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PubMed1997

Impact of clonal evolution on the biological diversity of Trypanosoma cruzi.

Trypanosoma cruzi, the agent of Chagas' disease, exhibits considerable biological variability. Moreover, it has been postulated that populations of this protozoan are subdivided into natural clones, which can be separated from each other by considerable levels of evolutionary divergence. The authors have proposed that this long-term clonal evolution may have a profound impact on Trypanosoma cruzi biological diversity. In order to test this hypothesis, 16 T. cruzi stocks representing 3 major clonal genotypes of the parasite were analysed for 8 different in vitro biological parameters. The overall results show a strong statistical linkage between genetic and biological differences. This is in agreement with the working hypothesis, although a notable biological variability is observable among the stocks of each of the 3 major clonal genotypes. The authors propose that T cruzi genetic variability must be taken into account in any applied study dealing with this parasite.

Alleles↗
PubMed2001

Clonal evolution from trisomy into tetrasomy of chromosome 8 associated with the development of acute myeloid leukemia from myelodysplastic syndrome.

Tetrasomy 8, though rare, is usually associated with trisomy 8, a far more common chromosomal abnormality in acute myeloid leukemia (AML). Yet the clonal relationship between trisomy 8 and tetrasomy 8 in the cases with these chromosomal abnormalities has been unclear. Here, we report a case of a 17-year-old male, diagnosed as having a myelodysplastic syndrome (MDS). Chromosome analysis showed the presence of trisomy 8. Five years later, he developed overt AML exhibiting tetrasomy 8 only. After chemotherapy, the blast cells in the bone marrow decreased to 3.4%, and the karyotype showed trisomy 8 alone. Fluorescence in situ hybridization using a probe specific for chromosome 8 showed that the percentages of cells exhibiting 2/ 3 /4 signals were 7.8/89.2/2.0 at the MDS stage, 20.5/36.1/41.0 when overt AML developed and 24.0/72.1/2.4 after chemotherapy. These results suggested that tetrasomy 8 is derived from the AML clone, possibly evolved from the MDS clone with trisomy 8. To our knowledge, this is the first detailed case report of clonal evolution from trisomy 8 into tetrasomy 8 associated with the development of AML from MDS.

Adolescent↗
PubMed1995

Tumor suppressor genes and clonal evolution in B-CLL.

This review highlights the genetic alterations that have been detailed in the malignant B-cell clones of patients with B-chronic lymphocytic leukemia (CLL). In particular, the alterations seen in p53 and the retinoblastoma (Rb) genes are reviewed. In addition, the multiplicity of cytogenetic alterations observed at baseline and on sequential analysis are summarized. The cytogenetic and molecular biologic analysis of B-CLL clones has revealed that there is a dynamic array of genetic events which occur within a B-cell clone. This latter data strongly suggests that clonal evolution may occur in B-CLL patients. However the relationship of the clonal instability to the patient's clinical course is still unclear. The relatively frequent detection of multiple tumor suppressor gene alterations in the B-CLL clones offer several interesting clues regarding the transformation event within B-CLL. A model is proposed which attempts to explain the potential contribution and interaction of p53 and Rb gene alterations in a malignant B-cell transformation.

Clone Cells↗
PubMed1970

Clonal evolution in two patients with autoimmune disease and lymphoreticular neoplasia.

Two cases are described, one with proven lymphosarcoma and doubtful autoimmune disease, and the second with the reverse situation, in which circulating abnormal mononuclear cells showed PHA responsiveness and an abnormal chromosomal constitution (clonal evolution). These findings are discussed in the light of previous cytogenetic studies of lymphoreticular neoplasia and autoimmune disease and the relationship between these two conditions.

Adult↗
PubMed2005

CML clonal evolution with resistance to single agent imatinib therapy.

We describe a 58-year-old male diagnosed with chronic myeloid leukaemia (CML) who failed to have a cytogenetic response to interferon-alpha and hydroxyurea. On subsequent therapy with imatinib mesylate he failed to have any cytogenetic response but also developed a complex clonal evolution with an additional Philadelphia (Ph) chromosome and trisomy 8 respectively in two Ph-positive subclones. The addition of cytosine arabinoside to imatinib resulted in reversion to single Ph-chromosome positivity with the disappearance of the previous additional clonal abnormalities. The case demonstrates the efficacy of combined treatment with imatinib and cytarabine in the management of CML resistant to single agent imatinib.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Clonal evolution following chemotherapy-induced stem cell depletion in cats heterozygous for glucose-6-phosphate dehydrogenase.

The number of hematopoietic stem cells necessary to support normal hematopoiesis is not known but may be small. If so, the depletion or damage of such cells could result in apparent clonal dominance. To test this hypothesis, dimethylbusulfan [2 to 4 mg/kg intravenously (IV) x 3] was given to cats heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD). These cats were the daughters of domestic X Geoffroy parents. After the initial drug-induced cytopenias (2 to 4 weeks), peripheral blood counts and the numbers of marrow progenitors detected in culture remained normal, although the percentages of erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony-forming cells (CFU-GM) in DNA synthesis increased, as determined by the tritiated thymidine suicide technique. In three of six cats treated, a dominance of Geoffroy-type G-6-PD emerged among the progenitor cells, granulocytes, and RBCs. These skewed ratios of domestic to Geoffroy-type G-6-PD have persisted greater than 3 years. No changes in cell cycle kinetics or G-6-PD phenotypes were noted in similar studies in six control cats. These data suggest that clonal evolution may reflect the depletion or damage of normal stem cells and not only the preferential growth and dominance of neoplastic cells.

Animals↗
PubMed1996

Clonal evolution in B-lineage acute lymphoblastic leukemia by contemporaneous VH-VH gene replacements and VH-DJH gene rearrangements.

B-cell acute lymphoblastic leukemia (B-ALL), more frequently than any other B-lineage neoplasm, exhibits oligoclonal Ig heavy chain (IgH) gene rearrangement in 15% to 43% of all cases studied. To study the molecular processes that promote multiple IgH rearrangements, a comprehensive sequence analysis of a B-ALL case was performed in which seven clonal IgH gene rearrangements were identified. The genetic profiles suggested that a single leukemic progenitor clone evolved into several subclones through dual processes of variable (VH) to preexisting diversity-joining (DJH) gene segment rearrangement and VH to VH gene replacement. Predominant IgH-V usage and the uniquely rearranged clonotype-specific VHDJH region gene sequences were identified using a novel DNA-based gene amplification strategy. Polymerase chain reaction (PCR) was directed by an IgH-J generic primer and a complement of family-specific IgH-V primers that defined the major B-cell IgH-V gene usage. Clonality of rearranged VHDJH bands was substantiated by high resolution denaturant gel electrophoretic analysis. Sequence patterns of the amplified VHDJH fragments segregated into two groups defined by common DJH sequences. Partial N region homology at the VHD junction as well as shared DJH sequences firmly established VH to VHDJH gene replacement as a mechanism generating clonal evolution in one group. In the second subset, oligoclonality was propagated by independent VH gene rearrangements to a common DJH precursor. The contributions of all clonal Ig-VHDJH repertoires for each group was approximately 50% and reflected a symmetric distribution of leukemic subclones generated by either process. Thus, oligoclonal rearrangements evolved by two independent, yet seemingly contemporaneous molecular genetic mechanisms. All seven clones displayed nonfunctional Ig-VHDJH recombinations. These observations may have relevance to the recombinatorial opportunities available during normal B-cell maturation.

Base Sequence↗
PubMed2002

Loss of heterozygosity in the clonal evolution of flat colorectal neoplasms.

In contrast to invasive colorectal carcinomas that develop in typical exophytic adenoma-carcinoma sequences, some invasive cancers may evolve from flat mucosal dysplastic lesions. Despite their relatively small size, these flat colorectal lesions are often associated with high-grade dysplasia and may show an aggressive clinical course. To delineate the genetic pathways in the clonal evolution of these tumors, multiple foci were microdissected from 13 cases and the allelic deletions of 15 chromosomal arms were analysed. Loss of heterozygosity (LOH) was detected most frequently on 17p (77%), followed by 18q (69%), and 5q (54%). In five cases with concomitant low-grade adenomas, only one case showed LOH in low-grade adenoma foci. In high-grade dysplasia with/without submucosal invasion, early and homogeneous LOH of one to several chromosomal arms was detected. Overall, homogeneous and thus early LOH were most frequently detected on 17p (seven of 10 cases with 17p LOH), followed by 3p (two of three cases with 3p LOH), and 5q (four of seven cases with 5q LOH). In addition to homogeneous LOH, the LOH patterns observed in different portions of dysplasias and invasive cancers in individual cases identified several different genetic patterns of tumour progression, either with linear or branching (divergent) trees. Positive immunostaining for p53 was detected in 10 of the 13 cases; of these, five cases were concomitant with 17p LOH in all of the microdissected foci, four cases were concomitant with 17p LOH in a majority of foci and, one case showed retention of 17p. Except for the flat configuration and early 17p LOH, genetic heterogeneity in the flat high-grade dysplastic foci was found to be similar to genetic chaos in the late dysplastic and preinvasive stages of exophytic adenoma. These findings suggest a potentially aggressive course for these neoplasms.

Adenoma↗
PubMed2004

Clonal evolution as pathogenetic mechanism in relapse of primary CNS lymphoma.

Comparative investigation of immunoglobulin (Ig) heavy chain gene rearrangements and DNA sequence analyses of a primary lymphoma of the CNS (PCNSL) and its recurrence revealed that both tumors used the same Ig gene segment. In addition to shared somatic mutations, the primary and the recurrent PCNSLs harbored somatic mutations unique to each tumor. Clonal evolution rather than subclone selection appears to underlie the development of tumor recurrence in this case.

Aged↗
PubMed1996

Clonal evolution of lung tumors.

Lung tumors, particularly squamous cell carcinomas, are believed to develop through a series of morphological abnormalities, driven by underlying somatic genetic changes. One way of studying this process is to analyze candidate somatic genetic changes in samples of squamous metaplasia and bronchial dysplasia of varying degrees of severity as well as tumor from the same patient. This assumes a clonal relationship between these lesions. In this article, we provide evidence that adjacent, physically distinct bronchial abnormalities are clonally related. This has been achieved using a plaque assay technique to detect the same p53 mutation, present throughout a tumor specimen, in a small proportion of cells in an adjacent squamous metaplasia. In addition, we have obtained two dysplasia samples from a tumor-free patient over a 9-month interval. The earlier sample had one p53 mutation, whereas the later sample has to p53 mutations on different alleles. Thus, the pattern of clonal evolution detected in the parallel samples mimics the pattern seen in longitudinal samples and supports the analysis of synchronously collected samples for the study of tumor progression.

Base Sequence↗
PubMed1994

Unclassifiable high grade malignant T-cell lymphoma with clonal evolution.

We report a case of leukemic malignant T-cell lymphoma with mixed small and large cells. The small cells displayed a mature CD8-positive phenotype, a diploid DNA distribution by cell cycle analysis, and structural karyotypic abnormalities. Large cells were near triploid, showed additional structural cytogenetic abnormalities and a more immature membrane phenotype without CD8 expression. Altogether, these data provide suggestive evidence for a clonal evolution from a mature small cell T-cell lymphoma to a more immature large cell proliferation.

Aged↗
PubMed1989

Clonal evolution in Ph-negative, bcr-positive chronic myeloid leukaemia before and after bone marrow transplantation.

A 26-year-old man, who presented with bilateral fundal haemorrhages, was found to have chronic myeloid leukaemia (CML). The Ph chromosome was not present but a clone with t(1;9) (p32;q34) was detected. On referral for bone marrow transplant (BMT) he was found to be in accelerated phase with clonal evolution in three cell lines inv(3)(q21q26); inv(3)(q),i(17q); inv(3q)+8. Molecular investigation revealed a breakpoint on chromosome 22 within the breakpoint cluster region (bcr) similar to that found in Ph+ cases. After BMT, from an HLA-identical sister, successful engraftment (46,XX) was accompanied by evidence of a residual host cell population with further evolution (del(7)(q22)) and persistence of the bcr+ clone. Acute myeloid leukaemia, detected 5 months later, was associated with predominance of the clone 46XY,t(1;9),inv(3q),del(7)(q22) which failed to respond to treatment and the patient died 6.5 months after BMT. This case indicates that BMT, after the acquisition of additional chromosomal change in accelerated phase, may fail owing to persistence of the leukaemic clone. In addition the BMT conditioning regimen may produce further abnormalities which confer drug resistance on the persisting clone, which can emerge as an intractable myeloid blast crisis.

Adult↗
PubMed1993

Childhood myelodysplastic syndrome with clonal evolution progressing to acute megakaryoblastic leukemia (ANLL-M7).

We treated a 16-month-old girl with myelodysplastic syndrome (MDS; refractory anemia with excess of blasts subtype, RAEB by FAB classification) that developed into acute megakaryoblastic leukemia (ANLL-M7). The blast cells were positive for CD41 shown by flow cytometry and for platelet peroxidase by electron microscopy. Cytogenetically, five kinds of abnormal karyotypes were apparent at the initial visit and karyotypic progression (clonal evolution) was also evident. These karyotypes were considered to be derived from the putative original clone, 48,XX, +6, +21. The observed karyotypes were considered 50,XX, +4,add(4)(q31), +6,add(7)(p22),add(10)(q24),add(12)(q11), +20, +21, + mar[karyotype A];48,XX,add(4)(q31), +6,add(10)(q24),add(12)(q11), +21 [karyotype B];48,XX, +6,t(6;13)(p23;q14), +21 [karyotype C];51,XX, +X, t(6;13)(p23;q14), + der(6)t(6;13)(p23;q14), +21, +21, + mar [karyotype D]; and 49,XX, +X, -3,t(6;13)(p23;q14), +der(6)t(6;13)(p23;q14), -12, +21, +21, + mar [karyotype E]. It seems karyotypes B and C were derived from the putative clone; karyotype B developed into karyotype A; and karyotype C developed into karyotype E through karyotype D. After development of ANLL-M7, the cytogenetic study showed a karyotype with further karyotypic progression. The patient was treated with high-dose cytosine arabinoside (HD AraC) followed by allogeneic bone marrow transplantation. Despite intensive care, she died 3 months after the transplantation.

Anemia, Refractory, with Excess of Blasts↗
PubMed1985

Clonal evolution of T-cell prolymphocytic leukemia to a T-large-cell lymphoma. A morphologic and immunologic study.

We describe a patient with T-cell prolymphocytic leukemia who developed a large-cell lymphoma of the T-cell type. The neoplastic cells of the large-cell lymphoma demonstrated the same immunologic phenotype (ER+, Leu-3+, Leu-2-, and HLA ABC+) as the cells of the prolymphocytic leukemia, which indicated a clonal evolution of a T-cell prolymphocytic leukemia into a large-cell lymphoma of the T-cell phenotype.

Aged↗
PubMed2002

Acquired trisomy 21 and distinct clonal evolution in acute megakaryoblastic leukaemia in young monozygotic twins.

An intrauterine origin of childhood acute lymphoblastic leukaemia (ALL) was proven by the identical clonotypic gene rearrangement in the concordant leukaemias of monozygotic twins, arising from a single clonogenic progeny. The monozygotic twins, presented at the age of 22 months with acute megakaryoblastic leukaemia (AML-M7) in one and myelodysplasia transformed to AML-M7 in the other. Leukaemic cells in both twins carried trisomy 21 and additional different clonal evolution changes of del(20q) in the first twin and trisomy 8 in the second. AML-M7 of late infancy with trisomy 21 may be included in the leukaemias of intrauterine origin, possibly a result of genotoxic insult.

Cytogenetic Analysis↗
PubMed2001

NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia.

The role of the BCR-ABL fusion gene in the pathogenesis of the chronic phase of chronic myelogenous leukemia (CML) has been well established. Several additional genetic changes have been reported to occur, at varying frequencies, during disease progression to "accelerated" and "blast crisis" phases. The NUP98 gene localized to chromosome band 11p15 has been found at the breakpoints of several distinct chromosomal translocations in patients with both de novo and therapy-related myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Using combined cytogenetic and molecular analyses, we have found rearrangements of the NUP98 gene in the leukemic cells of two patients with Philadelphia chromosome-positive CML, during disease evolution. As expected, analysis of the t(7;11)(p15;p15) from one of the patients showed an in-frame NUP98-HOXA9 fusion. The fusion points were similar to previously reported NUP98-HOXA9 fusion points from patients with MDS/AML. Our results indicate that the NUP98 gene is an additional, albeit infrequent, genetic target during clonal evolution of CML.

Chromosome Breakage↗
PubMed1991

Mixed blasts crisis following extramedullary involvement with the cytogenetic evidence of clonal evolutions in Philadelphia chromosome-positive chronic myelocytic leukemia.

We describe a unique case of a young girl with adult type chronic myelocytic leukemia (CML). Clinically she had an extramedullary blastic crisis (BC) prior to that in peripheral blood and in bone marrow. The blasts were primitive cells and always CD7, CD33, CD34 and HLA DR-positive. During the course of illness the blasts became negative for CD5 and positive for CD41a and for platelet-peroxidase. Additional chromosomal appearances and subsequently clonal evolution were seen during the clinical course. Surface antigen modulation and morphological changes, which were observed by microscopic examination and flow cytometry, were induced by in vitro incubation. Surface antigen modulation was more induced in the presence of phytohemagglutinine-conditioned media (PHA-CM) but the effects of PHA-CM on morphological changes were not clear.

Antigens, CD↗