Deconvoluting clonal and cellular architecture in IDH-mutant Acute Myeloid Leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA961765 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32506565.fastq.gz | Fastqsanger.gz | |||
| SRR32506566.fastq.gz | Fastqsanger.gz | |||
| SRR32506567.fastq.gz | Fastqsanger.gz | |||
| SRR32506568.fastq.gz | Fastqsanger.gz |
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Project description:Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.
2025-05-21 | GSE230559 | GEO
Project description:Little is known of the genetic architecture of cancer at the subclonal and single cell level or in the stem-like cells responsible for cancer clone maintenance and propagation. We have examined this issue in ALL in which ETV6-RUNX1 gene fuson is an early or initiating genetic lesion followed by a modest number of driver copy number alterations. By multiplexing FISH probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of sub-clones identified and a composite picture of sub-clonal architecture and putative ancestral trees assembled. Sub-clones in ALL have variegated genetics and complex, non-linear or branching evolutionary histories. CNA are independently and recurrently acquired in sub-clones of individual patients, and in no preferential order. Clonal architecture is dynamic and changes in the lead up to a diagnosis and in relapse. Leukaemic stem cells, assayed by transplantation in NOD/SCID IL2Rgamma deficient mice, are also genetically variegated, mirroring sub-clonal patterns. These findings have significant implications for the cancer stem cell concept, for interpretation of cancer genome data and for therapeutic targetting in cancer. Mononuclear cells were isolated at diagnosis of ALL for patient #3 and #7. Transplantation of 2 000 - 2 000 000 unsorted leukaemia cells was performed by intra-tibial injection into 7 - 14 week old NOD/SCID IL2Rgamma deficient mice. Mice were sacrificed when peripheral blood engraftment was >2%. An equivalent of 2 000 - 200 000 CD45 cells were used for serial transplantation. DNA was extracted from mononuclear cells at initial diagnosis and after second transplantation. Copy number analysis of Affymetrix 500K SNP arrays was performed in CNAG 3.0 for patients #3 and #7 at initial diagnosis and after second transplantation. Reference files were 9 samples from leukemia in remission.
2010-12-16 | E-GEOD-24412 | biostudies-arrayexpress
Project description:RNA-sequencing for myeloid inflammation-related genes was conducted on primary tumor samples from patients with IDH-wildtype glioblastoma (GBM) and grade 4 IDH-mutant astrocytoma (G4IMA). In addition, the IDH-wildtype murine glioma cell line GL261 and a strain of IDH-mutant GL261 were also sequenced using the murine counterpart of the RNA-sequencing myeloid innate immunity panel.
2024-05-29 | GSE268118 | GEO
Project description:Little is known of the genetic architecture of cancer at the subclonal and single cell level or in the stem-like cells responsible for cancer clone maintenance and propagation. We have examined this issue in ALL in which ETV6-RUNX1 gene fuson is an early or initiating genetic lesion followed by a modest number of driver copy number alterations. By multiplexing FISH probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of sub-clones identified and a composite picture of sub-clonal architecture and putative ancestral trees assembled. Sub-clones in ALL have variegated genetics and complex, non-linear or branching evolutionary histories. CNA are independently and recurrently acquired in sub-clones of individual patients, and in no preferential order. Clonal architecture is dynamic and changes in the lead up to a diagnosis and in relapse. Leukaemic stem cells, assayed by transplantation in NOD/SCID IL2Rgamma deficient mice, are also genetically variegated, mirroring sub-clonal patterns. These findings have significant implications for the cancer stem cell concept, for interpretation of cancer genome data and for therapeutic targetting in cancer.
2010-12-16 | GSE24412 | GEO
Project description:Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening.
2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress
Project description:BackgroundThe myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.MethodsWe performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.ResultsApproximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.ConclusionsNearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.).
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Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
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Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling, respectively. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for blocking functional differentiation in IDH-mutant gliomas to be causally related to enhanced metabolization of tryptophan to kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR), leading to a time-dependent uptake of extracellular tryptophan via LAT1-CD98 by intratumoral myeloid cells. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacologic inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent dynamic network of resident and recruited intratumoral myeloid cells shaping the immune microenvironment of IDH-mutant HGG and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166418 | GEO
Project description: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.
2020-09-08 | GSE156934 | GEO