# Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia

## TL;DR

This study uses single-cell analysis to uncover cellular hierarchies in APL and identifies a stemness score that predicts early death risk.

## Contribution

The study introduces an APL-specific stemness score for predicting early death risk and reveals cellular hierarchies in APL.

## Key findings

- APL contains a differentiation hierarchy rooted in leukemic stem-like cells.
- Leukemic stemness correlates with high white blood cell counts and FLT3-ITD mutations.
- An APL-specific stemness score effectively predicts early death risk.

## Abstract

Acute promyelocytic leukemia (APL) represents a paradigm for targeted differentiation therapy, with a minority of patients experiencing treatment failure and even early death. We here report a comprehensive single-cell analysis of 16 APL patients, uncovering cellular compositions and their impact on all-trans retinoic acid (ATRA) response in vivo and early death. We unveil a cellular differentiation hierarchy within APL blasts, rooted in leukemic stem-like cells. The oncogenic PML/RARα fusion protein exerts branch-specific regulation in the APL trajectory, including stem-like cells. APL cohort analysis establishes an association of leukemic stemness with elevated white blood cell counts and FLT3-ITD mutations. Furthermore, we construct an APL-specific stemness score, which proves effective in assessing early death risk. Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.

The cellular hierarchies in acute promyelocytic leukemia (APL) remain to be explored. Here, the authors perform single-cell RNA sequencing of 16 APL patients to characterise its cellular composition and develop an APL-specific stemness score for assessing the risk of early death in APL.