubMed1989

[Late appearance of Philadelphia chromosome with bcr gene rearrangement in an acute myelocytic leukemia patient].

A case of acute myelocytic leukemia (AML-M2) with a late appearance of Philadelphia chromosome (Ph1) is presented. Chromosome analysis revealed a normal karyotype at the time of diagnosis and for 23 months, when hematological relapse occurred, accompanied by abnormal clones, 46, XX, t(9;22) (q34;q11) (78%) and 45,XX, -16, t(9;22) (q34;q11), del (5) (q13q31) (22%). The patient died of GVHD after bone marrow transplantation. Molecular analysis confirmed bcr gene rearrangement in the cells with Ph1 chromosome. Acquisition of Ph1 chromosome during the course of hematological malignancies other than CML is extremely rare. This case is undoubtedly important for the understanding of leukemogenesis and the evolution of leukemia clones. The authors discussed possible mechanisms of Ph1 acquisition in the late stages of AML.

Adult↗
PubMed1995

Chromosome identification and mapping in the grass Zingeria biebersteiniana (2n = 4) using fluorochromes.

The grass Zingeria biebersteiniana is one of five angiosperms known with 2n = 2x = 4. Its chromosomes were studied using fluorochrome banding and fluorescence in situ hybridization (FISH). The large pericentromeric region fluoresced much more brightly on chromosome 2 than on chromosome 1, using two different fluorochrome banding methods. These offer rapid and reliable means for identifying chromosomes and work throughout mitosis. FISH located the major site of 18S-26S rDNA sequences at the secondary constriction, which is proximal to two minor sites, all on the short arm of chromosome 1. Two 5S sites were also detected, the most distinct on the short arm of chromosome 2 and the other apparently co-localized with part of the major 18S-26S rDNA cluster on chromosome 1. These results constitute the first steps in constructing a physical gene map for Z. biebersteiniana. Such information may facilitate future studies of the organization and reorganization of grass genomes, including research into the spatial arrangement of the genome in Zingeria nuclei and much wider comparisons of synteny and genome evolution in grasses.

Centromere↗
PubMed1990

Sinus histiocytosis with massive lymphadenopathy: immunological, cytogenetic and molecular studies.

We describe a case of "sinus histiocytosis with massive lymphadenopathy" (SHML) studied by immunohistochemical, cytogenetic and molecular analysis. The immunophenotyping showed that the lymph node histiocytes were strongly positive for the S-100 protein and MoAb LeuM3, OKM5, KP1 and DRC-1; a portion of these cells was also positive for OKT6 and Leu3A, suggesting a possible relationship with the veiled cells, which represent an intermediate step in the pathway from the Langerhans cell to the interdigitating reticulum cell. Cytogenetic analysis showed a normal prevalent clone and a small hypodiploid clone and the molecular study showed no detectable involvement of the c-fms proto-oncogene, which is related to monocyte/macrophages. Unfortunately all these data do not seem sufficient to define the benign or neoplastic nature of the disease. Further investigations, immunophenotypical, cytogenetic and molecular, are needed to elucidate the pathogenesis of the disease, especially for more aggressive cases or for cases with unfavorable evolution.

Blotting, Southern↗
PubMed1998

Cytogenetic and fluorescence in situ hybridization studies in a case of anaplastic thyroid carcinoma.

Cytogenetic analysis of a case of anaplastic thyroid carcinoma revealed multiple numerical and structural chromosomal changes, including a der(9) add(9)(p22)hsr(9)(p?). Fluorescence in situ hybridization (FISH) studies performed to identify the genetic nature of this derivative chromosome showed that both the additional material and the hsr region were composed of only chromosome 9 sequences and that the C-ABL oncogene was not one of the genes harbored at the hsr region. We suggest that amplification of gene(s) located at chromosome 9, other than the C-ABL, may play a significant role in anaplastic evolution of thyroid carcinomas.

Carcinoma↗
PubMed1988

Translocation t(13;14) in nine generations with a case of translocation homozygosity.

The Robertsonian translocation 5(13;14)(p11;q11) was studied in three families with probable common ancestry in Eastern Finland. In the largest family the translocation has segregated through at least nine generations. The same family also included a female who was homozygous for t(13;14). No clear-cut effect of the translocation on fertility could be demonstrated and only one case of trisomy 13 was recorded in the offspring of t(13;14) carriers. The results are discussed, with implication for human chromosomal evolution.

Abortion, Spontaneous↗
PubMed1999

Isolated tetrasomy 8 in minimally differentiated acute myeloid leukemia (AML-M0).

Tetrasomy 8 as a sole anomaly in hematological disorders is relatively rare. To the best of our knowledge, only 19 such cases have been described in the literature to date. Of them, acute myeloid leukemia (AML) in 13 (M1, one; M2, three; M4, one; M5, eight), acute lymphoblastic leukemia(ALL) in one, myelodysplastic syndrome(MDS) in 3, polycythemia vera(PV) and myelofibrosis(MF), one case each. Their median survival was 20 weeks. Here, we report the first case of a 29-year-old man with minimally differentiated AML (AML-M0) displaying a tetrasomy 8 clone. Immunophenotyping showed positivity with CD33, CD34 and intracellular MPO, but all lymphoid markers tested were negative. Conventional cytogenetics of bone marrow cells showed 84.9% of metaphases with tetrasomy 8 in addition to 15.1% with normal diploidy. However, Fluorescence in situ hybridization(FISH) using a centromeric probe specific for chromosome 8 revealed trisomy 8 in 14.2% of interphase nuclei besides tetrasomy 8 in 82.4%. The patient died four weeks after diagnosis without therapy. In conclusion, these findings suggest that tetrasomy 8 is associated with a heterogeneous group of myeloid disorders and heralds a bad prognosis. It may be a consequence of clonal evolution of trisomy 8.

Acute Disease↗
PubMed1988

Clonal evolution in human lymphoblast cultures.

We established lymphoblast cultures from normal females heterozygous for electrophoretic variants of glucose-6-phosphate dehydrogenase (G6PD), and the X-linked markers have permitted us to look at evolution of these cell populations in culture. The established cultures were phenotypically heterozygous at onset, having both of the mosaic cell populations resulting from X chromosome inactivation. However, by the tenth subculture, the population of cells no longer reflected the heterozygous genotype in 50% of the cultures, as only a single G6PD isozyme was expressed. The ultimate cell composition seems to be influenced by the initial composition, by the nature of alleles at heterozygous X-linked loci that may provide a growth advantage (or disadvantage), as well as by stochastic events. Our results show that lymphoblast cultures may not reflect the X-linked phenotype of the cells from which they were derived. The fate of such cultures seems to be evolution toward clonal cell populations.

Cells, Cultured↗
PubMed1975

17 long arm isochromosome. A common anomaly in malignat blood disorders.

A cytogenetic anomaly consisting in the replacement of a 17 by its long arm isochromosome was identified as the only alteration in the marrow cells of two patients with acute granulocytic leukemia. In one case, the specific nature of the abnormal chromosome was established by newly available techniques. Since its identification in 1965, this structural anomaly, which implies 17 long arm duplication and short arm deletion, has been observed, as a sole or as an associated finding, in the malignant cells of a spectrum of blood disorders, including acute granulocytic leukemias, the blast crisis of chronic myeloid leukemia and lymphoreticular proliferative disorders. Attention is called to this particular rearrangement for its clinical as well as fundamental implications, as its presence in blood forming cells unfailingly hearalds a fast, fatal course of evolution.

Aged↗
PubMed1995

A translocated erythropoietin receptor gene in a human erythroleukemia cell line (TF-1) expresses an abnormal transcript and a truncated protein.

We previously identified a translocation breakpoint in exon 8 of the erythropoietin receptor (EpoR) gene in TF-1 cells, a cell line derived from a human erythroleukemia. To investigate the potential pathogenetic significance of this abnormality, we more precisely mapped the breakpoint within exon 8 and studied the expression of the translocated gene by S1 nuclease mapping of EpoR transcripts and chemical crosslinking of labeled erythropoietin (Epo) to TF-1 cell surface receptors. Transcripts from the abnormal gene were found to be highly expressed in relation to normal EpoR transcripts in TF-1 cells. The breakpoint predicted by S1 mapping of abnormal EpoR transcripts agreed closely with that determined by Southern analysis. Chemical cross-linking of 125I-Epo to TF-1 cells showed an abnormal, low-molecular-weight cross-linked species directly recognized by anti-EpoR antibodies and present in considerable excess over the normal EpoR. Karyotype analysis showed that each of 10 TF-1 cell metaphases had, in addition to multiple other alterations, one chromosome 19 with additional chromosomal material translocated onto the short arm at 19p13.3, the location of the EpoR gene. We conclude that the structurally abnormal EpoR gene in TF-1 cells is highly expressed and produces an abnormal protein. We speculate that the chromosomal material brought into the EpoR locus by translocation is responsible for the high level of expression. We hypothesize that this translocation participated in the evolution of the erythroleukemia from which TF-1 cells were derived.

Base Sequence↗
PubMed2000

Cytogenetic and Southern blot analysis to demonstrate clonality and to estimate prognosis in patients with myelodysplastic syndromes.

We examined the bone marrow of 109 patients with myelodysplastic syndrome (MDS) at the time of diagnosis and during the course of the disease by means of Southern blot analysis and/or cytogenetic studies to detect and evaluate clonal markers, their implications for the prognosis of the disease, and the response to treatment. The patients either were enrolled in an EORTC study and received low-dose Ara-C with (n=31) or without (n=21) growth factors, according to the study protocol, or were treated supportively (only one patient received regular chemotherapy for concomitant lymphoma). Full or at least partial remission was achieved by 34% of the treated patients (n=54). In 57% (53 of 93) of all patients a clonal marker of either kind was detected by Southern blot analysis and/or cytogenetic examination. Clonal chromosomal aberrations were found in 45% (35 of 77) of the cases examined at diagnosis, with solitary del(5q) aberrations occurring in 10% of the cases and complex aberrations in 18%, trisomy 8 or monosomy 7 being a frequent finding. Of all patients, 49% (28 of 57) were characterized by one or more gene rearrangements (e.g., Ig-JH, TcR-beta, M-bcr, GM-CSF, G-CSF, or IL-3) at diagnosis. In five of 21 cases (24%) studied in hematological remission of the disease chromosomal aberrations were still detectable, and in seven of 23 (30%) a gene rearrangement persisted. We also found six cases with multiple clones exhibiting different susceptibilities to treatment and thereby indicating the oligoclonal character of this disease. Clinical evaluation revealed that the prognosis of the respective patients was directly related to the particular clonal markers detected at diagnosis: Risk groups were subdivided according to the karyotypes, with a solitary del(5q) aberration meaning a favorable, a normal karyotype an intermediate, solitary aberrations without del(5q) a poor, and complex karyotypes a very poor prognosis. We showed that densitometry helps to increase the sensitivity of Southern blot analysis by quantifying the amount of altered DNA, which often increases shortly before or at progression of MDS. Overall, there was a high level of concordance of both clonality examinations with the clinical course of the disease and the response rate. Therefore, we recommend cytogenetic studies and Southern blot analysis to detect clonal markers at diagnosis of MDS, to detect oligoclonality and clonal evolution, or to quantify the amount of clonal DNA, which appears to be a sensitive tool for evaluating the prognosis and response to therapy in MDS.

Aged↗
PubMed2003

Evolution of rRNA gene clusters and telomeric repeats during explosive genome repatterning in TATERILLUS X (Rodentia, Gerbillinae).

A survey of 28S and 5S rRNA gene clusters, and telomeric repeats was performed using single and double FISH in the Taterillus genus (Rodentia, Muridae, Gerbillinae). Taterillus was previously demonstrated to have undergone a very recent and extensive chromosomal evolution. Our FISH results demonstrate that rRNA genes can vary in location and number irrespective of the phylogenetic relationships. Telomeric repeats were detected in pericentromeric and interstitial regions of several chromosomes, thus providing nonambiguous evolutionary footprints of Robertsonian and tandem translocation events. These footprints are discussed in reference to the molecular process of these karyotypical changes. Also, examples of colocation of rDNA clusters and telomeric repeats lend support to their possible involvement in nucleolus formation. Finally, the presence of rRNA genes, and the extensive amplification of telomeric repeats at specific loci within a double X-autosome translocated element which were not observed on the homologous Y1 and Y2, served as basis for an epigenomic hypothesis on X-autosome translocation viability in mammals.

Animals↗