Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML::RARα.

Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34CD38 fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (PML::RARα) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the PML gene, concentrate in the CD34CD38 fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34CD38TIM-3 short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34 differentiated APL cells did not. Furthermore, CD34CD38TIM-3 short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.