Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.

Evidence-based support for phenotypic drug discovery in acute myeloid leukemia.

The discovery and development of effective drugs for cancer patients has seen limited success in the clinic from phase I trials onward. The high attrition rate of current drug development approaches requires careful evaluation to provide a better understanding of the factors that correlate with or predict positive clinical outcomes. Here, we examine pre-clinical drug development approaches and conduct a meta-analysis of 2918 clinical studies involving 466 unique drugs tested in clinical trials for acute myeloid leukemia (AML). Our goal was to determine whether there are key shared pre-clinical characteristics that ultimately relate to successful or unsuccessful drugs in patients. We provide an evidence-based recommendation for the use of phenotypic drug discovery rather than other methods during pre-clinical development. Although our analysis was limited to AML, similar analyses are likely to be informative for other tumor-specific drug discovery campaigns, informing and improving the foundational discovery screens and platforms for other cancers.