Single-Cell Atlas of AML Reveals Age-Related Gene Regulatory Networks in t(8;21) AML DOI Open Access
Jessica S. Whittle, Stefan Meyer, Georges Lacaud

et al.

Published: May 15, 2025

Abstract Background Acute myeloid leukemia (AML) is characterized by cellular and genetic heterogeneity, which correlates with clinical course. Although single-cell RNA sequencing (scRNA-seq) reflect this diversity to some extent, the low sample numbers in individual studies limit analytic potential of comparisons specific patient groups. Results We performed large scale integration published scRNA-seq datasets create a unique transcriptomic atlas for AML (AML scAtlas), totaling 748,679 cells, from 159 patients 44 healthy donors 20 different studies. This largest data resource our knowledge, publicly available at https://cellxgene.bmh.manchester.ac.uk/AML/. scAtlas, allowed exploration importance age t(8;21) an unprecedented level, given in-utero origin pediatric disease. uncovered age-associated gene regulatory network (GRN) signatures, we validated using bulk delineate distinct groups divergent biological characteristics. Furthermore, additional multiomic dataset (scRNA-seq scATAC-seq), created de-noised GRN reflecting previously defined age-related signatures. Conclusions Applying integrated analysis reveal age-dependent regulation t(8;21), perhaps immature/fetal HSC prenatal disease vs postnatal origin. Our revealed that BCLAF1, particularly enriched inferred origin, promising prognostic indicator. The scAtlas provides powerful investigate molecular mechanisms underlying subtypes.

Language: Английский

Massively parallel base editing to map variant effects in human hematopoiesis DOI Creative Commons
Jorge D. Martin-Rufino,

Nicole Castano,

Michael Pang

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(11), P. 2456 - 2474.e24

Published: May 1, 2023

Systematic evaluation of the impact genetic variants is critical for study and treatment human physiology disease. While specific mutations can be introduced by genome engineering, we still lack scalable approaches that are applicable to important setting primary cells, such as blood immune cells. Here, describe development massively parallel base-editing screens in hematopoietic stem progenitor Such enable functional variant effects across any differentiation state. Moreover, they allow rich phenotyping through single-cell RNA sequencing readouts separately characterization editing outcomes pooled genotyping. We efficiently design improved leukemia immunotherapy approaches, comprehensively identify non-coding modulating fetal hemoglobin expression, define mechanisms regulating differentiation, probe pathogenicity uncharacterized disease-associated variants. These strategies will advance effective high-throughput variant-to-function mapping hematopoiesis causes diverse diseases.

Language: Английский

Citations

83
Profiling cell identity and tissue architecture with single-cell and spatial transcriptomics DOI
Gunsagar S. Gulati,

Jeremy Philip D’Silva,

Yunhe Liu

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 26(1), P. 11 - 31

Published: Aug. 21, 2024

Language: Английский

Citations

34
Mitochondrial genetics through the lens of single-cell multi-omics DOI
Lena Nitsch,

Caleb A Lareau,

Leif S Ludwig

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(7), P. 1355 - 1365

Published: July 1, 2024

Language: Английский

Citations

18
Multi-omics advances for molecular characterization, precision medicine, and prognostic implications in leukemia DOI Creative Commons

Shangyu Hou,

Junya Liu,

Yinghui Zhu

et al.

Cell investigation., Journal Year: 2025, Volume and Issue: 1(1), P. 100007 - 100007

Published: Jan. 30, 2025

Language: Английский

Citations

4
Targeting cancer cell dormancy DOI
Judith Agudo, Julio A. Aguirre‐Ghiso, Mickie Bhatia

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 24(2), P. 97 - 104

Published: Dec. 7, 2023

Language: Английский

Citations

23
Integrative genotyping of cancer and immune phenotypes by long-read sequencing DOI Creative Commons
Livius Penter, Mehdi Borji, Adi Nagler

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract Single-cell transcriptomics has become the definitive method for classifying cell types and states, can be augmented with genotype information to improve lineage identification. Due constraints of short-read sequencing, current methods detect natural genetic barcodes often require cumbersome primer panels early commitment targets. Here we devise a flexible long-read sequencing workflow analysis pipeline, termed nanoranger , that starts from intermediate single-cell cDNA libraries lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences chimeric antigen TCRs. Through systematic these classes ‘barcodes’, define optimal targets nanoranger, namely those loci close 5’ end highly expressed genes transcript lengths shorter than 4 kB. As proof-of-concept, apply longitudinal tracking subclones acute myeloid leukemia (AML) describe heterogeneous isoform landscape thousands marrow-infiltrating immune cells. We propose enhanced cellular genotyping using tumor co-evolution.

Language: Английский

Citations

12
Flow cytometry evaluation of acute myeloid leukemia minimal residual disease based on an understanding of the normal maturation patterns in the blast compartments DOI
Mikhail Roshal, Qi Gao

American Journal of Clinical Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Detection of minimal/measurable disease (MRD) in acute myeloid leukemia (AML) is critical for both clinical decision-making and prognostication, yet remains a challenge. Flow cytometry well-established method MRD detection. cytometric (FC) evaluation must consider complex maturational pattern normal hematopoietic development to separate from abnormal progenitors. Here, we offer an example interpretive approach based on thorough understanding stage- lineage-specific maturation. We provide comprehensive overview blast maturation early precursors (hematopoietic stem cells) committed late-stage unilineage progenitors commonly observed stage-specific abnormalities cases have encountered practice. emphasize the importance comparisons accurate detection by flow cytometry. The AML blasts almost invariably show phenotypes, phenotypes may evolve upon therapy. detected are necessarily confined target antigens included panel. It therefore evaluate range establish specific stage/state lineage commitment detect potential common abnormalities. Moreover, enough cells be acquired allow at desired levels. Significant technical analytical validation critical. offers powerful single-cell-based platform AML, results been proven management. Leukemia-associated phenotype-informed difference presented this review presents framework sensitive

Language: Английский

Citations

1
A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML DOI Creative Commons
Lanpeng Chen, Eline Pronk, Claire van Dijk

et al.

Blood Cancer Discovery, Journal Year: 2023, Volume and Issue: 4(5), P. 394 - 417

Published: July 19, 2023

Abstract Cancer initiation is orchestrated by an interplay between tumor-initiating cells and their stromal/immune environment. Here, adapted single-cell RNA sequencing, we decipher the predicted signaling tissue-resident hematopoietic stem/progenitor (HSPC) neoplastic counterparts with native niches in human bone marrow. LEPR+ stromal are identified as central regulators of hematopoiesis through interactions all Inflammatory niche remodeling resulting deprivation critical HSPC regulatory factors to repress high-output stem cell subsets NPM1-mutated acute myeloid leukemia (AML), relative resistance clonal cells. Stromal gene signatures reflective associated reduced relapse rates favorable outcomes after chemotherapy across genetic risk categories. Elucidation intercellular defining AML, thus, predicts that inflammatory drives tissue repression selection but may pose a vulnerability for relapse-initiating context chemotherapeutic treatment. Significance: Tumor-promoting inflammation considered enabling characteristic tumorigenesis, mechanisms remain incompletely understood. By deciphering environment, identify determinant normal clinical AML. See related commentary Lisi-Vega Méndez-Ferrer, p. 349. This article featured Selected Articles from Issue, 337

Language: Английский

Citations

18
Application of single-cell sequencing to the research of tumor microenvironment DOI Creative Commons
Sijie Chen, Zhiqing Zhou, Yu Li

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 27, 2023

Single-cell sequencing is a technique for detecting and analyzing genomes, transcriptomes, epigenomes at the single-cell level, which can detect cellular heterogeneity lost in conventional hybrid samples, it has revolutionized our understanding of genetic complexity tumor progression. Moreover, microenvironment (TME) plays crucial role formation, development response to treatment tumors. The application ushered new age TME analysis, revealing not only blueprint pan-cancer immune microenvironment, but also differentiation routes cells, as well predicting prognosis. Thus, combination analysis provides unique opportunity unravel molecular mechanisms underlying In this review, we summarize recent advances highlighting their potential applications cancer research clinical translation.

Language: Английский

Citations

17
Somatic epimutations enable single-cell lineage tracing in native hematopoiesis across the murine and human lifespan DOI Creative Commons
Michael Scherer, Indranil Singh, M Braun

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 1, 2024

Summary Current approaches to lineage tracing of stem cell clones require genetic engineering or rely on sparse somatic DNA variants, which are difficult capture at single-cell resolution. Here, we show that targeted measurements methylation single-CpG resolution deliver joint information about cellular differentiation state and clonal identities. We develop EPI-clone, a droplet-based method for transgene-free tracing, apply it study hematopoiesis, capturing hundreds trajectories across almost 100,000 single-cells. Using ground-truth barcodes, demonstrate EPI-clone accurately identifies lineages throughout hematopoietic differentiation. Applied unperturbed describe an overall decline complexity during murine ageing the expansion rare low-output clones. In aged human donors, identified expanded with without lesions, various degrees complexity. Taken together, enables accurate scale.

Language: Английский

Citations

8