Systematic analysis of hematopoietic gene expression profiles for prognostic prediction in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a hematopoietic disorder initiated by the leukemogenic transformation of myeloid cells into leukemia stem cells (LSCs). Preexisting gene expression programs in LSCs can be used to assess their transcriptional similarity to hematopoietic cell types. While this relationship has previously been examined on a small scale, an analysis that systematically investigates this relationship throughout the hematopoietic hierarchy has yet to be implemented. We developed an integrative approach to assess the similarity between AML patient tumor profiles and a collection of 232 murine hematopoietic gene expression profiles compiled by the Immunological Genome Project. The resulting lineage similarity scores (LSS) were correlated with patient survival to assess the relationship between hematopoietic similarity and patient prognosis. This analysis demonstrated that patient tumor similarity to immature hematopoietic cell types correlated with poor survival. As a proof of concept, we highlighted one cell type identified by our analysis, the short-term reconstituting stem cell, whose LSSs were significantly correlated with patient prognosis across multiple datasets, and showed distinct patterns in patients stratified by traditional clinical variables. Finally, we validated our use of murine profiles by demonstrating similar results when applying our method to human profiles.