Autonomous TGFß signaling induces phenotypic variation in human acute myeloid leukemia

Heterogeneity of leukemia stem cells (LSCs) is involved in their collective chemoresistance. To eradicate LSCs, it is necessary to understand the mechanisms underlying their heterogeneity. Here, we aimed to identify signals responsible for variation in LSCs in human acute myeloid leukemia (AML). While healthy human hematopoietic stem/progenitor cells robustly expressed endothelial cell-selective adhesion molecule (ESAM), AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM- and ESAM+ AML cells were mutually interconvertible, and RNA sequencing revealed activation of TGFß signaling in these cells. AML cells secreted TGFß1, which autonomously activated TGFß pathway and induced their phenotypic variation. Surprisingly, TGFß signaling blockade inhibited the variation and proliferation of AML cells. Therefore, autonomous TGFß signaling underlying LSC heterogeneity may be a promising therapeutic target. Overall design: We conducted RNA sequencing on ESAM-Hi and ESAM-Neg KG1a fractions immediately after sorting.