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PubMed1995

Clonality in hepatocellular carcinoma: analysis of methylation pattern of polymorphic X-chromosome-linked phosphoglycerate kinase gene in females.

Analysis of X-chromosome inactivation patterns in women has been used to assess the clonality of various tumors. In this report, we analyzed 27 liver tumors in women, including 18 samples obtained by the performance of ultrasonically guided thin-needle biopsies. By analysis of the heterogeneity of phosphoglycerate kinase gene, 11 of 27 (41%) cases were found to be heterozygous at the gene. Of these informative 11 cases with liver tumors, 7 cases were "large" tumors (> 25 mm in diameter) and 4 cases were "small" tumors (< 25 mm in diameter). All 7 large tumors showed monoclonal patterns by the phosphoglycerate kinase gene analysis. Of the 4 small tumors, 2 showed monoclonal, and 2 showed polyclonal patterns. The 2 with monoclonal patterns were pathologically diagnosed as hepatocellular carcinoma despite their small sizes (20 mm and 23 mm). Of the two with polyclonal patterns, the smallest one (15 mm) was diagnosed as benign adenomatous hyperplasia, and the other as hepatocellular carcinoma heavily infiltrated by lymphocytes. These data suggest that analysis of the methylation pattern of the phosphoglycerate kinase gene may be helpful on rare occasions in elucidating the nature of liver tumors but must in fact be used in conjunction with histological appearances to avoid errors secondary to inflammatory infiltrates.

Base Sequence↗
PubMed1996

Role of granulocyte-macrophage colony-stimulating factor in Philadelphia (Ph1)-positive acute lymphoblastic leukemia: studies on two newly established Ph1-positive acute lymphoblastic leukemia cell lines (Z-119 and Z-181).

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is a malignant disorder characterized by a poor prognosis. In recent years hematopoietic growth factors have been used to recruit myeloid leukemia blasts into the proliferative phase of the cell cycle and as supportive agents, both with cytotoxic regimens and in the setting of bone marrow transplantation. This approach prompted us to investigate whether myeloid growth factors have a role in Ph1 positive ALL. To do this, we utilized two newly established Ph1-positive cell lines, Z-119 and Z-181. Both lines have L2 morphology, ultrastructural characteristics of lymphoblasts and typical B-lineage surface markers identical to those observed in the two Ph1-positive ALL patients from whom they were derived. In addition, a single rearranged immunoglobulin heavy-chain gene (JH) band was found in both cell lines by Southern blot analysis, confirming B-cell clonality. Cytogenetic analysis of the two lines revealed t(9;22). Polymerase chain reaction (PCR) amplified cDNA from both Z-119 and Z-181 cells revealed an e1--a2 BCR-ABL junction, and p190BCR-ABL protein was detected in them by the immune complex kinase assay. Both cell lines produce interleukin (IL)-1 beta, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), but neither IL-1 beta, G-CSF, their corresponding antibodies and inhibitory molecules, nor GM-CSF, affected the cell lines' growth. However, GM-CSF neutralizing antibodies inhibited Z-181 but not Z-119 colony formation in a dose-dependent fashion by up to 77% and addition of GM-SCF reversed this inhibitory effect. Receptor studies with radiolabeled GM-CSF demonstrated specific binding to Z-181 but not to Z-119 cells, and Scatchard analysis revealed that Z-181 cells express high-affinity GM-CSF receptors. Furthermore, PCR analysis showed that Z-181 but not Z-119 bears the transcript for the GM-CSF receptor. Finally, studies using PH1-positive ALL patients' marrow cells revealed similar data. In 3 of 8 samples we detected significant concentrations of GM-CSF (7.5-13 pg/2 x 10(7) cells) and in 2 of 3 cases GM-CSF significantly stimulated Ph1-positive ALL colony proliferation. These data suggest that Ph1-positive ALL cells may produce GM-CSF, express GM-CSF receptors and thus show a proliferative response to this cytokine.

Adult↗
PubMed2003

Retrovirally transduced muscle-derived cells contribute to hematopoiesis at very low levels in the nonhuman primate model.

Recent studies have suggested a remarkable potential of adult stem cells from a variety of organs to give rise to cells of disparate organs, but evidence of such potential at a clonal level is lacking in most if not all studies to date. To assess directly the hematopoietic potential of muscle-derived cells in a relevant large animal, we initiated retroviral-tagging studies in the rhesus macaque to allow tracking at the clonal level by integration site analysis. Four rhesus macaques underwent transplantation with transduced muscle-derived cells after lethal irradiation followed by delayed infusion of an autologous hematopoietic graft. The first animal showed no evidence of hematopoietic recovery and, despite infusion of the backup hematopoietic graft, succumbed due to complications of prolonged cytopenias. In the remaining three animals, the overall contribution of retrovirally tagged muscle-derived cells toward hematopoiesis was exceedingly low. Retroviral integration site analysis among clonally derived muscle cells and bone marrow cells in vivo in one animal suggests a common source. These results demonstrate that harvesting disparate organs for cellular therapy is currently highly inefficient at best.

Animals↗
PubMed1998

Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract.

Recent molecular genetic studies have suggested that multifocal urothelial cancers are derived from an identical progenitor cell. However, the clonal origin of multifocal urothelial cancers of a low-grade superficial type has not been fully defined. Using microsatellite markers, we examined genetic alterations at 20 loci on eight chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) in 87 metachronous and/or synchronous multifocal urothelial cancers, which included 84 low-grade superficial papillary tumors from 29 patients. Judging from the patterns of loss of heterozygosity, microsatellite shifts, and the subchromosomal partial deletion, multifocal tumors in at least 20 (80%) of the 25 evaluable patients were considered to be derived from a single progenitor cell, although the possibility remained that multifocal tumors in a small subset of patients might develop from distinct progenitor cells due to field cancerization. In 13 of the 20 patients, a chronological genetic analysis was available: genetic heterogeneity was detected in 3 (23%) patients, and an apparent accumulated pattern of genetic alterations was detected in only 1 (8%) patient. In the 20 patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed, with significantly lower frequencies on chromosome 9 compared to those on the other chromosomes tested. The results indicate that most multifocal low-grade superficial urothelial cancers are genetically stable despite their incidence of frequent recurrence, and genetic divergence occurs in a subset of patients. This heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. These data support the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of low-grade superficial urothelial cancers.

Chromosome Aberrations↗
PubMed1988

Analysis of treatment response in chronic lymphocytic leukemia: new approaches.

As therapeutic protocols to treat chronic lymphocytic leukemia evolve, new criteria will be required to define remission and identify early relapse. Two techniques that detect low numbers of residual monoclonal B-lymphocytes currently include immunoglobulin (Ig) gene rearrangement and clonal excess analysis. Ig-gene rearrangement studies are time consuming and expensive. Clonal excess analysis by FC may be insensitive because of minimal surface immunoglobulin (SIg) expression. Three antigens, CD5, CD11c and CD14 are expressed on B-lymphocytes of CLL. CD14 is also expressed on most normal B-lymphocytes. In contrast, CD5 and CD11c are expressed on few normal B-lymphocytes. Consequently CD5 and CD11c are useful markers for detecting residual CLL cells. Appropriate selection of the second B-cell marker such as SIg, CD19, CD20 or other, is critical. We evaluated this approach in persons with CLL receiving therapy. Preliminary results will be presented.

Biomarkers, Tumor↗
PubMed2006

T-large granular lymphocyte leukemia: current molecular concepts.

T-large granular lymphocyte (T-LGL) leukemia is a chronic and often indolent T cell lymphoproliferation characterized by extreme expansion of a semi-autonomous cytotoxic T lymphocyte (CTL) clone. Clinically, T-LGL can be associated with various cytopenias; neutropenia constitutes the most frequent manifestation. LGL clone represents a pathologic counterpart of the cytotoxic effector T cell but an abnormal memory CD8 cell seems to provide the supply of the matured LGL population. Analysis of clonal T cell receptor (TCR) rearrangement and complementarity determining region 3 (CDR3) of the TCR beta-chain is a useful tool to investigate clonal expansions, track the frequency of expanded clones and also clinically useful to monitor the response to therapy. The lessons learned from molecular analysis of clonal repertoire support a clinically-derived conclusion that the LGL clone arises in the context of an initially polyclonal immune response or an autoimmune process. Consequently, specific manifestations of T-LGL may be a result of the recognition spectrum of the transformed clone and the cytokines it produces. Due to the often monoclonal manifestation, T-LGL constitutes a suitable model to investigate polyclonal CTL-mediated processes. Application of new technologies, including TCR repertoire analysis by sequencing, clonotypic quantitative PCR and VB flow cytometry facilitate clinical diagnosis and may allow insights into the regulation of TCR repertoire and consequences resulting from the contraction of clonal diversity.

Adult↗
PubMed1991

Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction.

The myeloproliferative syndromes are acquired disorders of hematopoiesis that provide insights into the transition from somatic cell mutation to neoplasia. The clonal origin of specific blood cells can be assessed in patients with X chromosome-linked polymorphisms, taking advantage of random inactivation of the X chromosome. We have adapted the PCR for determination of clonality on as few as 100 cells, including individual colonies grown in culture. Amplifying a polymorphic portion of the X chromosome-linked phosphoglycerate kinase (PGK) gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme gave results fully concordant with standard Southern blotting of DNA samples from normal (polyclonal) polymorphonuclear cells (PMN) as well as clonal PMN from patients with myelodysplastic syndrome and polycythemia vera (PCV). We have used this technique to demonstrate heterogeneity of lineage involvement in patients with PCV. The same clinical phenotype may arise from clonal proliferation of different hematopoietic progenitors.

Base Sequence↗
PubMed2006

Pseudo-outbreak of Mycobacterium gordonae: usefulness of randomly amplified polymorphic DNA analysis to assess the clonality of the isolates.

Mycobacterium gordonae was detected in 18 of 21 clinical samples processed during the same day from patients with clinical suspicion of tuberculosis. Randomly amplified polymorphic DNA (RAPD) analysis revealed that all the isolates generated an identical pattern with each of the five primers used, and that these patterns were different from those of epidemiologically non-related isolates of M. gordonae. M. gordonae was not detected in the distilled water used for the procedures, and following replacement of the commercial products and sterilisation of home-made reagents, no more isolates belonging to the same clone of M. gordonae were detected.

Disease Outbreaks↗
PubMed1990

Genotypic and immunophenotypic characterization of two human light chain-only B-cell non-Hodgkin's lymphomas.

Two atypical human non-Hodgkin's lymphomas (NHLs) that exhibited unusual genotypic and in situ immunophenotypic abnormalities are described. Immunophenotypically, both NHLs lacked surface Ig heavy chains. With the exception of the MB2 B-cell-associated antigen, no B- and T-cell differentiation antigen was detected in case 1. NHL 2 failed to show evidence of clonality by immunohistochemical analysis but revealed the presence of many B-lymphocytes with an abnormal phenotypic profile: CD19+, CD20+, CD22+, kappa-, lambda-, CD9-, CD10-, CD21-, and CD24-. Genotypic analysis indicated that both lymphomas derived from anomalously matured pre-B-cells that had rearranged the lambda or kappa light chain genes but not the Ig heavy chain gene. The neoplastic cells of the two NHLs resemble the light chain-only B-cells recently discovered, following Epstein-Barr virus immortalization, in the human bone marrow. The authors' data confirm, therefore, the existence of the light chain-only B-cells in the human hematopoietic compartment. Moreover, their results emphasize the conclusive role of the immunogenotypic analysis in defining clonality, lineage, and maturation abnormalities of such atypical NHLs.

Adult↗
PubMed1996

Detection of clonal immunoglobulin heavy-chain gene rearrangements in cases of suspected lymphoproliferative disorders: comparison of polymerase chain reaction and Southern blot analysis.

Demonstration of clonality is supportive of a diagnosis of malignancy in cases of lymphoproliferative disorders. Determination of clonality at the molecular level is currently accomplished by Southern analysis; however, the polymerase chain reaction offers a potential alternative that is rapid, simple, and less expensive. To test its feasibility as a diagnostic test, we amplified the DNA from 121 suspected lymphoproliferative disorders submitted for gene rearrangement studies. In comparison to Southern analyses, a sensitivity of 70% and specificity of 96% were obtained. To test the effect of primer variability in the joining region of the heavy-chain gene, we substituted a more degenerate primer but found no changes in sensitivity or specificity. We conclude that the polymerase chain reaction has current application with minute or fixed specimens and may generally serve as a rapid, initial evaluation for B-cell clonality, followed by Southern analysis in negative cases. However, higher overall sensitivity must be achieved before this technique can replace Southern analysis as the method of choice in determining clonal gene rearrangements.

Base Sequence↗
PubMed2004

Real-time lineage analysis reveals oriented cell divisions associated with morphogenesis at the shoot apex of Arabidopsis thaliana.

Precise knowledge of spatial and temporal patterns of cell division, including number and orientation of divisions, and knowledge of cell expansion, is central to understanding morphogenesis. Our current knowledge of cell division patterns during plant and animal morphogenesis is largely deduced from analysis of clonal shapes and sizes. But such an analysis can reveal only the number, not the orientation or exact rate, of cell divisions. In this study, we have analyzed growth in real time by monitoring individual cell divisions in the shoot apical meristems (SAMs) of Arabidopsis thaliana. The live imaging technique has led to the development of a spatial and temporal map of cell division patterns. We have integrated cell behavior over time to visualize growth. Our analysis reveals temporal variation in mitotic activity and the cell division is coordinated across clonally distinct layers of cells. Temporal variation in mitotic activity is not correlated to the estimated plastochron length and diurnal rhythms. Cell division rates vary across the SAM surface. Cells in the peripheral zone (PZ) divide at a faster rate than in the central zone (CZ). Cell division rates in the CZ are relatively heterogeneous when compared with PZ cells. We have analyzed the cell behavior associated with flower primordium development starting from a stage at which the future flower comprises four cells in the L1 epidermal layer. Primordium development is a sequential process linked to distinct cellular behavior. Oriented cell divisions, in primordial progenitors and in cells located proximal to them, are associated with initial primordial outgrowth. The oriented cell divisions are followed by a rapid burst of cell expansion and cell division, which transforms a flower primordium into a three-dimensional flower bud. Distinct lack of cell expansion is seen in a narrow band of cells, which forms the boundary region between developing flower bud and the SAM. We discuss these results in the context of SAM morphogenesis.

Arabidopsis↗
PubMed1999

T-cell clonality in immune responses.

Recent methodological advances allow the analysis of clonal composition within T-cell subsets. Here, Mala Maini and colleagues review the available data on clonality in acute immune responses and steady-state situations. They highlight and explore reasons for the striking differences in clonality between the CD4+ and CD8+ T-cell subsets.

Animals↗
PubMed2001

Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCRalphabeta T-cell proliferations.

Clonality assessment through Southern blot (SB) analysis of TCRB genes or polymerase chain reaction (PCR) analysis of TCRG genes is important for diagnosing suspect mature T-cell proliferations. Clonality assessment through reverse transcription (RT)-PCR analysis of Vbeta-Cbeta transcripts and flow cytometry with a Vbeta antibody panel covering more than 65% of Vbeta domains was validated using 28 SB-defined clonal T-cell receptor (TCR)alphabeta(+) T-ALL samples and T-cell lines. Next, the diagnostic applicability of the V(beta) RT-PCR and flow cytometric clonality assays was studied in 47 mature T-cell proliferations. Clonal Vbeta-Cbeta RT-PCR products were detected in all 47 samples, whereas single Vbeta domain usage was found in 31 (66%) of 47 patients. The suspect leukemic cell populations in the other 16 patients showed a complete lack of Vbeta monoclonal antibody reactivity that was confirmed by molecular data showing the usage of Vbeta gene segments not covered by the applied Vbeta monoclonal antibodies. Nevertheless, this could be considered indirect evidence for the "clonal" character of these cells. Remarkably, RT-PCR revealed an oligoclonal pattern in addition to dominant Vbeta-Cbeta products and single Vbeta domain expression in many T-LGL proliferations, providing further evidence for the hypothesis raised earlier that T-LGL derive from polyclonal and oligoclonal proliferations of antigen-activated cytotoxic T cells. It is concluded that molecular Vbeta analysis serves to assess clonality in suspect T-cell proliferations. However, the faster and cheaper Vbeta antibody studies can be used as a powerful screening method for the detection of single Vbeta domain expression, followed by molecular studies in patients with more than 20% single Vbeta domain expression or large suspect T-cell populations (more than 50%-60%) without Vbeta reactivity.

Adolescent↗
PubMed1998

Restriction-PCR fingerprinting of the immunoglobulin VH repertoire: direct detection of an immune response and global analysis of B cell clonality.

Here we describe a method for fingerprinting the mouse immunoglobulin heavy chain variable region (VH) repertoire. Using a novel combination of existing techniques, large numbers of expressed VH genes can be simultaneously displayed as a fingerprint of VH gene fragments on a sequencing gel. This is achieved using isotype-specific reverse transcription-PCR amplification, restriction digestion and end-labeled primer run-offs. This technique (Res-PCR) allows analysis of the immune response, in this case to phenyloxazolone, in several different tissues and enables molecular cloning and sequencing of the VH genes involved in vivo. In addition, with Res-PCR, a "global" picture of expressed immunoglobulin genes is represented. This elucidates B cell clonality in different tissues and isotypes and detects a preference for shorter complementarity-determining region 3 in IgM-expressing cells. Res-PCR is a rapid and revealing method which will allow analysis of the complexity and sequence composition of the B cell immunoglobulin repertoire and so perhaps better define the B cell memory compartment and immune responses in vivo.

Amino Acid Sequence↗
PubMed2002

Polymerase chain reaction-based diagnosis of bone marrow involvement in 170 cases of non-Hodgkin lymphoma.

BACKGROUND: Up to the current time, diagnosis of bone marrow (BM) involvement in non-Hodgkin lymphoma (NHL) has been based on morphologic findings. Polymerase chain reaction (PCR) for antigen receptor gene rearrangements has the potential to increase the detection sensitivity of minimal degrees of BM involvement. The authors therefore assessed PCR-based clonalities of BM concurrently with morphology from 170 cases with NHL and evaluated the usefulness of comparative analysis of clonalities between bilateral BMs and the lymph node and the clinical significance of PCR based clonalities of BM. METHODS: Bilateral BM clot sections of 170 cases and 47 lymph nodes were tested for immunoglobulin heavy chain gene rearrangement or T-cell receptor gamma gene rearrangement according to the B- or T-lineage of the lymph node. RESULTS: When compared with morphology, the results of PCR showed an unexpectedly low positive concordance rate of 61.0% for B-cell NHL and 57.1% for T-cell NHL. When the clonality of BM was compared with that of lymph nodes in B-cell NHL, bilateral clonalities of BM showed high concordance with the clonality of the lymph nodes. PCR-based clonality did not show significant impact on survival. CONCLUSIONS: Morphology remains the gold standard in the evaluation of BM involvement by NHL. Although the comparative analysis of BM clonality and that of the lymph nodes is considered a valuable tool that increases the reliability of clonality, PCR-based clonality of BM does not significantly add to the sensitivity of diagnosing BM involvement by NHL.

Adolescent↗
PubMed1997

Automated high resolution PCR fragment analysis for identification of clonally rearranged immunoglobulin heavy chain genes.

The development of rapid polymerase chain reaction (PCR) protocols for amplification of rearranged heavy chain immunoglobulin (IgH) gene sequences has facilitated the identification of clonal IgH rearrangements in non-Hodgkin's lymphomas (NHL) and leukemias of B lineage. In the present report we have explored the recently described improved strategy for assessment of clonality of rearranged immunoglobulin heavy chain (IgH) genes in more detail in a series of 101 B cell malignancies and 50 polyclonal controls. The assay is based on an IgH-PCR with an automated fluorescence-based strategy for PCR detection of IgH gene rearrangements. Third complementarity determining region (IgH-CDR3) sequences were amplified using fluorescent dye labeled consensus primers homologous to the corresponding variable (V[H]) and joining (J[H]) gene segments in combination with a thermostable proofreading DNA polymerase. PCR products were size separated on a high resolution polyacrylamide gel and analyzed for clonality by exact size determination and fluorescence quantification in an automated DNA sequencer. PCR findings obtained with the optimized IgH-CDR3-PCR assay showed an overall monoclonality detection rate of 97% (97 of 101 cases with B cell neoplasms). The specificity was 100% as determined by analysis of 50 controls, all of which gave polyclonal PCR results. We found a high rate of monoclonal IgH-CDR3-PCR results not only in the leukemias and diffuse lymphoma but also in the group of follicular lymphoma, where a high rate of false negative results is frequently reported in the literature. In summary, we identified monoclonal IgH-CDR3 junctions in 55 out of 59 cases (93%) with B cell lymphoma and in 42 of 42 (100%) cases with leukemia, immunocytoma and multiple myeloma. The results demonstrate that automated fluorescence detection of IgH-CDR3-PCR products is an ideal tool for detection of clonal and polyclonal lymphoid B cells. In combination with allele-specific primers the procedure may improve current experimental approaches to detect occult malginant B cells during initial staging and follow-up of NHL and ALL patients.

Alleles↗
PubMed1993

Transformation of mycosis fungoides: T-cell receptor beta gene analysis demonstrates a common clonal origin for plaque-type mycosis fungoides and CD30+ large-cell lymphoma.

It is well recognized that patients with classical mycosis fungoides (MF) may develop a large-cell lymphoma (LCL), a phenomenon known as "transformation." An unresolved issue regarding the transformation of MF is whether MF and LCL represent two separate lymphomas or whether they are derived from the same T-cell clone. We report the clinicopathologic, immunophenotypic, and immunogenotypic analysis of MF and LCL in a white male. He developed a rash at age 51 that was diagnosed at age 56 as clinical stage IA patch/plaque MF. After topical nitrogen mustard and total skin electron beam therapy for progressive generalized CD3+CD4+ patch/plaque lesions, he developed nodules of Ki-1+ (CD30+) T-LCL at age 72. Southern blot analysis of DNA digested with Bg/II or BamHI and probed with a T-cell receptor (TCR)-beta gene J beta 1/J beta 2 probe showed a single, identical rearranged band in both the MF and LCL skin lesions that had been obtained 4 years apart. V beta gene family--specific gene amplification assays demonstrated dominant V beta 6 PCR products in both types of lesions. These PCR products and lesional cDNA exhibited a monoclonal pattern when amplified with consensus TCR-beta gene VDJ joint primers and electrophoresed under conditions that allowed the resolution of small differences in size. Furthermore, sequence analysis of the V beta 6 PCR products amplified from both the MF and LCL lesions showed an identical nucleotide sequence involving V beta 6.4, D beta 1.1, J beta 1.2, and C beta 1. These findings indicate that both the MF and the LCL in this patient arose from the same T-cell clone and that these diseases developed at a stage in the clone's differentiation subsequent to rearrangement of the TCR-beta gene.

Aged↗
PubMedDate not supplied

Retroviral transduction models of Ph+ leukemia: advantages and limitations for modeling human hematological malignancies in mice.

There are two commonly used approaches to modeling human leukemia in mice: generation of mutant mice by traditional transgenic or knock-out/knock-in methods and retroviral bone marrow transduction and transplantation. For modeling leukemia, the retroviral model system has some distinct advantages over transgenic mice. Testing different forms and mutants of a given oncogene is much easier with the retroviral system and avoids the potential deleterious effects of expression of a transgene in nonhematopoietic tissues and during development. The retroviral provirus serves as a clonal marker of a transduced cell, facilitating analysis of clonality and transplantability of the malignancy. Finally, the retroviral system allows the assessment of the action of an oncogene in different subsets of hematopoietic precursor cells in the bone marrow, which is difficult or impossible with transgenic models. This article summarizes recent progress in modeling human Philadelphia-positive leukemia in mice with the retroviral bone marrow transduction/transplantation system and emphasizes the advantages and limitations of this approach with examples from the BCR-ABL leukemogenesis literature.

Animals↗