RNA sequencing of patient-derived AML xenografts treated with Fedratinib

The treatment landscape of AML is evolving with promising therapies entering clinical translation, yet patient responses remain heterogeneous and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy make-up from bulk transcriptomes of over 1000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor, and mature cell types. Leukemia hierarchy composition was associated with functional, genomic, and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP, and Intermediate. Critically, variation in hierarchy composition along the Primitive vs GMP or Primitive vs Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A 7-gene biomarker derived from the Primitive vs Mature axis was predictive of patient response to 105 investigational drugs. Thus, hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML. Overall design: RNA sequencing was performed on 26 AML patient-derived xenograft samples from 13 AML patients, each treated with either Fedratinib or Vehicle control. Treatment data for these samples was originally reported in Chen et al (Cancer Research 2016). Each patient sample is annotated based on in vivo response to Fedratinib, based on the relative reduction (RR) in leukemic engraftment in drug-treated compared to vehicle-treated mice. Samples were classified as either Responder: RR >50% in injected right femur (RF); Partial-Responder: RR 20%-50% in RF or >20% in non-injected bone marrow (BM) only; Non-Responder: RR <20% in both RF and BM.