Detecting and quantifying clonal selection in somatic stem cells
Verena KörberNaser Ansari‐PourNiels Asger JakobsenRachel MooreNina ClaudinoMarlen MetznerF HorschBatchimeg UsukhbayarMirian Angulo SalazarSimon P. NewmanBenjamin KendrickAdrian TaylorRasheed Afinowi-LuitzRoger GundleBridget WatkinsKim WhewayDebra BeazleyStephanie G. DakinAndrew CarrParesh VyasThomas Höfer
1
Citation
66
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the underlying driver event. Moreover, SCIFER infers the self-renewal and mutation dynamics of the tissue’s stem cells, and, if selection is present, the size and growth rate of the largest selected clone. We benchmark SCIFER with published data and then probe bone marrow of 22 non-leukemic individuals for clonal hematopoiesis (CH), identifying CH with known and unknown driver events. Unexpectedly, we find accelerated division of all stem cells in CH, compared to age-matched non-CH individuals, suggesting that the bone marrow environment alters stem cell dynamics in individuals with CH. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection.Keywords:
clone (Java method)
Negative selection
clone (Java method)
Cite
Citations (1)
Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10(-3) vs. 0.13 × 10(-3); p =0.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.
clone (Java method)
Malignant Transformation
Cite
Citations (32)
The introduction of next generation sequencing technology has greatly broadened our view on the genetic landscape of hematological malignancies. The first comprehensive experiment of acute myeloid leukemia(AML) using genome-wide analysis has also shed light on the clonal evolution of AML, which seems to have been underestimated. It is now possible to precisely define clonal size and selection at different stages. This approach demonstrated that AML at diagnosis is either monoclonal or oligoclonal, harboring a selected number of genetically defined subclones. Furthermore, targeted deep sequencing of diagnosis and relapse pairs revealed that founding clones or subclones present at diagnosis obtain some additional mutations that contribute to clonal expansion and/or chemoresistance. Some subclones may be eradicated by treatment, whereas others are resistant to chemotherapeutic agents and ultimately grow out. The molecular heterogeneity in AML will have a great impact on the development of targeted therapies.
Cite
Citations (0)
The clonal selection principle explains the basic features of an adaptive immune response to a antigenic stimulus. It established the idea that only those cells that recognize the antigens are selected to proliferate and differentiate. This paper explains a computational implementation of the clonal selection principle that explicitly takes into account the affinity maturation of the immune response. The clonal selection algorithm in this paper finds the antigen by the 3 kinds of combination types of Immunological Memory cells and the proliferation of immune cells. This paper tried to classify the medical database of Heart Disease database in the the UCI Repository.
Negative selection
Clonal selection algorithm
Immunological memory
Clonal deletion
Cite
Citations (2)
The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy.
clone (Java method)
Univariate analysis
Cite
Citations (4)
clone (Java method)
Cite
Citations (0)
Clonal Selection Theory indicates that only the highest affinity cells are selected to proliferate by cloning. Unlike the constant clone population in CIONALG, we propose a novel algorithm based on dynamic clone population. The novel algorithm dynamically updates the clone population by replacing low affinity cells with high affinity ones. Simulation results show that the novel algorithm has effective learning abilities and better performance when compared to CLONALG for noisy pattern recognition.
clone (Java method)
Cloning (programming)
Cite
Citations (2)
Multicellular organism
Cite
Citations (3)
clone (Java method)
Minimal Residual Disease
Cite
Citations (1)
SUMMARY Serial haematopathological and cytogenetic studies disclosed three distinct clinical phases in a case of refractory anaemia (RA), a subtype of myelodysplastic syndrome (MDS; FAB group, 1982): first, chronic MDS phase (1 year 10 months) with karyotypic abnormality (45, XY, –7) (Clone I); second, hypo‐aplastic phase concurrent with first clonal evolution (45, XY, –7, 12p –) (Clone II); third, acute myelomonocytic leukaemia phase (6 months) with second clonal evolution (45, XY, ‐ 7, t (lq‐; Bq +), Bq ‐, 12p ‐) (Clone III). In the second phase the bone marrow became almost aplastic as Clone II expanded progressively, indicating simultaneous occurrence in Clone II stem cells of growth advantage for self‐renewal function over Clone I and normal stem cells, and arrest of differentiation. These observations support the hypothesis that leukaemic change in MDS, at least in RA, occurs by stepwise clonal evolution(s), not by progressive arrest of differentiation in original MDS clone.
clone (Java method)
Acute myelomonocytic leukemia
Chronic myelomonocytic leukemia
Bone Marrow Aplasia
Aplastic anemia
Bone marrow failure
Cite
Citations (25)