A gene signature derived from leukemia associated macrophages provides a compelling risk stratification for human AML patients

In a mouse model of FGFR1-driven leukemia, we demonstrated a role for circulating non-conventional monocyte-derived macrophages in the peripheral blood, which suppressed T-cell function and promoted leukemogenesis. A single cell RNA sequencing (scRNA-Seq) analysis of these leukemia-associated macrophages (LAMs) identified LAM-specific dysregulation of gene expression associated with leukemogenesis. Based on the top markers identified in these LAMs, we generated a LAM score based on the expression levels of a 32 gene signature. This scoring system was then applied to the transcriptomic data from a cohort of 838 newly diagnosed patients treated on Alliance/CALGB protocols, who were similarly treated with intensive cytarabine/daunorubicin-based chemotherapy on the CALGB/Alliance for the Clinical Trials in Oncology protocol. Patients were subclassified as those with high and low LAM scores. Patients with a high LAM score had shorter overall survival, disease-free survival and event-free survival compared to those with a low LAM score. We also noted a strong association of FLT3-ITD, RUNX1 and TP53 mutations with high LAM scores. Applying the LAM score to the current European Leukemia Network risk group criteria, independent prognostic implications and a refined prognostic significance of each subgroup were provided, indicating the value of including immune microenvironment data into AML risk stratification.