The cellular state space of AML unveils novel NPM1 subtypes with distinct clinical outcomes and immune evasion properties

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Abstract Acute myeloid leukemia (AML) is a genetically and cellularly heterogeneous disease. We characterized 120 AMLs using genomic and transcriptomic analyses, including single-cell RNA sequencing. Our results reveal an extensive cellular heterogeneity that distorts the bulk transcriptomic profiles. Selective examination of the transcriptional signatures of >90,000 immature AML cells identified four main clusters, thereby extending current genomic classification of AML. Notably, NPM1 mutated AML could be stratified into two novel, clinically relevant classes, with NPM1 class I associated with downregulation of MHC class II and excellent survival following hematopoietic stem cell transplantation (HSCT). NPM1 class II was instead associated with resistance to allogeneic T cells in an ex vivo co culture assay, and importantly, dismal survival following HSCT. These findings provide new insights into the cellular state space of AML, define new diagnostic entities, and highlight potential therapeutic intervention points. Key Points The bulk transcriptional profiles of AML are mainly driven by a diverse set of cellular signatures. Single cell RNA-sequencing of the most common AML subtypes reveals marked heterogeneity extending beyond current genomic classification schemes. NPM1 -mutated AML can be divided into two new classes, with distinct immune evasion mechanisms and survival after transplantation.

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