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bioRxiv · 10.1101/2024.10.29.620871

Single-Cell Atlas of AML Reveals Age-Related Gene Regulatory Networks in t(8;21) AML

Whittle, J.·Meyer, S.·Lacaud, G.·Baker, S. M.·Iqbal, M.
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Abstract

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

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Whittle, J., Meyer, S., Lacaud, G., Baker, S. M., Iqbal, M.. 2024-11-03. Single-Cell Atlas of AML Reveals Age-Related Gene Regulatory Networks in t(8;21) AML. https://doi.org/10.1101/2024.10.29.620871

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