Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.

ABSTRACT: Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.

SUBMITTER: Hoell JI

PROVIDER: S-EPMC6849953 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Clinical and biological predictors of outcome following relapse of CML post-allo-SCT.

Project description:Although there are now fewer allo-SCTs performed for CML, leukemic relapse post transplant remains a persistent problem. To better define clinical and biological parameters determining postrelapse outcome, we studied 59 patients with CML relapsing after HLA-identical sibling allo-SCT between 1993 and 2008. Eighteen (30.5%) were transplanted in advanced phase and 41 (69.5%) in chronic phase. With a median follow-up from relapse of 7.9 years, 5-year post relapse survival (PRS) was 62%. Multivariate analysis found disease status at transplant, time to diagnosis of relapse from transplant and pretransplant tyrosine kinase inhibitor (TKI) use as significant factors associated with PRS. Analysis of BCR-ABL transcript expression in the hematopoietic progenitor compartment was performed in 36 patients (22 relapsed, 8 non-relapsed and 6 TKI alone controls). Patients with BCR-ABL expression in their early hematopoietic stem cell compartment (Lineage(-)CD34(+)CD38(-)CD90(+)) had worse survival irrespective of the disease status. We conclude that disease status remains the strongest clinical prognostic factor for PRS in CML following allo-SCT. The persistence of BCR-ABL expression in the progenitor cell compartment in some patients after SCT emphasizes the need to target CML-leukemia stem cells.

| S-EPMC4318796 | biostudies-literature

Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution.

Project description:The mechanisms underlying T-ALL relapse remain essentially unknown. Multilevel-omics in 38 matched pairs of initial and relapsed T-ALL revealed 18 (47%) type-1 (defined by being derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). In both types of relapse, we observed known and novel drivers of multidrug resistance including MDR1 and MVP, NT5C2 and JAK-STAT activators. Patients with type-1 relapses were specifically characterized by IL7R upregulation. In remarkable contrast, type-2 relapses demonstrated (1) enrichment of constitutional cancer predisposition gene mutations, (2) divergent genetic and epigenetic remodeling, and (3) enrichment of somatic hypermutator phenotypes, related to BLM, BUB1B/PMS2 and TP53 mutations. T-ALLs that later progressed to type-2 relapses exhibited a complex subclonal architecture, unexpectedly, already at the time of initial diagnosis. Deconvolution analysis of ATAC-Seq profiles showed that T-ALLs later developing into type-1 relapses resembled a predominant immature thymic T-cell population, whereas T-ALLs developing into type-2 relapses resembled a mixture of normal T-cell precursors. In sum, our analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia.

| S-EPMC9252914 | biostudies-literature

Behavioural individuality determines infection risk in clonal ant colonies.

Project description:In social groups, infection risk is not distributed evenly across individuals. Individual behaviour is a key source of variation in infection risk, yet its effects are difficult to separate from other factors (e.g., age). Here, we combine epidemiological experiments with chemical, transcriptomic, and automated behavioural analyses in clonal ant colonies, where behavioural individuality emerges among identical workers. We find that: (1) Caenorhabditis-related nematodes parasitise ant heads and affect their survival and physiology, (2) differences in infection emerge from behavioural variation alone, and reflect spatially-organised division of labour, (3) infections affect colony social organisation by causing infected workers to stay in the nest. By disproportionately infecting some workers and shifting their spatial distribution, infections reduce division of labour and increase spatial overlap between hosts, which should facilitate parasite transmission. Thus, division of labour, a defining feature of societies, not only shapes infection risk and distribution but is also modulated by parasites.

| S-EPMC10460416 | biostudies-literature

The emergence and development of behavioral individuality in clonal fish.

Project description:Behavioral individuality is a ubiquitous phenomenon in animal populations, yet the origins and developmental trajectories of individuality, especially very early in life, are still a black box. Using a high-resolution tracking system, we mapped the behavioral trajectories of genetically identical fish (Poecilia formosa), separated immediately after birth into identical environments, over the first 10 weeks of their life at 3 s resolution. We find that (i) strong behavioral individuality is present at the very first day after birth, (ii) behavioral differences at day 1 of life predict behavior up to at least 10 weeks later, and (iii) patterns of individuality strengthen gradually over developmental time. Our results establish a null model for how behavioral individuality can develop in the absence of genetic and environmental variation and provide experimental evidence that later-in-life individuality can be strongly shaped by factors pre-dating birth like maternal provisioning, epigenetics and pre-birth developmental stochasticity.

| S-EPMC9616841 | biostudies-literature

Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure.

Project description:The prevalence of high blood pressure (also known as hypertension) has steadily increased over the last few decades. Known as a silent killer, hypertension increases the risk for cardiovascular disease and can lead to stroke, heart attack, kidney failure and associated sequela. While numerous hypertensive therapies are currently available, it is estimated that only half of medicated patients exhibit blood pressure control. This signifies the need for a better understanding of the underlying cause of disease and for more effective therapies. While blood pressure homeostasis is very complex and involves the integrated control of multiple body systems, smooth muscle contractility and arterial resistance are important contributors. Strong evidence from pre-clinical animal models and genome-wide association studies indicate that smooth muscle contraction and BP homeostasis are governed by the small GTPase RhoA and its downstream target, Rho kinase. In this review, we summarize the signaling pathways and regulators that impart tight spatial-temporal control of RhoA activity in smooth muscle cells and discuss current therapeutic strategies to target these RhoA pathway components. We also discuss known allelic variations in the RhoA pathway and consider how these polymorphisms may affect genetic risk for hypertension and its clinical manifestations.

| S-EPMC7235948 | biostudies-literature

Behavioural individuality in clonal fish arises despite near-identical rearing conditions.

Project description:Behavioural individuality is thought to be caused by differences in genes and/or environmental conditions. Therefore, if these sources of variation are removed, individuals are predicted to develop similar phenotypes lacking repeatable individual variation. Moreover, even among genetically identical individuals, direct social interactions are predicted to be a powerful factor shaping the development of individuality. We use tightly controlled ontogenetic experiments with clonal fish, the Amazon molly (Poecilia formosa), to test whether near-identical rearing conditions and lack of social contact dampen individuality. In sharp contrast to our predictions, we find that (i) substantial individual variation in behaviour emerges among genetically identical individuals isolated directly after birth into highly standardized environments and (ii) increasing levels of social experience during ontogeny do not affect levels of individual behavioural variation. In contrast to the current research paradigm, which focuses on genes and/or environmental drivers, our findings suggest that individuality might be an inevitable and potentially unpredictable outcome of development.

| S-EPMC5442312 | biostudies-literature

Druggable Targets in Endocannabinoid Signaling.

Project description:Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2-arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling. This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.

| S-EPMC7811746 | biostudies-literature

Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics.

Project description:Given age-related differences in drug metabolism and indications for hematopoietic SCT (HSCT), personalized drug dosing of the conditioning regimen and post-transplant immunosuppression may reduce graft rejection, relapse rates and toxicity in pediatric HSCT recipients. This manuscript summarizes the pharmacokinetic/dynamic data of HSCT conditioning and post-grafting immunosuppression, presented at the First Annual Pediatric Bone Marrow Transplant Consortium (PBMTC) meeting in April 2013. Personalized dosing of BU to a target plasma exposure reduces graft rejection in children and improves relapse/toxicity rates in adults. Current weight-based dosing achieves the target BU exposure in only a minority (24.3%) of children. The initial BU dose should be based on the European Medicines Agency nomogram or population pharmacokinetic models to improve the numbers of children achieving the target exposure. There are limited pharmacokinetic data for treosulfan, CY, fludarabine and alemtuzumab as HSCT conditioning in children. For post-grafting immunosuppression, mycophenolic acid (MPA) clearance may be increased in younger children (<12 years). The preferred MPA pharmacokinetic monitoring parameters and target range are still evolving in HSCT recipients. Multi-institutional trials incorporating properly powered pharmacokinetic/dynamic studies are needed to assess the effect of variability in the plasma exposure of drugs/metabolites on clinical outcomes in pediatric HSCT recipients.

| S-EPMC5996991 | biostudies-other

Pre-transplantation iron chelation in patients with MDS or acute leukemia and iron overload undergoing myeloablative allo-SCT.

Project description: Not available

| S-EPMC3954511 | biostudies-literature

Therapy-Acquired Clonal Mutations in Thiopurine Drug-Response Genes Drive Majority of Early Relapses in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.

Project description:MethodsForty pediatric (0-12 years) B-ALL DNA samples (20 paired Diagnosis-Relapse) and an additional six B-ALL DNA samples (without relapse at 3 years post treatment), as the non-relapse arm, were retrieved from the biobank for advanced genomic analysis. Deep sequencing (1050-5000X; mean 1600X) was performed using a custom NGS panel of 74 genes incorporating unique molecular barcodes.ResultsA total 47 major clones (>25% VAF) and 188 minor clones were noted in 40 cases after bioinformatic data filtering. Of the forty-seven major clones, eight (17%) were diagnosis-specific, seventeen (36%) were relapse-specific and 11 (23%) were shared. In the control arm, no pathogenic major clone was noted in any of the six samples. The most common clonal evolution pattern observed was therapy-acquired (TA), with 9/20 (45%), followed by M-M, with 5/20 (25%), m-M, with 4/20 (20%) and unclassified (UNC) 2/20 (10%). The TA clonal pattern was predominant in early relapses 7/12 (58%), with 71% (5/7) having major clonal mutations in the NT5C2 or PMS2 gene related to thiopurine-dose response. In addition, 60% (3/5) of these cases were preceded by an initial hit in the epigenetic regulator, KMT2D. Mutations in common relapse-enriched genes comprised 33% of the very early relapses, 50% of the early and 40% of the late relapses. Overall, 14/46 (30%) of the samples showed the hypermutation phenotype, of which the majority (50%) had a TA pattern of relapse.ConclusionsOur study highlights the high frequency of early relapses driven by TA clones, demonstrating the need to identify their early rise during chemotherapy by digital PCR.

| S-EPMC10001400 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data