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PubMed2005

A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS.

Two major genetic categories of multiple myeloma (MM) exist. Hyperdiploid MM (48 to 74 chromosomes, median 53 chromosomes) is associated with trisomies especially of chromosomes 3, 7, 9, 11, 15, and 19, whereas the nonhyperdiploid (< 48 chromosomes or more than 74 chromosomes) MM is associated with primary translocations such as t(11;14), t(4;14), and t(14;16). Whether this dichotomy exists in monoclonal gammopathy of undetermined significance (MGUS) is uncertain due to limitations of current methods in the study of ploidy. This is especially true in MGUS where the number of clonal plasma cells is small. In this study, we derived a fluorescent in situ hybridization (FISH)-based trisomy index from pooled cytogenetic data (karyotype analysis) from 2 large cohorts of patients with MM with abnormal karyotype, and then validated it in 2 independent cohorts of patients who had known ploidy status either by karyotyping or DNA content measurement using flow cytometry. Using the criteria of 2 or more trisomies from a 3-chromosome combination, hyperdiploid myeloma can be detected with high specificity. Applying this index on 28 patients with smoldering multiple myeloma (SMM) or MGUS (11 SMM, 17 MGUS) who had normal karyotype, 11 cases of hyperdiploid SMM/MGUS were detected. This percentage (40%) is remarkably similar to the percentage of hyperdiploid MM reported in the literature, suggesting that hyperdiploid MM may originate early during disease evolution.

Cohort Studies↗
PubMed2005

[Clonal evolution of abnormal Philadelphia chromosome-negative cells after imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia].

OBJECTIVE: To investigate clonal evolution of abnormal Philadelphia chromosome-negative cells (Ph- CE) after imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). METHODS: Bone marrow cells G-banding karyotype was evaluated every 3 months in 100 patients with Ph+ CML after achieving hematologic responses on the course of imatinib therapy. There were 54 patients in chronic phase (CP), 37 in accelerated phase (AP) and 9 in blast phase (BP). RESULTS: After a median follow-up of 32 months (ranged 25-34 months), 11 patients, including 5 cases in CP, 5 in AP and 1 in BP, developed transient, interrupted or continuous Ph- CE after 3 - 29 months on imatinib therapy. Ph- CE emerged at the beginning of Ph+ cells decreasing or after Ph+ cells disappearing. The proportion of Ph- CE, was negatively correlated with the proportion of Ph+ cells (P < 0.05). Ph- CE commonly included +8 (45.5%) and +Y (27.3%). Five patients had additional cytogenetic abnormalities besides Ph+ in Ph- CE. Seven of the patients with Ph- CE achieved a major cytogenetic response while 9 of them achieved a complete hematologic response. One patient with Ph- CE in AP progressed to BP 20 months after the initiation of the therapy while the rests remained in hematologic or cytogenetic responses. CONCLUSION: Ph- CE occurred in about 11% of the patients with Ph+ CML who achieved major or minor cytogenetic responses on imatinib therapy. After a median follow-up of more than 2 years, most of the patients with Ph- CE were in a stable status with no disease progression.

Adult↗
PubMed1985

[Chromosomes and carcinogenesis. Study on the evolution of an epithelial cell line of porcine origin].

The PFT cell line was established in 1969 from diploid cells of the inner lining of a uterine tube of a 2 year-old sow and has been continuously subcultured more than 500 times over a decade. Three chromosomal rearrangements have occurred during this time. The first translocation was shown at the 100th passage with the concomitant and spontaneous release of an endogeneous type C virus. The second translocation was observed at the 290th passage along with the appearance of gap junctions and the induction of malignant tumors in athymic nude mice following the inoculation of PFT cells. The third translocation was found towards the 470th passage with the simultaneous appearance of annulate lamellae. Since the translocations were accompanied by the spontaneous release of a retrovirus and then by malignancy of PFT cells when inoculated in athymic nude mice, it is likely that the chromosomal abnormalities are associated with the viral carcinogenesis of the cell line. The third translocation appears to confirm the perenniality of the multistep evolution hypothesis of malignancy.

Animals↗
PubMed2005

Rate of chromosome changes and speciation in reptiles.

The chromosome changing rate (i.e. the number of chromosome rearrangements per million years) was studied in 1,329 reptile species in order to evaluate the karyological evolutionary trend and the existence of possible correlations between chromosome mutations and some aspects of the evolution of this class. The results obtained highlight the existence of a general direct correlation between chromosome changing rate and number of living species, although different trends can be observed in the different orders and suborders. In turtles, the separation of pleurodires from cryptodires was accompanied by a considerable karyological diversification. Among pleurodires, the evolution of the Chelidae and Pelomedusidae was also characterised by chromosome variation, while in cryptodires a marked karyological homogeneity is observed between and within infra-orders. Similarly there is no correlation between changing rate and species number in crocodiles, where the evolution of the families and genera has entailed few chromosome mutations. Chromosome variability was greater in lizards and snakes. In the formers variations in chromosome changing rate accompanied the separation of the infra-orders and the evolution of most of the families and of some genera. The origin of snakes has also been accompanied by a marked karyological diversification, while the subsequent evolution of the infra-orders and families has entailed a high level of chromosome variability only in colubroids. The karyological evolution in reptiles generally entailed a progressive reduction in chromosome changing rate, albeit with differences in the diverse orders and suborders. This trend seems to be consistent with the "canalization model" as originally proposed by Bickham and Baker in [Bickham, J.W. & R J. Baker, 1979. Bull. Carnegie Mus. Nat. Hist. 13: 70-84.] However, several inconsistencies have been found excluding that in this class the ultimate goal of chromosome variations was the achievement of a so-called "optimum karyotype'' as suggested by the above-mentioned theory. Other mechanisms could underpin chromosome variability in Reptiles. Among them a genomic composition more or less favourable to promoting chromosome rearrangements and factors favouring the fixation of a mutant karyotype in condition of homozygosis. Turtles and crocodiles would have a genome characterised by large chromosomes and a low level of chromosome compartmentalisation limiting the recombination and the frequency of rearrangements. A low rate of chromosome variability modifying little if at all the gene linkage groups would have favoured a conservative evolutionary strategy. In the course of evolution, lizards and snakes could have achieved a genome characterised by smaller chromosomes and a higher level of compartmentalisation. This would have raised the frequency of recombination and consequently an evolutionary strategy promoting a higher degree of variability and a greater level of speciation.

Animals↗
PubMed1991

The molecular evolution of the alcohol dehydrogenase locus and the phylogeny of Hawaiian Drosophila.

DNA sequences in the alcohol dehydrogenase genes of flies representing the major groups of Hawaiian Drosophila are used to clarify the relationships of these groups, among themselves and with mainland Drosophila. The topology of the tree derived from these sequences agrees with karyotypic and morphological data but disagrees, in part, with the results of an earlier study that used immunological comparisons between variants of a larval hemolymph protein. A time scale, derived from a comparison of closely related Hawaiian Drosophila species, provides divergence-time estimates that are substantially more recent than those obtained from the immunological studies, although they are still within the bounds set by fossil and biogeographical evidence. The two major lineages of Hawaiian Drosophila, the scaptomyzoids and the drosophiloids, are shown to be widely separated from one another. The scaptomyzoids appear to have diverged early in the history of the subgenus Drosophila, greater than 25 Mya. While hundreds of scaptomyzoid species are found in the Hawaiian archipelago, many fewer are found elsewhere around the world, suggesting that they could have originated outside Hawaii. The drosophiloid lineage is strictly endemic to Hawaii and originated little more than 10 Mya, according to the alcohol dehydrogenase molecular clock. Thus, Drosophila apparently inhabited the Hawaiian archipelago (greater than or equal to 5 Myr before the emergence of the oldest existing high island, Kauai, 5 Mya.

Alcohol Dehydrogenase↗
PubMed2000

Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients.

The biological and clinical importance of cytogenetic analysis in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML) is being increasingly recognized. Recently, cytogenetic similarities were noted between elderly de novo AML and secondary AML, suggesting common etiopathogenetic mechanisms. In the present study we analyzed the cytogenetic similarities between patients with AML of different age and patients with MDS consecutively diagnosed during a 5-year period at a single, primary referral, hematologic center. Of 246 patients aged <86 years, 195 (80%) had a cytogenetic study at diagnosis. Informative metaphases were obtained in 182 cases (93%), including 17 (9.3%) with secondary MDS/AML. Patients were classified according to FAB criteria and were subdivided into four groups: (1) 'early MDS': 42 patients with MDS of FAB subtypes other than refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-T); (2) 'late MDS': 35 patients with RAEB and RAEB-T; (3) 'old AML': 48 patients with AML aged 65 to 85 years; (4) 'young AML': 57 patients with AML aged <65 years. Results showed that 'late MDS' and 'old AML' had striking cytogenetic similarities both in the frequency of normal karyotypes (31% and 27%), single abnormalities (14% and 13%), double abnormalities (17% and 14%), complex karyotypes (37% and 46%), and numerical abnormalities (89% and 93%), as well as in the frequency of rearrangements involving chromosome 5 (20% and 31%) and 7 (27% and 27%). The only difference between the two groups was found in the median number of chromosomes involved in complex karyotypes (5 vs 8; P=0.03). 'Early MDS' had significantly less complex karyotypes (21%; P<0.05), but its cytogenetic features resembled otherwise those of 'late MDS' and 'old AML', and any significant difference disappeared when patients with chronic myelomonocytic leukemia (CMML) were excluded. CMML markedly differed from other MDS subtypes in the frequency of normal (57%) and of complex karyotypes (6%). Secondary MDS/AML and AML with trilineage dysplasia shared the same cytogenetic features of 'late MDS' and 'old AML'. 'Young AML' strikingly differed from all other groups, particularly in the higher frequency of balanced translocations (29%; P<0.001) and single karyotype abnormalities (32%; P<0.02), and in the lower frequency of complex karyotypes (19%; P<0.01) and of chromosome 5 (2%; P<0.001) and 7 (9%; P<0.01) involvement. We conclude that in a population-based series of patients, the cytogenetic profile of MDS, particularly of RAEB/RAEB-T, was nearly identical to that of elderly patients with AML both in the frequency and in the type of chromosomal abnormalities. These results support the possibility that MDS and AML of elderly patients may represent the same disease seen at different stages of evolution.

Acute Disease↗
PubMed2002

Comprehensive genotypic analysis of human prostate cancer cell lines and sublines derived from metastases after orthotopic implantation in nude mice.

We recently reported on a prostate cancer progression model which was based on repeated orthotopic implantation of human prostate cancer cell lines into athymic nude mice leading to an increase of tumor cell aggressiveness. To assess progression-associated clonal evolution of genotypic changes, we now performed comparative cytogenetic characterization of the original cell lines DU145 and PC3 with derived sublines DU145MN1 and PC3-N. Cell line PC3-125-1L, isolated from a lung metastasis after subcutaneous inoculation of PC3 into nude mice, was included in the study. Whole-genome analysis was performed using spectral karyotyping and comparative genomic hybridization. Fluorescence in situ hybridization was used to assess amplification of selected genes, which are supposed to play a role in prostate cancer progression. Differences in the genetic constitution between parental cell lines and sublines involved gains of genetic material at 2q, 5q, 12p/q, and 18p as well as losses at 6p, 7q, 17p, 18q, and 22q. Loss of 17p in DU145MN1 and high-level amplification of MYC in PC3-125-1L resulted in loss of p53 expression and upregulation of Myc expression, respectively, as was assessed by Western blotting. Thus, the nude mice model is very useful to follow clonal evolution of genetic changes during increase of prostate cancer aggressiveness and possibly to clone genes associated with the progression of prostate cancer.

Animals↗
PubMed1990

Evolution of nuclear DNA and the occurrence of sequences related to new small chromosomal DNAs in the trypanosomatid genus Endotrypanum.

Comparisons of nuclear DNA restriction fragment patterns were used to examine the evolutionary relatedness among 17 strains previously identified as Endotrypanum, a trypanosomatid parasite of sloths. Fragments were obtained with 6 restriction enzymes and analyzed by Southern blotting with hybridization probes from three loci. An estimate of the percent nucleotide sequence divergence among strains, delta, was calculated and used to construct molecular evolutionary trees. The 17 isolates fell into four distinct groups, one of which (group D) showed no more relationship to groups A-C than it did to other genera (Leishmania, Crithidia, Leptomonas, Trypanosoma), being too distant to be resolved with this method. These and other data suggest that group D may not actually be Endotrypanum. Molecular karyotype analysis revealed considerable variation among the chromosomes of these strains. One strain (LV88, group B) contained a linear 70-kb chromosome not evident in other isolates. Hybridization probes specific for this chromosome (LV88-70) were developed and revealed that related sequences were present at high levels in group B isolates and low levels in group A isolates, although a complex hybridization pattern was evident. Sequences related to LV88-70 were not present in groups C and D, nor in Leishmania major, showing that this DNA has a disjunct distribution which curiously parallels that of virus-like particles present in these isolates.

Animals↗
PubMed1985

Establishment of two new myeloma cell lines from bilateral pleural effusions: evidence for sequential in vivo clonal change.

Two new human myeloma cell lines have been established from a 36-year-old woman with refractory IgG kappa multiple myeloma in whom bilateral malignant pleural effusions developed. The malignant plasma cells from each effusion were set up in a liquid culture using an L-15 medium containing catalase, glutathione, selenous acid, ascorbic acid, insulin, transferrin, additional glutamine hydrocortisone, and 2-mercaptoethanol and designated as M-3 medium. Two IgG kappa cell lines, LB -831 and LB-832, were established and proved to be Epstein-Barr virus negative using the internal repeat sequence DNA probe. Characteristic plasma cell morphology was evident by light and electron microscopy. Immunotyping revealed an IgG kappa , B1+, B2-, Ia (HLA-DR)+, CALLA+ phenotype for each cell line as well as for the original pleural fluid and bone marrow myeloma cells. The supernatants also contained IgG kappa, beta 2 microglobulin, and large amounts of osteoclast-activating factor (indicating bone-resorbing activity). Cytogenetic analysis of the LB-831 cell line revealed a nearly triploid highly abnormal karyotype with numerous clonal chromosomal abnormalities involving chromosomes 1, 3, 5, 7, 13, and 15; several structurally abnormal marker chromosomes; and a putative homogeneously staining region on chromosome 7p at band p22. Analysis of the LB-832 cell line revealed several additional clonal abnormalities. These additional cytogenetic changes suggest that in vivo sequential clonal evolution occurred in this patient. Therefore, two new but related cell lines have been established, which should prove useful for further biological studies.

Adult↗
PubMed2002

Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas.

We have identified a novel human cDNA overexpressed in a colon carcinoma cell line, TC7, established from a tumor with a normal karyotype arising in a patient with a hereditary nonpolyposis colorectal carcinoma. The OCC-1 (overexpressed in colon carcinoma-1) gene is composed of six exons and located in the q24.1 region of chromosome 12. It is transcribed as two mRNA species that differ in their 5'- and 3'-terminal ends. Abundant accumulation of both transcripts was found in placenta, skeletal muscle, kidney, and pancreas tissues. Absent or very faint expression was observed in heart, brain, lung and liver tissues. Overexpressed in colon carcinoma-1 cDNA direct in vitro translation of several polypeptides whose size is shorter than 9 kDa. Attempts to produce antibodies against these synthesized polypeptides in Escherichia coli failed. The absence of sequences at the mRNA and DNA levels hybridizing with mouse sequences together with the absence of a large open reading frame raise the possibility that OCC-1 sequences appeared recently in evolution and are transcribed as two noncoding regulatory RNA. Elevated levels of OCC-1 mRNA were observed in three of eight colon carcinomas as compared to normal mucosa of the same patient. Since these tumors shared the same characteristics of having a near diploid karyotype, OCC-1 overexpression may be a hallmark of this subset of colon carcinomas.

Adult↗
PubMed2004

Normal bone marrow function over 6 years in a patient with dysplastic hematopoiesis and a complex karyotype.

Myelodysplasia associated with a complex karyotype is usually associated with advanced stage myelodysplastic syndrome (MDS) and an enhanced risk to develop secondary leukemia. We report on a 36-year-old female patient who was first presented in 1997 because of 'Pseudo Pelger-Huet' neutrophils. The remaining blood and differential counts were normal. Bone marrow examination revealed dysplasia in the erythroid and granulocytic series, no increase in blasts, and a karyotype with complex aberrations involving chromosomes 7, 13, 20 and 22. Almost all metaphases examined appeared to be affected. During the next few months, the patient was closely monitored and considered as candidate for bone marrow transplantation. However, blood counts remained stable without occurrence of significant cytopenias or an increase in blasts. Re-examinations of the bone marrow in 1998 and 1999 disclosed identical results compared to that obtained in 1997. After a total follow up of 6 years, the patient is still in good health with normal blood counts and persisting 'Pseudo Pelger-Huet' neutrophils. This exceptional case supports the notion that complex chromosomes are not invariably associated with rapid disease evolution in MDS.

Adult↗
PubMed1995

Clonal evolution of an immunoblastic type non-Hodgkin's lymphoma with der(6)t(1;6)(q11;p11) as its primary cytogenetic abnormality.

Recurrent pleural effusions from a 45-year-old man who was diagnosed as having non-Hodgkin's lymphoma of immunoblastic type were studied cytogenetically. The majority of the metaphases were tetraploid, but there were also lymphoma cells observed with pseudodiploid chromosome constitutions. Cytogenetic analysis by G-banding revealed the existence of at least two cell populations. The karyotype of the minor pseudodiploid clone, which exhibited partial trisomy of 1q11qter and monosomy of 6p11pter as sole abnormalities, was 46,XY,der(6)t(1;6)(q11;p11). The karyotype of the major clone was 92,XXYY,-1,der(6)t(1;6)(q11;p11)x2, +9. The ancestral diploid clone, carrier of the balanced translocation involving chromosomes 1 and 6, was not observed even in the first pleural effusion harvest. The high proportion of tetraploid cells in the recurrent effusions was an indication that these cells were favorably selected in the environment of the somatic cavity. Our cytogenetic findings suggest that partial trisomy of 1q may be a crucial secondary chromosomal abnormality in highly malignant non-Hodgkin's lymphoma. This genetic imbalance was predetermined from the primary abnormality and may be responsible for further tumor progression, as suggested from the clonal evolution in this particular case and, therefore, may be associated with the aggressive biologic behavior of malignant cells.

Chromosome Aberrations↗
PubMed1988

Cytogenetic study of chronic myeloid leukemia.

A total of 122 patients with chronic myeloid leukemia (CML) were cytogenetically examined. At the first cytogenetic examination 68 of them were in chronic phase (CP) and 54 in blastic phase (BP) of the disease. The mean age of the whole group was 44.8 +/- 15.2 years. All patients included in this study were Ph-positive. In two of them constitutional chromosomal aberrations were ascertained. In two patients the standard Ph translocation was accompanied within onset of BP by a clone with complex translocation and in three patients Ph chromosome was found in mosaics with normal karyotype. Standard translocation t(9.22) (q34;q11) as the sole chromosomal abnormality was found in 17 (31%) patients in BP and in 47 (69%) of patients in CP. The most frequent additional abnormalities found were +8, i(17q), +Ph and their combination, and other nonrandom chromosomal changes. Clonal evolution was proved in 11 out of 24 serially examined patients during the progression of the disease. The analysis of relationship between prognosis of the disease and the results of cytogenetic examination revealed significant differences, and a more favorable course of the disease was observed for the group of patients in CP and with Ph chromosome as the sole chromosomal aberration.

Adult↗
PubMed1989

Haematopoietic and immunologic abnormalities in severe aplastic anaemia patients treated with anti-thymocyte globulin.

Thirty-five patients with severe aplastic anaemia (SAA) were extensively evaluated 0.3-12.4 years (median 3.8) after anti-thymocyte globulin (ATG) treatment. All but one were transfusion independent. Most patients revealed a normal Hb level and a granulocyte count over 1.5 x 10(9)/l but were still thrombocytopenic due to decreased platelet production. Lymphocytopenia and/or monocytopenia was found in about 30%. Two patients had a monocytosis. Although there was a great range in degree of recovery at various time intervals after ATG, patients tested more than 4 years after ATG tended to have higher cell counts. Lymphocyte counts correlated with the interval between ATG and evaluation, and with haematopoietic recovery. Qualitative abnormalities were found in all cell lines. Most patients showed a homogeneous macrocytic RBC population, and almost 50% a positive sucrose lysis test; only three patients showed evidence of haemolysis and only two of these showed a positive Ham test. Mean platelet volumes were reduced out of proportion to their number. Platelet function, determined by bleeding time and aggregometry, was impaired in over 30%. The granulocytic series showed a shift to the left in about 30%. Hypersegmentation and pseudo Pelger-Huet anomaly were seen in some patients. Lymphocyte subset distribution in blood and bone marrow was within the normal range but absolute blood levels of CD4 cells in particular were slightly decreased, and tended to increase gradually with time after ATG. IgG and IgA levels were significantly decreased. In only one patient cytogenetic analysis of unstimulated bone marrow cells revealed an abnormal karyotype, but in eight of eight patients an increased sensitivity of lymphocytes to X-rays was found. These data suggest impairment at the level of the very early haematopoietic progenitor cell in all patients up to 10 years after ATG. Since similar findings have been reported in clonal (pre-)malignant disease, SAA, improved after ATG treatment, might be prone to clonal (malignant) evolution.

Adolescent↗