Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity
Open accessAbstract
Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies. VIDEO ABSTRACT.
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TP53-sAML differed from de novo AML with an enrichment into HSC and early erythroid populations, whereas de novo AML was enriched in myeloid progenitors.
“TP53-sAML differed from de novo AML with an enrichment into HSC and early erythroid populations, whereas de novo AML was enriched in myeloid progenitors (Fig. 2c,d)25.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [25]
The Results section on AML cellular hierarchies links clusters enriched for TP53 mutations to differing cell compositions, but does not compare TP53-associated secondary AML with de novo AML. Searches for secondary AML, early erythroid populations, and de novo AML with myeloid progenitors found no passage establishing the claimed contrast. The indexed passages provide no page numbers. (LLM, conf=0.73)
Experimental — accuracy not yet measuredOther studies mapped cells to known reference cell types or states, using only marker genes.
“Alternatively cells were mapped to known reference cell (sub)types or states4,5,11,12, making effective use only of cell-state or cell-type specific marker genes.”
From Targeted Perturb-seq enables genome-scale genetic screens in single cells (2020) · cites this paper as [11]
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- Authors
- van Galen, P., Hovestadt, V., Wadsworth II, M. H., Hughes, T. K., Griffin, G. K., Battaglia, S., Verga, J. A., Stephansky, J., Pastika, T. J., Lombardi Story, J., Pinkus, G. S., Pozdnyakova, O., Galinsky, I., Stone, R. M., Graubert, T. A., Shalek, A. K., Aster, J. C., Lane, A. A., & Bernstein, B. E.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Corresponding author
- Bernstein, Bradley E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 176
- Issue
- 6
- Pages
- 1265-1281.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6515904
- OpenAlex
- W2916458303
- Cited by
- 1,164
- References
- 38
- Citations by year
- 2026: 151 · 2025: 189 · 2024: 168 · 2023: 175 · 2022: 165 · 2021: 156 · 2020: 127 · 2019: 31 · 2018: 1
- FWCI
- 87.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- NCI
- Leukemia & Lymphoma Society
- HFSP
- EMBO
- Searle Scholars Program
- Beckman Young Investigator Program
- Pew-Stewart Scholars Program
- Sloan Fellowship
- Bill and Melinda Gates Foundation
- NIH
- Doris Duke Charitable Foundation
- NHGRI
- Ludwig Center
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- acute myeloid leukemia, tumor heterogeneity, FLT3-ITD, progenitor-like cells, stemness genes, immunomodulatory genes, T cell suppression, tumor microenvironment, subclonal heterogeneity, prognostic gene signature, bone marrow, single-cell atlas
- MeSH terms
- Machine Learning, Exome Sequencing, Adult, Base Sequence, Bone Marrow, Bone Marrow Cells, Female, Genotype, Humans, Male, Middle Aged, Mutation, Prognosis, RNA, Signal Transduction, Leukemia, Myeloid, Acute, Disease Progression, Cell Line, Tumor, Single-Cell Analysis, Tumor Microenvironment, Transcriptome
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