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Results for “clonality”

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PubMed2001

Clonality in wild rice (Oryza rufipogon, Poaceae) and its implications for conservation management.

Correlations were examined between habitat characters and clonal structures determined by the RAPD (random amplified polymorphic DNA) assay in five populations of Oryza rufipogon in China. Nine of 175 decameric primers were used in the study because they reproducibly amplified polymorphisms. The extent of clonality together with the clonal and sexual reproductive strategies varied greatly among the five populations and correlated with the habitats where they occur. The populations under serious disturbance or seasonal drought tended to have small clones with relatively high clonal diversity caused by sexual reproduction, whereas the populations with little disturbance and sufficient supply of water were prone to have large clones with relatively low clonal variation and low sexual reproduction. Therefore, the dynamics of sexual vs. clonal reproduction of this species depended mainly on environmental factors, such as external disturbance and water supply, rather than latitudes indicated by previous study. These results have important implications for in situ conservation of O. rufipogon. Adequate external disturbance and water supply control are essential for maintaining high clone diversity of in situ conserved populations. According to the extent of clonality of the populations examined, we recommend that an interval of >12 m should be required for collecting samples for ex situ conservation and for population genetic studies to capture possible genetic diversity for O. rufipogon in China.

Journal Article↗

PubMed2003

Molecular immunoglobulin/T- cell receptor clonality analysis in cutaneous lymphoproliferations. Experience with the BIOMED-2 standardized polymerase chain reaction protocol.

BACKGROUND AND OBJECTIVES: Molecular clonality analysis of immunoglobulin (Ig) and T-cell receptor (TCR) genes is a widely used diagnostic tool for discrimination between polyclonal, oligoclonal, and monoclonal lymphoproliferative skin lesions. We studied Ig/TCR clonality in a series of 60 patients with an initial suspicion of (primary) cutaneous B- or T-cell lymphoma (CBCL/CTCL). Clonality of Ig/TCR gene rearrangements was assessed by Southern blot (SB) and polymerase chain reaction (PCR) analysis using standardized PCR primers and protocols of the BIOMED-2 Concerted Action BMH4-CT98-3936. The obtained PCR products were subjected to heteroduplex (HD) and GeneScan (GS) analysis. We compared the data of 154 samples with the histopathologic diagnosis, based on the EORTC classification of skin lymphomas. DESIGN AND METHODS: Molecular results were largely concordant with histopathology. In 12 CBCL patients PCR analysis of Ig gene rearrangements detected clonality in 83% of cases whereas SB did so in 92%. Clonal TCR gene rearrangements were detected by SB in 68% of CTCL patients, whereas TCRG and TCRB PCR analysis detected clonality in 76% and 66% of cases, respectively. PCR GS analysis of TCR rearrangements appeared to be slightly more informative than HD analysis. Clonality assessment was particularly informative for studying involvement of extracutaneous sites, such as regional lymph nodes, peripheral blood, and bone marrow. INTERPRETATION AND CONCLUSIONS: Our study shows that the BIOMED-2 multiplex PCR analysis strategy is a reliable and useful technique in the diagnostic process of patients with an initial suspicion of (primary) CBCL/CTCL and for assessment of extracutaneous dissemination, provided that the results are interpreted in the context of clinical, histologic and immunophenotypic data.

Clone Cells↗

PubMed1992

Frequency and prognostic significance of clonal T-cell receptor beta-gene rearrangements in the peripheral blood of patients with mycosis fungoides.

BACKGROUND: Previous studies have shown that peripheral blood involvement is a poor prognostic sign in patients with cutaneous T-cell lymphoma. However, evaluation of the results of these studies is difficult. In this study peripheral blood mononuclear cells from 45 patients with various stages of mycosis fungoides (MF) were investigated for the presence of clonal T-cell populations by T-cell receptor beta (TCR beta)-gene rearrangement analysis. RESULTS: Clonal TCR beta-gene rearrangements were found in five (11%) of 45 patients with MF, including one (3%) of 31 patients without MF and four (27%) of 15 patients with histologically confirmed lymph node involvement. With respect to skin stage, clonal T-cell populations were detected in one (4%) of 23 patients with plaque stage disease, two (10%) of 19 patients with tumor stage disease, and two (50%) of four patients with erythrodermic MF. In the group of patients with lymph node involvement the median survival of patients with detectable clonal T-cell rearrangements in the peripheral blood was much shorter (3 months) than that of patients without clonal rearrangements (16 months). CONCLUSIONS: The results of this study indicate that clonal TCR beta-gene rearrangements, as detected by Southern blot analysis, are uncommon in the peripheral blood of patients with MF, in particular in patients without histologically documented lymph node involvement. The presence of clonal T-cell populations in the peripheral blood of MF patients with lymph node involvement is usually associated with rapidly fatal disease.

Clone Cells↗

PubMed2004

T cell receptor Vbeta repertoire usage and clonal expansion of T cells in chronic myelogenous leukemia.

BACKGROUND: In general, it is very important to understand the state of T cell immune response against tumor cells in leukemia patients and it is especially critical to assess the T cell repertoire of untreated patients. As we know, few studies have dealt with the distribution of oligoclonal T cells in leukemia, so we investigated the distribution and clonality of TCR Vbeta repertoire of T cells in patients with chronic myelogenous leukemia (CML) in chronic phase. METHODS: The complementarity determining region 3 (CDR3) of TCR Vbeta24 subfamily genes were amplified in peripheral blood mononuclear cells from 27 cases with CML using reverse transcription-polymerase chain reaction (RT-PCR). In order to observe the distribution of TCR Vbeta repertoire, the PCR products were further analyzed by genescan technique to evaluate clonality of the detectable TCR Vbeta T cells. The PCR products of the oligoclonal T cells from three cases were analyzed by direct sequencing to define the sequence of CDR3. RESULTS: The expression pattern of TCR Vbeta repertoire in different individuals are different. Vbeta2-21 subfamilies could be detected in CML cases. The frequent usage Vbeta repertoire in CML was Vbeta1, Vbeta2 or Vbeta13. Most of the PCR products from 27 patients displayed polyclonality, while a part of the PCR products from 21 out of 27 samples displayed clonal expansion pattern. The clonal expanded T cells in CML could be found in Vbeta16 subfamilies. The frequent usage of Vbeta genes in clonal expansion was Vbeta3, Vbeta13 or Vbeta21. Multiple Vbeta clonal expansion was a general phenomenon in the same patient. The CDR3 sequence of Vbeta21 oligoclonal T cells from 3 cases showed some difference in splice regions and in the usage of J segments. CONCLUSIONS: These results indicated that clonal expanded T cells could be found in patients with CML and were tendentious in Vbeta3, Vbeta13 and Vbeta21 subfamilies that may be related to the specific immune response for leukemia cell associated antigen.

Clone Cells↗

PubMed2005

Epstein-Barr virus genome level, T-cell clonality and the prognosis of angioimmunoblastic T-cell lymphoma.

BACKGROUND AND OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AILT) is a peripheral T-cell tumor of unknown etiology with variable biological and clinical presentations. Previous clonality studies have shown heterogeneous clonal restrictions of B- and T-cell populations in this tumor. AILT is characterized by the presence of increased numbers of Epstein-Barr virus (EBV) infected cells. The aim of this study was to clarify the correlation between clonality, EBV and prognosis. DESIGN AND METHODS: Frozen material from 59 cases of AILT was used for DNA isolation and gene analysis by Southern blotting. A real-time polymerase chain reaction was used to quantify the amount of EBV-DNA in the tissue. Survival data were retrieved from clinical records. RESULTS: Clonal T cells were found in 15/50 and clonal B-cells in 2/50 tumors, using Southern blot analysis. Bands of EBV-W were found in 10/50 tumors. Survival rate did not correlate with either T-cell clonality (p=0.84), or presence of EBV-infected cells (p=0.84). The EBV-DNA copy number in EBV-infected tissue did not correlate with disease progression (p=0.87). The survival rate and clinical status according to the international prognostic index (IPI) did not correlate with T-cell clonality status or EBV infection. INTERPRETATION AND CONCLUSIONS: AILT remains a heterogeneous disease with clinical behavior that varies irrespective of the genomic parameters investigated.

Adult↗

PubMed1995

Single or multistep origin of hemopoietic tumors: the contribution of clonality studies.

Clonality assays may provide an additional and helpful approach to understanding the problem of the single or multistep pathogenesis of hematologic malignancies. In the absence of specific cytogenetic and/or molecular abnormalities, the study of X chromosome inactivation pattern in female patients represents a useful indirect approach for determination of the clonal or polyclonal nature of a cell population of unknown origin or the persistence of clonal hemopoiesis in leukemia after treatment. An intriguing observation was the documentation of an apparent clonal hematopoiesis in a quite high proportion of AML patients during morphological remission. These data were interpreted as evidence of a multi-step origin of AML, in which a first 'hit' was responsible for the growth advantage of a cytogenetically silent and morphologically normal preleukemic clone, whereas a second 'hit' would give rise to the overt leukemic phenotype. More recent surveys on the frequency of clonal remission, however, arrived at discordant results and could detect the occurrence of true clonal remission in a much lower percentage of cases than previously reported. These apparent discrepancies, which in part may be explained by differences in the series studied and in the approach used to detect clonality, for the moment leave open the fascinating issue of the single or multistep origin in many human leukemias.

Acute Disease↗

PubMed1995

[Clonal study of hematopoietic cells].

Clonal analyses using X-chromosome inactivation patterns of the phosphoglycerate kinase (PGK) and DXS255 (M27 beta) genes were performed in women with various hematological diseases or normal hematopoiesis. Four (17%) of 24 hematologically normal females had a skewed Lyonization pattern. It, however, appeared that in the majority of cases clonality determination of myeloid cells would be possible in comparison with lymphocytes. Blasts of acute myeloid leukemia (AML) (21) and granulocytes and bone marrow cells of chronic myeloproliferative disorders (6) were all shown to be clonal, suggesting that this method was useful for the concept formation of a clonal disorder. Twelve of 14 patients with the myelodysplastic syndromes had a clonal pattern and 8 of 10 patients with aplastic anemia had a polyclonal pattern. Three of 34 patients with AML during remission were diagnosed as a clonal hematopoiesis and associated with features of myelodysplasia during remission, when clonal patterns are different in patients with the same disease, it seems important to elucidate their clinical implications.

Clone Cells↗

PubMed1994

Lineage analysis reveals neurotransmitter (GABA or glutamate) but not calcium-binding protein homogeneity in clonally related cortical neurons.

Studies of cell lineage in the rat cerebral cortex have provided new insights into the mechanisms of neuronal and glial determination. They have shown that clonally related cells, marked with retrovirus injection at embryonic day 16 (E16), express the same glial or neuronal phenotype, suggesting that separate progenitors for each of these cell phenotypes exist in the ventricular zone at that stage of corticogenesis. However, it is not known if such committed progenitors are present in the ventricular zone before E16. Another important question concerns which neurochemical features are shared by clonally related cells of the adult cerebral cortex. In this study we have addressed the first question by injecting a retroviral vector expressing beta-galactosidase into the telencephalic ventricles of rat embryos at different stages (E14-E19). In order to classify clonally related neurons in the cerebral cortex of these rats, we have used postembedding immunohistochemistry for the amino acid neurotransmitters glutamate, aspartate, and GABA. Glutamate and GABA immunoreactivity marked nonoverlapping populations of cells that corresponded to the pyramidal and nonpyramidal neuron types of the rat cerebral cortex. Clonally related neurons, marked by retrovirus injection at any day between E14 and E19, homogeneously expressed one or other phenotype and accordingly displayed glutamate or GABA immunoreactivity. This finding indicates that committed progenitor cells for pyramidal and nonpyramidal neurons are present in the ventricular zone before E16. To investigate whether lineage dictates other features in clonally related neurons, we performed an immunohistochemical analysis for the calcium-binding proteins calbindin, parvalbumin, and calretinin in clusters of clonally related nonpyramidal neurons. The same calcium-binding protein was rarely found in members of the same cluster, suggesting that lineage does not control the expression of calcium-binding proteins in cortical nonpyramidal neurons. As a result of examining a large number of clonally related neurons from brains injected at different ages, we observed remarkable differences in number and laminar distribution of pyramidal and nonpyramidal neurons marked with retrovirus. Clusters of nonpyramidal neurons were usually composed of two or three cells, and resided in the cortical layers that were just being generated at the time of injection. Clusters of pyramidal neurons were larger and dispersed in several layers in the earlier injections; their size and laminar distribution were progressively reduced for later injections. These observations suggest the existence of different mechanisms that generate the pyramidal and nonpyramidal neurons of the cerebral cortex.

Animals↗

PubMed1996

Clonal analysis of focal nodular hyperplasia of the liver.

Recent evidence suggests that focal nodular hyperplasia of the liver (FNH) may represent a hyperplastic response to a vascular malformation, but the precise etiology remains unclear. We performed a clonal analysis of ten FNHs from nine patients by patterns of X chromosome inactivation. DNA isolated from paraffin-embedded specimens was subjected to polymerase chain reaction amplification for a highly polymorphic region of the human androgen receptor gene (HUMARA). Predigestion of tumor DNA with the methylation-sensitive, restriction enzyme HpaII allowed for selective amplification of the methylated (inactivated) allele. Of the nine patients analyzed, seven were heterozygous for the HUMARA polymorphism and informative for analysis. One informative patient had two lesions, for a total of eight FNHS. Amplification of lesional DNA after HpaII digestion demonstrated clonality in six of the eight informative cases. Paired tissue samples from different lesional areas were available in four of the six FNHs with evidence of clonality. In three of the four cases, DNA extracted from the two tissue samples showed both evidence of clonality and an identical pattern of X chromosome inactivation. In the remaining case, one sample showed evidence of clonality whereas the other was nonclonal. Three hepatic adenomas from two informative patients were also analyzed for comparative purposes, all of which showed evidence of clonality after HpaII digestion. The current study illustrates that most cases of FNH show a uniform pattern of X chromosome inactivation consistent with clonality.

Adenoma↗

PubMed1996

B lymphocytic clonal expansion in rheumatoid arthritis.

OBJECTIVE: To learn whether rheumatoid factor (RF), HLA-DR4, or current therapy influences clonal expansion of B lymphocytes (B cells) in persons with rheumatoid arthritis (RA). METHODS: We measured clonal expansion by analysis of cell surface staining for immunoglobulin light chains. Double staining methods detected a B cell marker (CD19) plus either kappa or lambda on peripheral blood lymphocytes from subjects with RA (n = 26) and controls (n = 26). The difference between frequency histograms of surface kappa and lambda staining was determined by the Kolmogorov-Smirnov statistic D that represents the fraction of clonally expanded B cells. RESULTS: The mean D value in RA was over 50% higher than in the controls [0.225 +/- SD 0.155 versus 0.144 +/- 0.025 (p < 0.0001)]. Ten subjects with RA had values exceeding +2 SD for controls (p = 0.0007). Mean D correlated with RF titer (Spearman's rank correlation coefficient rSp + 0.53, p = 0.006). All 10 high D values were found in the RA subgroups with positive serum tests for RF and with the HLA-DR4 positive genotype. The channel of maximal difference between kappa and lambda staining was higher in the RA group than in controls, showing that clonal expansion was most marked among brightly staining cells. Patients with RA currently receiving low dose methotrexate (MTX) tended to have higher D values than those not receiving MTX (mean 0.29 versus 0.18, respectively, p < 0.025). The RA group currently receiving MTX had a higher frequency of abnormal D values (7 of 11 versus 3 of 15 not currently receiving MTX, p = 0.03). This probably reflects preferential use of MTX for severely affected individuals. Confirmatory studies to detect clonal immunoglobulin gene rearrangements were attempted in selected individuals with high D values, but none was demonstrated in total leukocytic or B cell enriched fractions. CONCLUSION: Findings consistent with B cell clonal expansion occur in about 40% of persons with RA, particularly in the subgroups with positive serum tests for RF and with the HLA-DR4 genotype. However, the clonal expansion level must be below the sensitivity of confirmatory methods.

Adult↗

PubMed1997

Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by a sustained elevation of the platelet count in the absence of other causes of thrombocytosis. ET is difficult to diagnose, and the demonstration of clonal hematopoiesis may be of value. However, clonality analysis of hematopoietic cells based on the study of the X-chromosome inactivation pattern is complicated by the observation that some normal females present skewed lyonization. Moreover, DNA methylation of X-linked genes in hematopoietic cells may differ from that in other tissues. Appropriate controls for skewed lyonization are therefore critical for the study of clonality. We developed two techniques based on X-chromosome inactivation and polymerase chain reaction (PCR) analysis of polymorphisms, to study clonality in ET patients. Reverse transcriptase-PCR analysis of IDS, P55, and G6PD mRNAs was used to examine the different hematopoietic cell lineages including platelets in patients heterozygous for these polymorphisms and analysis of the HUMARA gene methylation pattern permitted us to study clonality in all nucleated cell fractions of the other patients. Using both types of assay and T lymphocytes as a control tissue for lyonization, clonal hematopoiesis was demonstrated in 28 patients. In 14 patients, the granulocytes were polyclonal; among these patients, platelets were monoclonal in 3 cases, polyclonal in 7 cases, and in the remaining 4 cases this fraction could not be studied because the patients were homozygotes for all RNA markers. No conclusion about clonality could be drawn in 6 cases. Polyclonal hematopoiesis was found in all the cases of reactive thrombocytosis. These findings confirm the high frequency of monoclonal hematopoiesis in ET, the utility of studying platelets, and the possibility of using T lymphocytes as a control tissues for X-chromosome inactivation patterns.

Adolescent↗

PubMed1997

Evidence for clonal origin of neoplastic neuronal and glial cells in gangliogliomas.

Gangliogliomas are rare tumors of the central nervous system that account for approximately 1% of all brain tumors. Histologically, gangliogliomas are composed of intimately admixed glial and neuronal components, the pathological origins of which remain to be characterized. Clonal analysis through examination of the pattern of the X chromosome inactivation allows one to distinguish monoclonal differentiation of a genetically abnormal progenitor cell from parallel, but independent, clonal expansion of two different cell types during tumorigenesis in biphasic neoplasms, such as gangliogliomas. In the present study, we investigated the clonality of eight gangliogliomas from female patients using both methylation- and transcription-based clonality assays at the androgen receptor locus (HUMARA) on the X chromosome. Among tumors from seven patients who were heterozygous at the HUMARA locus, five were identified as monoclonal with the methylation-based clonality assay, and the results were confirmed by the transcription-based method, whereas two were shown to be polyclonal by the methylation-based clonality assay but monoclonal by transcription-based clonality analysis. We conclude that the predominant cell types in most gangliogliomas are monoclonal in origin and derive from a common precursor cell that subsequently differentiates to form neoplastic glial and neuronal elements.

Adult↗

PubMed1997

Demonstration of frequent occurrence of clonal T cells in the peripheral blood of patients with primary cutaneous T-cell lymphoma.

Clonal T cells have been demonstrated in skin lesions of all stages of cutaneous T-cell lymphomas (CTCLs). However, there are conflicting data regarding the CTCL stage at which dissemination of clonal cells into peripheral blood occurs. Although the multifocal occurrence of cutaneous CTCL lesions and T-cell recirculation suggest an early appearance of neoplastic cells in the blood, circulating clonal T cells have only been detected in advanced stages. We investigated their occurrence by a highly sensitive polymerase chain reaction (PCR) assay amplifying T-cell receptor gamma rearrangements and subsequent heteroduplex temperature gradient gel electrophoresis (HD-TGGE) of the amplification products. Circulating clonal T cells were found in 26 of 45 patients with mycosis fungoides (MF), six of seven with Sezary's syndrome (SS), 10 of 13 pleomorphic CTCLs, and three of four unclassified CTCLs. Corresponding skin specimens carried clonal T cells in 29 of 40 MF, three of four SS, 12 of 12 pleomorphic, and two of two unclassified CTCL patients. Except for the blood specimen of a psoriatic patient, all samples of 60 controls (psoriasis vulgaris, atopic dermatitis, and healthy volunteers) revealed polyclonal amplification products. In 30 of 32 CTCL patients carrying a clonal rearrangement in blood and skin, identity of both clones was indicated by HD-TGGE and confirmed by sequencing six of these cases. We found an unexpected high frequency of identical clonal T cells in peripheral blood and skin of CTCL patients, including early stages of MF. This supports the concept of an early systemic disease in CTCL and raises new questions concerning the pathogenesis.

Adult↗

PubMed1998

Clonality of lymphomas at multiple sites in SJL mice.

SJL mice are an inbred strain of mice with a high incidence of spontaneous lymphomas of B-cell type often involving multiple abdominal organs, and are therefore a useful model for studying the clonal relationship among lymphomas at multiple sites. Thirteen SJL mice with well-developed tumors were killed at a median age of 56 weeks. Autopsy samples were taken from various enlarged lymphoid organs, and the histologic appearance of lymphomas was recorded. Using rearrangements of immunoglobulin genes (heavy and kappa-light chain genes) and integration patterns of murine leukemia virus as clonal markers, 7 of the 13 informative mice showed complete clonal identity among the different sites selected from each mouse; 5 of 13 mice demonstrated at least one shared clonal band with one or more markers being different among the different sites. The histologic appearance of the lymphomas from the various sites was found to be heterogeneous, even when there was clonal identity. These findings suggest that SJL lymphomas in multiple sites within one mouse are usually derived from a single clone but may show development of subclones within a major clonal population, thus supporting the notion that clonal evolution is a common event in the course of development of lymphoid neoplasia.

Animals↗

PubMed1998

Detection of clonal Hodgkin and Reed-Sternberg cells with identical somatically mutated and rearranged VH genes in different biopsies in relapsed Hodgkin's disease.

Hodgkin's disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg (H-RS) cells are rare and surrounded by abundant reactive cells. Single-cell analyses showed that H-RS cells regularly bear clonal Ig gene rearrangements. However, there is little information on the clinical evolution of HD in a given patient. In this study, we used the single-cell polymerase chain reaction (PCR) to identify H-RS cells with clonal Ig gene rearrangements in biopsy specimens of patients with relapsed HD. The obtained clonal variable region heavy-chain (VH) gene rearrangements were used to construct tumor-clone-specific oligonucleotides spanning the complementarity determining region (CDR) III and somatically mutated areas in the rearranged VH gene. A number of biopsies were obtained during a period of 3 years from two HD patients. H-RS cells with identical VH rearrangements were detected in two separate infiltrated lymph nodes from one patient with nodular sclerosis HD. In a second patient with mixed cellularity HD subtype, clonal VH rearrangements with identical sequences were detected in infiltrated spleen and two lymph node biopsies. Despite the high sensitivity of the PCR method used (one clonal cell in 10(5) mononuclear cells), residual H-RS cells were not found in peripheral blood, leukapheresis material, purified CD34(+) stem cells or bone marrow. The results show that different specimens from relapsed patients suffering from classical HD carry the same clonotypic IgH rearrangements with identical somatic mutations, demonstrating the persistence and the dissemination of a clonal tumor cell population. Thus, PCR assays with CDRIII-specific probes derived from clonal H-RS cells are of clinical importance in monitoring the dissemination of HD and tumor progression and could be useful for analysis of minimal residual disease after autologous stem cell transplantation.

Adult↗

PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗

PubMed1999

Association of clonally expanded T cells with the syndrome of primary biliary cirrhosis and limited scleroderma.

Clinical features of the CREST (calcinosis cutis, Raynaud's syndrome, esophageal dysmotility, sclerodactyly, and telangiectasias) syndrome are sometimes exhibited in patients with primary biliary cirrhosis (PBC), but the postulated autoimmune mechanisms behind these conditions are poorly understood. Clonally expanded T cells may play an important role in disease pathogenesis. In this study, overrepresentation of one T-cell receptor beta chain variable region, TCRBV3, was documented in patients with PBC and/or CREST. Overrepresentation of the TCRBV3 gene mRNA was demonstrated by semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR). T cells expressing TCRBV3 were analyzed by flow cytometry, were primarily CD8(+), and contained activated cells as assessed by expression of CD69. Clonally expanded T cells within this population were documented by both complementarity determining region 3 (CDR3) length polymorphism analysis and sequencing of T-cell receptor CDR3 cDNA. TCRBV3(+) clonal expansions were stable when followed for up to 5 years. The results of this study demonstrate that the T-cell repertoire of patients with PBC and CREST is characterized by expanded clonal populations of CD8(+) TCRBV3(+) T cells. These clonal expansions provide evidence that stimulation of clonal populations of CD8(+) T cells is associated with the clinical syndrome of PBC with CREST.

Adult↗

PubMed2026

Mutational Landscape and Clonal Dynamics in AML Undergoing PTCy Hematopoietic Cell Transplantation.

To improve risk stratification, we performed targeted NGS at diagnosis in 191 patients with AML undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. We also investigated clonal evolution using paired diagnostic and relapse samples from 39 individuals. A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in ∼70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. Incorporating TP53 and WT1 into risk models, recognizing context-dependent effects of DNMT3A and RUNX1, and applying longitudinal genomic monitoring may help guide personalized strategies to prevent relapse. Extended abstract BACKGROUND Relapse remains the leading cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), yet the genetic mechanisms underlying post-transplant relapse remain poorly understood, particularly in the era of post-transplant cyclophosphamide (PTCy). Characterizing the mutational landscape at diagnosis and the clonal evolution leading to relapse may improve post-transplant risk stratification and identify opportunities for personalized surveillance and intervention. OBJECTIVES To characterize the diagnostic mutational landscape, evaluate its prognostic significance, and investigate clonal evolution from diagnosis to relapse in AML patients undergoing myeloablative HCT with PTCy-based graft-versus-host disease prophylaxis. STUDY DESIGN We performed targeted next-generation sequencing (NGS) at diagnosis in 191 consecutive AML patients undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. Paired diagnostic and relapse samples were available for 39 patients to evaluate clonal evolution. RESULTS A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in ∼70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. CONCLUSIONS This study provides a comprehensive characterization of the mutational landscape and clonal evolution of AML undergoing contemporary PTCy-based allogeneic HCT. TP53 and WT1 identify patients at particularly high risk of post-transplant relapse, whereas NPM1 retains favorable prognostic significance. The frequent acquisition of new genetic lesions at relapse underscores the dynamic nature of post-transplant clonal evolution and supports longitudinal molecular monitoring together with genomically informed post-transplant surveillance and relapse-prevention strategies.

Clonal Dynamics↗