The Clonal Development of Antibody-Forming Cells

1973 ◽  
pp. 606-611
Author(s):  
A. J. Cunningham
Keyword(s):  
Clonal Development

scholarly journals RGB-Marking to Identify Patterns of Selection and Neutral Evolution in Human Osteosarcoma Models

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2003
Author(s):  
Stefano Gambera ◽  
Ana Patiño-Garcia ◽  
Arantzazu Alfranca ◽  
Javier Garcia-Castro
Keyword(s):  
Clonal Selection ◽  
Clonal Evolution ◽  
Phylogenetic Reconstruction ◽  
Experimental Models ◽  
Neutral Evolution ◽  
Immunodeficient Mice ◽  
Nsg Mice ◽  
Clonal Development ◽  
Clonal Composition

Osteosarcoma (OS) is a highly aggressive tumor characterized by malignant cells producing pathologic bone; the disease presents a natural tendency to metastasize. Genetic studies indicate that the OS genome is extremely complex, presenting signs of macro-evolution, and linear and branched patterns of clonal development. However, those studies were based on the phylogenetic reconstruction of next-generation sequencing (NGS) data, which present important limitations. Thus, testing clonal evolution in experimental models could be useful for validating this hypothesis. In the present study, lentiviral LeGO-vectors were employed to generate colorimetric red, green, blue (RGB)-marking in murine, canine, and human OS. With this strategy, we studied tumor heterogeneity and the clonal dynamics occurring in vivo in immunodeficient NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ (NSG) mice. Based on colorimetric label, tumor clonal composition was analyzed by confocal microscopy, flow cytometry, and different types of supervised and unsupervised clonal analyses. With this approach, we observed a consistent reduction in the clonal composition of RGB-marked tumors and identified evident clonal selection at the first passage in immunodeficient mice. Furthermore, we also demonstrated that OS could follow a neutral model of growth, where the disease is defined by the coexistence of different tumor sub-clones. Our study demonstrates the importance of rigorous testing of the selective forces in commonly used experimental models.

Clonal development of a blastoid mantle cell lymphoma studied with comparative genomic hybridization

2002 ◽  
Vol 139 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Emma Flordal ◽  
Mattias Berglund ◽  
Richard Rosenquist ◽  
Martin Erlanson ◽  
Gunilla Enblad ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Comparative Genomic Hybridization ◽  
Cell Lymphoma ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Mantle Cell ◽  
Clonal Development

scholarly journals Evidence for clonal development of childhood acute lymphoblastic leukemia

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 902-907
Author(s):  
LW Dow ◽  
P Martin ◽  
J Moohr ◽  
M Greenberg ◽  
LG Macdougall ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Progenitor Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Childhood All ◽  
Hla Dr ◽  
Blast Cells ◽  
Leukemic Clone ◽  
Clonal Development ◽  
Glucose 6 Phosphate Dehydrogenase

To determine whether acute lymphoblastic leukemia (ALL) is a clonal disease and to define the pattern of differentiation shown by the involved progenitor cells, we studied the glucose-6-phosphate dehydrogenase (G6PD) types in the cells of 19 girls heterozygous for this X chromosome-linked enzyme. Lymphoblast immunophenotypes were those of HLA-DR+, CALLA+ ALL (six patients); HLA-DR+, CALLA- ALL (four patients); pre-B cell ALL (two patients); T cell ALL (four patients); and undefined ALL (three patients). Malignant blast cells at diagnosis from ten patients displayed a single G6PD type, indicative of clonal disease. In contrast, both A and B G6PD in ratios similar to those found in skin were observed in morphologically normal blood cells from the same patients. The leukemic cells of three patients were examined at both diagnosis and relapse; in each instance the same G6PD type was found, consistent with regrowth of the original leukemic clone at relapse. Results of studies of cells from nine additional patients tested only at relapse were similar. Our results indicate that childhood ALL is a clonally derived disease involving progenitor cells with differentiation expression detected only in the lymphoid lineage.

scholarly journals Role of oncoviruses in oncogenesis

2020 ◽  
Vol 76 (12) ◽  
pp. 684-689
Author(s):  
Madej J.A.
Keyword(s):  
Growth Factors ◽  
Cell Growth ◽  
Neoplastic Transformation ◽  
Genetic Changes ◽  
Stimulate Cell Growth ◽  
Stimulate Cell ◽  
Optimization Principle ◽  
Clonal Development ◽  
Transcription Activators

The author describes DNA oncoviruses and RNA oncoviruses, their ways of infiltrating the host’s cells, and the possibilities of neoplastic transformation of cells by these microorganisms. The role of protooncogenesis and oncogenesis in both humans and animals is discussed. The transformation of cells by viruses is normally insufficient for oncogenesis; the cells also need to gain “immortality,” which usually requires 4-5 genetic changes (the so-called clonal development of cells), (Fig. 1). Oncoviruses remove suppressor growth factors while enhancing the effects that stimulate cell growth through e.g. hormones, cytokines, or transcription activators. In addition, the author discusses the role of the optimization principle in neogenesis.

scholarly journals Chimeric mice reveal clonal development of pancreatic acini, but not islets

2009 ◽  
Vol 379 (2) ◽  
pp. 526-531 ◽  
Author(s):  
E. Scott Swenson ◽  
Julie Xanthopoulos ◽  
Timothy Nottoli ◽  
James McGrath ◽  
Neil D. Theise ◽  
...  
Keyword(s):  
Chimeric Mice ◽  
Pancreatic Acini ◽  
Clonal Development

scholarly journals Automated Cell Lineage Construction: A Rapid Method to Analyze Clonal Development Established with Murine Neural Progenitor Cells

Cell Cycle ◽  
2006 ◽  
Vol 5 (3) ◽  
pp. 327-335 ◽  
Author(s):  
Omar Al-Kofahi ◽  
Richard J. Radke ◽  
Susan K. Goderie ◽  
Qin Shen ◽  
Sally Temple ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Rapid Method ◽  
Neural Progenitor Cells ◽  
Cell Lineage ◽  
Neural Progenitor ◽  
Clonal Development

scholarly journals Heterogeneity of clonal development in chronic myeloproliferative disorders

1999 ◽  
Vol 60 (2) ◽  
pp. 158-160 ◽  
Author(s):  
Anna Maria Ferraris ◽  
Rosa Mangerini ◽  
Omar Racchi ◽  
Davide Rapezzi ◽  
Michela Rolfo ◽  
...  
Keyword(s):  
Myeloproliferative Disorders ◽  
Chronic Myeloproliferative Disorders ◽  
Clonal Development

Tracking the Somatic Mutations in Azacitidine-Treated MDS Patients Documents Clonal Development and AZA Responsiveness

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4103-4103
Author(s):  
Tomas Stopka ◽  
Karina Vargova ◽  
Vojtech Kulvait ◽  
Jarmila Vargova ◽  
Nina Dusilkova ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Gene Mutations ◽  
Dna Demethylation ◽  
Illumina Platform ◽  
Unstable Phase ◽  
Somatic Gene ◽  
Frequent Mutations ◽  
Mutation Pattern ◽  
Clonal Development ◽  
New Mutations

Abstract Introduction and hypothesis: Somatic gene mutations develop in ~78% Myelodysplastic syndrome (MDS) patients. MDS progresses into an unstable phase characterized by an accumulation of myeloblasts that is indicated for the DNA demethylation therapy with Azacitidine (AZA). To understand whether AZA is capable to eliminate tumor cells and whether a mutation pattern responds to AZA we herein tracked mutations in the bone marrow (BM) during AZA treatment. Two scenarios were postulated: 1) AZA treatment will/ will not eliminate clones characterized by specific mutations and this will relate to the clinical outcome, 2) during clinical progression on the AZA treatment either the new mutations will develop or the original mutations will be detected. Patients: 40 int-2/high-risk MDS patients (176 samples, median age 70, 22F/18M) indicated for AZA (75mg/m2, 5+2+2) were sequenced. The MDS subtypes included RAEB1, RAEB2, and MDS/AML. Half of the patients progressed from the 5q-syndrome. Libraries were prepared using TruSight DNA amplicon kit. Set of 54 myeloid genes (associated with MDS or AML) were sequenced by Illumina platform HiSeq 2500 with depth >100 per mutation, mutation should be heterozygous, non-synonymous, exonic with frequency >10%. As controls: 4 normal BM samples and 2 cord bloods (also applied for data filtering) and MOLM-13 cell line carrying FLT3-ITD mutation were used. Additional controls included CD3+ T cells isolated from the patient BM samples. Results: 70% of patients were informative for at least one somatic mutation with high impact on the amino acid sequence. Mutations in TET2 (in 13%) were overall the most frequent before AZA was started (followed by mutations in BCOR, RUNX1, STAG2, and NOTCH genes). In 36% of informative patients, the mutation pattern developed on AZA. Interestingly, the most frequent mutations after AZA were in ASXL1 in 10% (followed by mutations in TET2, BCOR, and CUX1 genes). While mutations in ASXL1 and NOTCH genes developped only in the non-5q derived patients, the mutations in RUNX1 developped only in the 5q-derived higher-risk MDS patients. Average number of mutations before AZA and on AZA was 2 per patient. Complete elimination of the mutation pattern was noted in 57% of informative patients during the first 8 months of AZA treatment and this was associated with the therapy responsiveness (PR or CR). In contrast in 7% of informative patients the mutation pattern remained the same and this was associated with the stable disease (leading to progression). Upon progression on the AZA treatment we have observed appearance of the new mutations in 73% of informative patients. 20% of patients progressing after 14 cycles of AZA were non-informative which suggests that these patients may carry mutations in genes not included within the tested set. We have assessed overall survival (OS) according to the mutation status in the following subgroups: non-informative patients, informative patients with mutations that were eliminated by AZA, and those retaining or gaining the mutations upon AZA. The group that developed or retained mutations during first 4-8 cycles of AZA displayed significantly lower OS (p=0.004, median OS:11 months) compared to either non-informative patients (26 months) or those where AZA completely eliminated the mutation pattern (28 months). Conclusions: Tracking the mutations in MDS patients during AZA therapy provides opportunity to detect clonal development in 2/3 of the MDS patients and relate these data to the clinical outcome. Moreover, progression on AZA therapy is usually associated with the development of a new mutation pattern and this coincides with the significantly lower OS. Grants: GACR P305/12/1033, UNCE 204021, PRVOUK-P24/LF1/1. Disclosures Stopka: Celgene: Research Funding.

Detection and Monitoring of BRAF and NRAS Mutant Clones in Myeloma Patients By Digital PCR of Circulating DNA

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4196-4196 ◽  
Author(s):  
Even Holth Rustad ◽  
Hong Yan Dai ◽  
Eivind Coward ◽  
Kristine Misund ◽  
Anders Sundan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Plasma Cells ◽  
Digital Pcr ◽  
Braf V600e ◽  
M Protein ◽  
Bone Marrow Biopsies ◽  
Blood Samples ◽  
Sequential Samples ◽  
Clonal Development

Abstract Introduction Targeted mutation specific therapy is a promising approach in cancer therapy. However, an obstacle for this approach is the vast heterogeneity of the clonal composition and development. Tumor biopsies represent only a snapshot of the situation. Furthermore, monitoring of the clonal development is difficult because biopsies may not be representative for the whole tumor and availability of repeat biopsies is limited. To meet these difficulties we have established and optimized a method based on Digital PCR (dPCR) for analyses of circulating cell free (cf)DNA from sequential samples of serum and plasma from patients with multiple myeloma. Methods We investigated 19 patients for the BRAF V600E mutation. Nine were previously confirmed as mutation positive in bone marrow biopsies/purfied plasma cells by two independent methods (PCR/immunohistochemistry/whole exome sequencing) whereas 10 were mutation negative (Rustad et al Blood Cancer J 2015). Two patients with NRAS Q61K mutation detected in serial bone marrow samples were also included. In total, 67 serum and 21 EDTA-plasma samples were analyzed. Blood samples were taken, processed and frozen at -800 C within 1,5 hour. The samples were stored for a median of 5 years (range 0-23) before DNA isolation and analysis. Mutation detection by dPCR was performed using a droplet-based system and validated primer/probe-sets (BioRad). In-house validation and optimization of the assay was carried out using cancer cell lines OH2 and HT29 with NRAS Q61 and BRAF V600E mutations respectively. The limit of detection was 1-3 copies of mutated DNA per reaction and no false positives were detected. The threshold of positivity was set to 1 droplet per sample. Experiments were performed in accordance with the Minimum Information for Publication of Digital PCR Experiments (dMIQE) guidelines (Huggett et al Clin Chem 2013). Results BRAF or NRAS mutated cfDNA was detected in all patients with a confirmed mutation in tumor tissue, and in none of the mutation-negative controls (p = 0.000003, Fisher's exact test). When looking only at tumor tissue and blood samples obtained at the same time, mutation positivity was confirmed in the blood of 9/10 patients (p = 0.00012). Furthermore, there was a positive correlation between the percentage of mutated plasma cells in bone marrow biopsies and the concentration of mutated cfDNA (Spearman correlation R = 0.63, p = 0.025). Serial samples were analyzed from 5 patients and provided information about 3 different aspects: 1. Patients 1 (figure), 2 and 3, had large clones (50-100 %) of BRAF or NRAS mutated cells in diagnostic and relapse bone marrow samples. Mutated cfDNA correlated closely to M-protein levels in these patients as demonstrated in the figure. A corollary of the figure is that the BRAF mutated clone produces M protein and is sensitive to MP. 2. Patient 4 developed a pelvic extra medullary plasmacytoma with 75-100% BRAF mutation positive cells (immunohistochemistry), however, time-matched serum samples showed only a modest peak with 23 mutated copies/ml. 3. Patient 5 had a moderately sized BRAF V600E mutated clone of 50-75 % at diagnosis, which, according to serum levels, persisted through the disease course. However, two months prior to death, the patient rapidly deteriorated and became refractory to treatment. BM aspirate showed 95 % plasma cells with plasmablastic morphology. A serum sample contained > 600 ng/ml of cfDNA, 10-100 fold more than any other sample in our study, and was highly positive for BRAF V600E mutation (59 000 copies/ml). The patient clearly had expansion of an aggressive BRAF mutated clone that could easily be detected by serum analysis. Conclusions This study demonstrates that mutations such as BRAF V600E and NRAS Q61K can be reliably detected and monitored in sequential serum or plasma samples from myeloma patients. Quantitative mutation analysis compared to M protein in sequential samples provided significant information with clinical relevance. The great advantage of this approach is the easy access to blood samples compared to bone marrow aspirate/biopsy. This will facilitate studies of clonal development during treatment and detection of druggable mutations. Figure 1. Co-variation of M-protein and circulating BRAF V600E mutated DNA in patient 1. Figure 1. Co-variation of M-protein and circulating BRAF V600E mutated DNA in patient 1. Disclosures Waage: Celgene: Research Funding; Amgen: Research Funding; Janssen: Research Funding.

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