scholarly journals Clonal Phylogeny and Evolution of Critical Cytogenetic Aberrations in Multiple Myeloma at Single Cell Level

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Yuting Yan ◽  
Xiaoqi Qin ◽  
Lanting Liu ◽  
Shuhui Deng ◽  
Jiahui Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Single Cell ◽  
Single Cell Analysis ◽  
Clonal Evolution ◽  
Evolutionary Patterns ◽  
Cytogenetic Abnormalities ◽  
Time Points ◽  
Evolution Pattern ◽  
Cytogenetic Evolution ◽  
13Q Deletion

Introductions Although intratumor heterogeneity and clonal evolution have been inferred in multiple myeloma (MM), this was largely focused at the bulk tumor population level. Single-cell analysis is of significant importance in delineating the exact phylogeny of subclonal population and in discovering subtle diversification. Here, we identified the clonal architecture of different time points using multi-gene fluorescence in situ hybridization (mFISH) at single cell level, and explored the prognostic values of different clonal evolution patterns in MM. Methods We performed mFISH in 129 longitudinal samples of 57 MM patients. All the patients had newly-diagnosed and relapsed paired samples, and 12 patients had cytogenetic evaluation for more than two time points. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. Results 43 of 57 patients (75.4%) harbored three or four cytogenetic clones at diagnosis. We delineated the phylogeny of subclonal tumor population in each patient and established robust trends for the timing of temporal acquisition in the whole cohort using the pairwise precedence. 13q deletion and the first 1q gain tended to be earlier cytogenetic alternation, whereas 16q and 17p deletion were acquired later. The sequence of 13q deletion and 1q21 gain occurrence was identified in 23 patients by the single-cell analysis. 1q21 gain and 13q deletion each occurred first in 12 and 11 patients respectively. Strikingly, patients in whom 13q deletion was acquired first showed a significantly worse survival than 1q21 gain-first patients (median OS 32.9 vs. 71.2 months, p=0.010). We inferred the most likely ancestral relationships between subclones and derived the evolutionary architecture in each patient. Four distinct evolutionary patterns were identified (Figure 1). 18 of 57 (31.6%) patients showed clonal stabilization. These patients were characterized by no novel subclones emerging and no existed subclones disappearing at relapse. Differential evolution was observed in 12 patients, where clonal dynamics resulted from a change in predominant clone from presentation to relapse. The major clone at diagnosis disappeared or decreased to a minor clone while a subclone showed growth advantage and turned to be a major clone at relapse. We found evidence of branching evolution in 9 patients. Here, one or more clones harboring novel cytogenetic abnormalities emerged between the early and late time points, whereas some disappeared. The remainder of patients demonstrated a linear evolution pattern (18/57, 31.6%). The predominant clones acquired one or more novel cytogenetic abnormalities at the later time point. Patients with clonal stabilization had a significantly improved OS than those with other evolutionary patterns (median OS, 71.2 vs. 39.7 vs. 35.2 vs. 25.5 months, for stable, differential, branching and linear patterns, respectively, p=0.001). However, there is no difference in sampling interval among four evolutionary patterns (p=0.131). Therefore, the survival differences were mostly attributable to a significantly shorter failure free survival from relapse (p<0.001). In order to evaluate the accuracy of abnormalities detection by mFISH, we performed cFISH in these 57 MM patients. Cell fractions of cytogenetic abnormalities detected by mFISH were significantly correlated with that detected by cFISH (p<0.001). Besides, a high degree of consistency and complementarity across cFISH and mFISH was observed in evaluation of cytogenetic evolution pattern in MM. Then we expanded our cohort to 188 patients to further discuss the prognostic value of cytogenetic evolution. Survival from relapse were greater influenced by the presence of high-risk aberrations at relapse (HR=2.07) rather than present at diagnosis (HR=1.55). There was no difference in OS for patients who had primary high-risk aberrations at diagnosis compared with those who developed high-risk aberrations after relapse (p=0.800). Conclusions These findings suggest that mFISH is a valuable tool for the analysis of clonal phylogeny and evolution pattern of critical cytogenetic aberrations. Patients may benefit from the repeated cytogenetic evaluation, especially for the risk stratification of survival after relapse. Personalized treatment strategy is required for MM patients based on their clonal evolution patterns. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Clonal Heterogeneity and Evolutionary Phylogeny of Critical Cytogenetic Aberrations in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1608-1608
Author(s):  
Yuting Yan ◽  
Xiaoqi Qin ◽  
Jiahui Liu ◽  
Huishou Fan ◽  
Lanting Liu ◽  
...  
Keyword(s):  
High Risk ◽  
Copy Number ◽  
Prognostic Value ◽  
Clonal Evolution ◽  
Clone Size ◽  
Time Points ◽  
Evolution Pattern ◽  
Group A ◽  
Cytogenetic Evolution ◽  
Time Point

Abstract Single-cell analysis is of significant importance in delineate the exact phylogeny of subclonal population and in discovering subtle diversification. So far studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused at the bulk tumor population level. Here, we performed quantitative multi-gene fluorescence in situ hybridization (QM-FISH) in 129 longitudinal samples of 57 MM patients. All the patients had newly-diagnosed and relapsed paired samples. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. 43 of 57 patients (75.4%) harbored three or four cytogenetic clones at diagnosis. We delineated the phylogeny of subclonal tumor population and derived the evolutionary architecture in each patient.13q deletion and the first 1q gain tended to be earlier cytogenetic alternation, whereas 16q and 17p deletion were acquired later. Patients with clonal stabilization had a significantly improved OS than those with other evolutionary patterns (median OS, 71.2 vs. 39.7 vs. 35.2 vs. 25.5 months, for stable, differential, branching and linear patterns, respectively, p=0.001). Besides, a high degree of consistency and complementarity across QM-FISH and cFISH was observed in evaluation of cytogenetic evolution pattern in MM. In total, at least two time-point cytogenetic evaluations by cFISH were underwent in 188 MM patients. The proportion of patients with high-risk cytogenetic features was 33% at diagnosis and 49% at relapse. The prognostic value of the presence of high-risk aberrations at diagnosis were attenuated over time (HR=1.79, p=0.002 for survival from diagnosis; HR=1.55, p=0.026 for survival from relapse, ). Survival from relapse were greater influenced by the presence of high-risk aberrations at relapse (HR=2.07, figure 5E) rather than present at diagnosis (HR=1.55). The present study investigated the prognostic value of evolution in copy number or clone size of 1q21 gain/amplification during follow-up. The incidence of patients carrying at least three copies of 1q21 was higher after relapse than at diagnosis (69% vs. 55%, p=0.004).Patients were categorized as six groups according to the change patterns in copy number and clone size of 1q21 gain between the two time-point samplings. Patients without 1q21 gain/amplification at both time points (group B) and patients who had obvious decrease in clone size or loss of 1q21 gain at relapse (group A) experienced similar superior outcome (Failure free survival after relapse (2 nd FFS), 18.1 vs. 27.8 months, p=0.469), whereas patients carrying 1q21 gain/amplification at both time points with or without increase (group C,D) in clone size relatively worse survival (2 nd FFS 12.4 and 10.5 months, respectively, p<0.05 compare to group A and B). The remaining patients who had an increase in copy number of 1q21 and those who developed de novo 1q21 gain at relapse were observed poorest outcome (group E and F,2 nd FFS 6.7 and 8.9 months). The interval time between two time-point samplings were similar among groups, whereas the different evolution pattern of 1q21 gain could clearly stratify both overall survival and post-relapse survival (p<0.001). This study shows that QM-FISH is a valuable tool to elucidate the clonal architecture at single cell level. Clonal evolution pattern is of prognostic significance, highlighting the need for repeated cytogenetic evaluation in relapsed MM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Eltrombopag for Refractory Severe Aplastic Anemia: Dosing Regimens, Long-Term Follow-up, Clonal Evolution and Somatic Mutation Profiling

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 777-777
Author(s):  
Thomas Winkler ◽  
James N. Cooper ◽  
Danielle M. Townsley ◽  
Phillip Scheinberg ◽  
Sophia Grasmeder ◽  
...  
Keyword(s):  
High Risk ◽  
Aplastic Anemia ◽  
Research Funding ◽  
Somatic Mutations ◽  
Clonal Evolution ◽  
Chromosome 7 ◽  
Fixed Dose ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Evolution

Abstract Eltrombopag (EPAG) received FDA approval for treatment of refractory severe aplastic anemia (rSAA) in 2014, based on our phase I/II dose escalation trial of single agent EPAG at 50-150 mg daily over a period of 12 weeks (Olnes NEJM 2012; Desmond Blood 2014). Two observations warranted further investigation of EPAG in this unique patient population. First, cell count kinetics and lack of acute toxicities suggested that extended administration of EPAG at a fixed dose of 150mg could speed and improve response rates. Second, 19% of patients developed new cytogenetic abnormalities on EPAG, raising concerns that EPAG might promote progression to MDS/AML. We conducted a subsequent phase II study of EPAG given at a fixed daily dose of 150mg for 6 months in patients with rSAA (NCT01891994). Thirty-nine patients enrolled between July 2013 and April 2017. Primary endpoint was hematologic response at 6 months. Responding participants could continue EPAG treatment. Secondary endpoints included response at 3 months and the rate of clonal cytogenetic evolution. Nineteen of 39 (49%) patients met criteria for hematologic response at 6 months. Of these, 5/19 (26%) patients would have been deemed non-responders at 3 months of treatment. EPAG was continued in 18 patients on the extension arm. EPAG was discontinued for robust response in 13/18 (72%) after a median duration of drug administration of 12 months (6-27.5 months). EPAG was re-initiated for relapse in 3/13 patients, and all 3 recovered response. At median follow up of 6 months (range 2 - 39 m), 6/39 patients (15%) developed marrow cytogenetic abnormalities, a rate comparable to our previous cohort. Given the similar rates of response and clonal evolution in our two consecutive studies, we analyzed the relationship between outcomes and cytogenetic progression for all patients (n=83) at up to 8 years of follow-up. Sixteen of 83 (18%) patients clonally evolved (Table 1). Clonal evolution was an early event after EPAG initiation. Evolution occurred within 6 months in 13/16 evolvers (81%), and in 6/6 evolvers with high risk chromosome 7 abnormalities (5/6 within 3 months). The frequency of high risk clonal evolution 24 months post intervention is comparable to historic controls with rSAA. However, direct temporal comparisons of evolution events are limited by differences in the sequence of cytogenetic tests. Non-chromosome 7 cytogenetic abnormalities were often transient, and not associated with dysplasia. Two evolvers continued EPAG off the rSAA protocol and cytogenetics normalized (UPN 71,14). The acquisition and selection of somatic mutations, particularly of myeloid candidate genes recurrently mutated in MDS/AML, has been proposed to be an initiating step in clonal evolution. We performed whole exome sequencing (WES) on samples obtained pre-EPAG treatment and at the primary response endpoint and/or time of clonal evolution in 21 responding patients and in 11 patients with cytogenetic evolution. Candidate gene mutations were detected in patients who responded (6/21) and in those with cytogenetic evolution (4/11). Clonal hematopoiesis without an identifiable driver mutation was common. In post-EPAG samples, additional myeloid candidate gene somatic mutations were detected in 2 cytogenetic evolvers and in 4 responding patients, all at low variant allele frequencies (VAF) that were close to the 2.5% detection threshold. There was no significant change in VAF in either candidate or in non-candidate genes in responders and in cytogenetic evolvers. Only one early cytogenetic evolver (UPN 01) showed an expansion of mutated clones (SETBP1 and RUNX1), from VAF of 5% to 40%, when 80% of bone marrow metaphases showed chromosome 7q deletion. In summary, extended administration of EPAG at a fixed dose of 150 mg daily for 6 instead of 3 months induces additional responses in a subgroup of patients with rSAA. After EPAG was discontinued, most patients maintained durable robust responses. The temporal relationship between clonal evolution and drug exposure suggests that in a subgroup of patients, EPAG may promote expansion of dormant pre-existing clones with an aberrant karyotype. No clinical or laboratory findings prior to therapy, including WES, predicted response or risk of clonal evolution. Careful monitoring of refSAA patients treated with EPAG is indicated, particularly in the first 6 months of treatment. Table 1 Table 1. Disclosures Winkler: Novartis/GSK to institute: Research Funding. Cooper: Novartis/GSK to institute: Research Funding. Townsley: Novartis/GSK to institute: Research Funding. Grasmeder: Novartis/GSK to institute: Research Funding. Young: Novartis/GSK to institute: Research Funding. Dunbar: Novartis/GSK to institute: Research Funding.

scholarly journals MBRS-59. SINGLE-CELL WHOLE-GENOME SEQUENCING DISSECTS INTRA-TUMOURAL GENOMIC HETEROGENEITY AND CLONAL EVOLUTION IN CHILDHOOD MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii408-iii408
Author(s):  
Marina Danilenko ◽  
Masood Zaka ◽  
Claire Keeling ◽  
Stephen Crosier ◽  
Rafiqul Hussain ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Single Cell ◽  
Genome Sequencing ◽  
Copy Number ◽  
Single Cell Analysis ◽  
Mutational Analysis ◽  
Single Cells ◽  
Clonal Evolution ◽  
Whole Genome ◽  
Clinically Significant

Abstract Medulloblastomas harbor clinically-significant intra-tumoral heterogeneity for key biomarkers (e.g. MYC/MYCN, β-catenin). Recent studies have characterized transcriptional heterogeneity at the single-cell level, however the underlying genomic copy number and mutational architecture remains to be resolved. We therefore sought to establish the intra-tumoural genomic heterogeneity of medulloblastoma at single-cell resolution. Copy number patterns were dissected by whole-genome sequencing in 1024 single cells isolated from multiple distinct tumour regions within 16 snap-frozen medulloblastomas, representing the major molecular subgroups (WNT, SHH, Group3, Group4) and genotypes (i.e. MYC amplification, TP53 mutation). Common copy number driver and subclonal events were identified, providing clear evidence of copy number evolution in medulloblastoma development. Moreover, subclonal whole-arm and focal copy number alterations covering important genomic loci (e.g. on chr10 of SHH patients) were detected in single tumour cells, yet undetectable at the bulk-tumor level. Spatial copy number heterogeneity was also common, with differences between clonal and subclonal events detected in distinct regions of individual tumours. Mutational analysis of the cells allowed dissection of spatial and clonal heterogeneity patterns for key medulloblastoma mutations (e.g. CTNNB1, TP53, SMARCA4, PTCH1) within our cohort. Integrated copy number and mutational analysis is underway to establish their inter-relationships and relative contributions to clonal evolution during tumourigenesis. In summary, single-cell analysis has enabled the resolution of common mutational and copy number drivers, alongside sub-clonal events and distinct patterns of clonal and spatial evolution, in medulloblastoma development. We anticipate these findings will provide a critical foundation for future improved biomarker selection, and the development of targeted therapies.

Cytogenetic Clonal Evolution in Chronic Myeloid Leukemia during Imatinib Mesylate Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4844-4844
Author(s):  
Hana Klamova ◽  
Jana Brezinova ◽  
Kyra Michalova ◽  
Zuzana Zemanova ◽  
Marek Trneny
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Cytogenetic Abnormalities ◽  
Ph Chromosome ◽  
Cytogenetic Evolution

Abstract Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH). Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%). Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities. A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.

scholarly journals Longitudinal cancer evolution from single cells

2020 ◽  
Author(s):  
Daniele Ramazzotti ◽  
Fabrizio Angaroni ◽  
Davide Maspero ◽  
Gianluca Ascolani ◽  
Isabella Castiglioni ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Heterogeneity ◽  
Single Cells ◽  
Clonal Evolution ◽  
Multiple Time ◽  
Cancer Evolution ◽  
Weighted Likelihood ◽  
Time Points ◽  
Single Cell Sequencing ◽  
The Impact

ABSTRACTThe rise of longitudinal single-cell sequencing experiments on patient-derived cell cultures, xenografts and organoids is opening new opportunities to track cancer evolution in single tumors and to investigate intra-tumor heterogeneity. This is particularly relevant when assessing the efficacy of therapies over time on the clonal composition of a tumor and in the identification of resistant subclones.We here introduce LACE (Longitudinal Analysis of Cancer Evolution), the first algorithmic framework that processes single-cell somatic mutation profiles from cancer samples collected at different time points and in distinct experimental settings, to produce longitudinal models of cancer evolution. Our approach solves a Boolean matrix factorization problem with phylogenetic constraints, by maximizing a weighted likelihood function computed on multiple time points, and we show with simulations that it outperforms state-of-the-art methods for both bulk and single-cell sequencing data.Remarkably, as the results are robust with respect to high levels of data-specific errors, LACE can be employed to process single-cell mutational profiles as generated by calling variants from the increasingly available scRNA-seq data, thus obviating the need of relying on rarer and more expensive genome sequencing experiments. This also allows to investigate the relation between genomic clonal evolution and phenotype at the single-cell level.To illustrate the capabilities of LACE, we show its application to a longitudinal scRNA-seq dataset of patient-derived xenografts of BRAFV600E/K mutant melanomas, in which we characterize the impact of concurrent BRAF/MEK-inhibition on clonal evolution, also by showing that distinct genetic clones reveal different sensitivity to the therapy. Furthermore, the analysis of a longitudinal dataset of breast cancer PDXs from targeted scDNA-sequencing experiments delivers a high-resolution characterization of intra-tumor heterogeneity, also allowing the detection of a late de novo subclone.

Cytogenetic Progression in Patients with Multiple Myeloma As Assessed By Serial Bone Marrow Biopsy Is Associated with Worse Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4209-4209
Author(s):  
Catherine Randall Paschal ◽  
Jens C Eickhoff ◽  
Aric C Hall ◽  
Jennifer Laffin ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
High Risk ◽  
Risk Group ◽  
Clonal Evolution ◽  
Intermediate Risk ◽  
Disease Course ◽  
Cytogenetic Abnormalities ◽  
Standard Risk

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal, mutated plasma cells, which ultimately leads to multi-organ damage and in most cases death. Despite improved treatments, clinical heterogeneity remains, with some patients succumbing to disease within 1-2 years. Certain cytogenetic and FISH abnormalities at diagnosis confer a higher likelihood of poor outcomes (Mikhael et al., 2013). Still, the utility of repeated cytogenetic assessment over the course of disease is unknown. Methods: We performed a retrospective review to identify MM patients with cytogenetics (CG) performed at diagnosis who had two or more bone marrow (BM) examinations performed during follow up over a five year period at UW Carbone Cancer Center. We reviewed the pathology and CG results from each BM sample. CG data was categorized into risk groups using the mSMART stratification criteria: High risk - deletion 17p13, t(14;16), t(14;20); intermediate risk - t(4;14), hypodiploid, deletion 13, gain of 1q21; standard risk - hyperdiploidy and all other abnormalities, and normal CG. CG progression over disease course was categorized based on stability or change in CG risk group. We measured survival from date of diagnosis to death or last follow up. Results: 130 patients with CG at diagnosis were identified over the five year period of the study. These patients had 365 follow-up bone marrow (BM) aspirates, 341 with repeat CG study. Initial cytogenetics were as follows: 90 (69%) of 130 patients had normal CG at diagnosis, 13 (10%) standard risk CG, 16 (13%) intermediate risk CG, and 11 (8%) high risk CG. Serial CG studies showed both development of new CG abnormalities in patients with previously normal studies, and clonal evolution with CG abnormal patients acquiring additional abnormalities on repeat testing. 24 (27%) of 90 patients with normal CG at diagnosis developed abnormal CG during disease course: 12 had intermediate risk CG and 9 high risk CG, the latter all due to p53 deletion. Clonal evolution and drift among initially CG abnormal patients were also common. Of the 34 patients with abnormal CG results on diagnosis and subsequent bone marrow samples, clonal evolution was identified in 19 patients (56%) and 4 (12%) patients developed new CG abnormalities unrelated to the prior clone, while 11 (32%) showed stable CG. Despite this high rate of change, only two patients with abnormal CG at diagnosis moved from a lower to a higher cytogenetic risk group. When we correlated CG at diagnosis with survival, we found that patients with high risk CG at diagnosis appeared to have shorter median overall survival at 3.8 yrs (range 1-12 yrs) compared with 7.4 yrs (range 2-12 yrs) for intermediate risk, 8.5 yrs (range 2-9 yrs) for standard risk, and 8.2 yrs (range 1-12 yrs) for normal CG. Comparison among all four groups was not statistically significant however, possibly due to the small proportion of high risk CG patients. When we examined the effect of acquiring CG abnormalities, we found that development of abnormal CG in patients with normal CG at diagnosis was associated with shorter median OS (4.0 yrs) compared to either persistent normal CG (11.3 yrs) or any CG abnormality at diagnosis (7.4 yrs), overall comparison p = 0.0048. Conclusion: Our longitudinal study of 130 unselected patients with MM revealed a cohort who showed cytogenetic progression. In patients with normal CG at diagnosis, the presence of cytogenetic abnormalities in follow-up BM specimens was associated with inferior overall survival. This finding indicates that serial testing may facilitate the detection of a higher risk patient cohort. Further analysis is underway to identify clinical parameters that underlie a higher risk of clonal evolution or development of new cytogenetic abnormalities. The results of our study will help elucidate the optimal prognostic utility of cytogenetic analysis in patient care. Disclosures No relevant conflicts of interest to declare.

scholarly journals The contribution of single-cell analysis of acute leukemia in the therapeutic strategy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lamia Madaci ◽  
Julien Colle ◽  
Geoffroy Venton ◽  
Laure Farnault ◽  
Béatrice Loriod ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Residual Disease ◽  
Single Cells ◽  
Clonal Evolution ◽  
High Rate ◽  
Leukemic Cells ◽  
Tumor Escape ◽  
Cell Analysis ◽  
Molecular Abnormalities

AbstractAfter decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.

scholarly journals Single-cell analysis based dissection of clonality in myelofibrosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Elena Mylonas ◽  
Kenichi Yoshida ◽  
Mareike Frick ◽  
Kaja Hoyer ◽  
Friederike Christen ◽  
...  
Keyword(s):  
Single Cell ◽  
Recurrent Events ◽  
Somatic Mutations ◽  
Single Cell Analysis ◽  
Clonal Evolution ◽  
Parallel Evolution ◽  
Myeloid Cell ◽  
Clonal Diversity ◽  
Multiple Time ◽  
Over Time

AbstractCancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.

scholarly journals Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyomi Morita ◽  
Feng Wang ◽  
Katharina Jahn ◽  
Tianyuan Hu ◽  
Tomoyuki Tanaka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Clonal Evolution ◽  
Evolutionary Process ◽  
Treatment Resistance ◽  
Clonal Diversity ◽  
Clonal Architecture ◽  
Acute Myeloid

AbstractClonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.

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