Single-cell transcriptional mapping reveals genetic and non-genetic determinants of aberrant differentiation in AML

Abstract

Initial classification of acute leukemia involves the assignment of blasts to cell states within the hematopoietic hierarchy based on morphological and immunophenotypic features. Yet, these traditional classification approaches lack precision, especially at the level of immature blasts. Single-cell RNA-sequencing (scRNA-seq) enables precise determination of cell state using thousands of markers, thus providing an opportunity to re-examine present-day classification schemes of acute leukemia. Here, we developed a detailed reference map of human bone marrow hematopoiesis from 263,519 single-cell transcriptomes spanning 55 cellular states. Cell state annotations were benchmarked against purified cell populations, and in-depth characterization of gene expression programs underlying hematopoietic differentiation was undertaken. Projection of single-cell transcriptomes from 175 samples spanning acute myeloid leukemia (AML), mixed phenotype acute leukemia (MPAL), and acute erythroid leukemia (AEL) revealed 11 subtypes involving distinct stages of hematopoietic differentiation. These included AML subtypes with notable lymphoid or erythroid lineage priming, challenging traditional diagnostic boundaries between AML, MPAL, and AEL. Quantification of lineage priming in bulk patient cohorts revealed specific genetic alterations associated with this unconventional lineage priming. Integration of transcriptional and genetic information at the single-cell level revealed how genetic subclones can induce lineage restriction, differentiation blocks, or expansion of mature myeloid cells. Furthermore, we demonstrate that distinct cellular hierarchies can co-exist within individual patients, providing insight into AML evolution in response to varying selection pressures. Together, precise mapping of hematopoietic cell states can serve as a foundation for refining disease classification in acute leukemia and understanding response or resistance to emerging therapies.

The Single-cell Pediatric Cancer Atlas: Data portal and open-source tools for single-cell transcriptomics of pediatric tumors

“…The Portal contains data from over 500 samples and over 50 tumor types [ 25,26,27,28,29,30,31 ]. Figure 1A summarizes all samples from patient tumors and patient-derived xenografts currently available on the Portal.…”

Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression

“…Recent ground-breaking studies exploring single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics have facilitated a comprehensive exploration of the intricate landscape of heterogeneous stromal populations within BM [79], illustrating how they are reprogramed by AML blasts [83,[98][99][100]. This has indeed been a hot topic in the quest to develop niche targeting therapies for LSC eradication.…”