Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Clonal Evolution of Acute Myeloid Leukemia Revealed by High-Throughput Single-Cell Genomics

ABSTRACT: Clonal diversity contributes to treatment resistance and cancer recurrence. Precise delineation of clonal substructure is essential to understand the resistance mechanism, however, bulk DNA sequencing cannot accurately resolve the complex clonal architectures. Here we report the single-cell DNA sequencing of 123 acute myeloid leukemia (AML) patients and provide cell-level evidence of co-occurrence and mutual exclusivity among driver mutations. Reconstruction of tumor phylogeny uncovers linear and branching clonal evolution patterns, with the latter involving functional convergence. Single-cell DNA sequencing of xenotransplanted samples reveales clonal diversity in leukemia initiating cell populations. Simultaneous single-cell profiling of mutations and cell surface proteins provides cellular genotype-phenotype associations. Analysis of longitudinal samples visualizes the behavior of each individual clone in response to therapy, illustrating the underlying evolutionary process of therapeutic resistance and disease recurrence. Together, these data portray clonal diversity, architecture, and evolution of AML, and highlight their clinical relevance in the era of precision medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156934 | GEO | 2020/09/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Combined Functional and Genomic Single clonal Stem Cell Analysis Pinpointed at Diagnosis Leukemic Clones Responsible for Acute Myeloid Leukemia Relapse

Project description:Acute myeloid leukemia (AML) is a hematological malignancy, associated with unfavorable patient outcome primarily due to disease relapse. Since specific early leukemic hematopoietic stem and progenitor cells (HSPCs) are suggested to be responsible for AML propagation, the present study used single cell analysis (SCA) to detect and explore rare relapse-initiating HSPC clones, appearing already at diagnosis. To address inherent SCA limitations, we developed a unique high-resolution technique capable to follow single cell-derived subclones of heterogeneous HSPC subpopulations during AML evolution. Each of these subclones was evaluated for chemo-resistance, in-vivo leukemogenic potential, mutational profile, and the subclone cell of origin identified using reconstruction of phylogenetic trees. This study, employing combined functional and genomic analyses, unraveled the patient-specific HSPC subpopulations involved in chemo-resistance and determined, at time of diagnosis, the phenotype of the relapse-initiating clone, allowing early prediction of AML recurrence and suggesting novel precise therapeutic targets for relapse prevention.

2022-11-12 | E-MTAB-12238 | biostudies-arrayexpress

Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells

Project description:Persistent therapy-resistant leukemic progenitor cells (LPC) are a main cause of disease relapse and recurrence in acute myeloid leukemia (AML). Specific LPC-targeting therapies may thus improve treatment outcome of AML patients. We demonstrate that LPCs present human leukocyte antigen (HLA)-restricted cancer antigens that induce T cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach we characterized the antigenic landscape of patient LPCs and identify AML/LPC-associated HLA-presented antigens as well as mutation-derived and cryptic neoepitopes as prime targets for development of T cell-based immunotherapeutic approaches. We observed frequent spontaneous memory T cells targeting these AML/LPC-associated antigens in AML patients and showed that antigen-specific T cell recognition and HLA class II immunopeptidome diversity impacts clinical outcome. Our results pave the way for implementation of AML/LPC-associated antigens for T cell-based immunotherapeutic approaches to specifically target and eliminate residual LPCs in AML patients.

2023-08-23 | PXD038691 | Pride

Deep Learning-based Pathway-Centric approach to characterize Recurrent Hepatocellular Carcinoma after Liver Transplantation

Project description:This study analyzed the clonal evolution at the transcriptomic level during the recurrence of hepatocellular carcinoma (HCC) after liver transplantation, utilizing a rare collection of primary and recurrent tumors.

2024-06-06 | GSE249913 | GEO

A network-based approach reveals a novel mechanism of resistance to TKI-therapy in AML

Project description:Internal tandem duplications (ITDs) in the FLT3 gene are frequently identified and confer a poor prognosis in patient affected by acute myeloid leukemia (AML). The insertion site of the ITDs in FLT3 significantly impacts the sensitivity to tyrosine kinase inhibitors (TKIs) therapy, affecting patient’s clinical outcome. To decipher the molecular mechanisms driving the different sensitivity to TKIs therapy of FLT3-ITD cells, we used high-sensitive mass spectrometry-based (phospho)proteomics and deep sequencing. Here, we developed a novel generally-applicable data analysis strategy, dubbed “Signaling Profiler”, that supports the integration of unbiased large-scale datasets with literature-derived signaling networks. The approach resulted in the generation of FLT3-ITDs specific predictive models and reveales a crucial and conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase significantly synergizes and strengths the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. In conclusion, this work proposes a new molecular mechanism of TKIs resistance in AML and suggests a combination therapy as option to improve therapeutic efficacy.

2023-03-10 | PXD033953 | Pride

Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

Project description:Resistant tumours are thought to arise from the action of Darwinian selection on intratumoral genetic heterogeneity. However, clonal selection is incompatible with the late recurrence often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. In the present study, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub-population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. PA cells show reduced oestrogen receptor α activity but increased features of quiescence and migration. We find evidence for sub-clonal expression of this PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

2019-07-17 | GSE122743 | GEO

Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance [scRNA-seq]

Project description:Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the evolution of treatment resistance as we have lacked technologies to map the evolution of cancer under the selective pressures. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines that are predisposed to AraC persistence and/or resistance via upregulation of cell adhesion and motility pathways. Additionally, we highlight heritable increased expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes, and we expect this high-resolution profiling of treatment response to be a useful tool to dissect the evolution of treatment response in a wide range of tumor types.

2025-02-12 | GSE289454 | GEO

Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance [DNA-seq]

2025-02-12 | GSE289459 | GEO

Single Stem Cell Lineage Analysis of the Leukemic Clones Responsible for Acute Myeloid Leukemia Relapse Based on the Functional and Genomic Properties at Diagnosis

Project description:Single cell lineage analysis was used to assess clonal genetic heterogeneity and functional aspects of AML HSPCs derived at diagnosis and relapse. To address inherent limitations of single cell analysis, we developed a unique high-resolution technique capable of following single cell-derived subclones of different HSPC subpopulations during the AML course. Each of these subclones was evaluated for chemo-resistance, in-vivo leukemogenic potential in Nod Scid Gamma (NSG) mice, mutational profile, and the subclone cell of origin identified using retrospective cell lineage reconstruction.

2022-08-12 | E-MTAB-11884 | biostudies-arrayexpress

Genomic profiling of the FaDu cell line and derived subclones using amplicon-based targeted sequencing

Project description:Mutational profiling by targeted next-generation sequencing of a SCCHN cell line model and single-cell derived subclones displaying varying sensitivity to cisplatin was used to determine the extent of intratumoral heterogeneity and to dissect the molecular mechanisms involved in primary cisplatin resistance and treatment-induced clonal evolution.

2017-12-04 | E-MTAB-6021 | biostudies-arrayexpress

Genotyping of human AMP patients using 27 pairs of diagnostic and relapsed AML samples

Project description:Relapse is the commonest cause of death in acute myeloid leukaemia (AML), but the mechanisms leading to relapse are unclear. Recently, acquisition of segmental uniparental disomy (UPD) by mitotic recombination (MR) has been reported in 15-20% of AML samples at diagnosis using whole genome single nucleotide polymorphism (SNP) arrays. These cytogenetically invisible abnormalities are associated with homozygous mutations in several types of malignancy. Clonal evolution of heterozygous to homozygous mutations by MR could provide a mechanism for relapse. Experiment Overall Design: DNA from 27 pairs of diagnostic and relapsed AML samples were analysed using Affymetrix 10K SNP arrays. The genotype data of relapsed AML were compared with the data from the corresponding presentation AML.

2008-06-15 | E-GEOD-7210 | biostudies-arrayexpress

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