Single-Cell Atlas of AML Reveals Age-Related Gene Regulatory Networks in t(8;21) AML
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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 the analytic potential of comparisons of specific patient groups.
Results
We 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 exploration of the clinical importance of age in t(8;21) AML to an unprecedented level, 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 created a de-noised GRN reflecting the previously defined age-related signatures.
Conclusions
Applying integrated data analysis of the AML scAtlas, we reveal age-dependent gene regulation in t(8;21), perhaps reflecting immature/fetal HSC origin in prenatal origin disease vs postnatal origin. Our analysis revealed that BCLAF1, which is particularly enriched in t(8;21) pediatric AML 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.
