Autonomous Tgf Beta 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 heterogeneity and variation of LSCs in human acute myeloid leukemia (AML). Monitoring expression levels of endothelial cell-selective adhesion molecule (ESAM), a hematopoietic stem cell-related marker, was useful to detect the plasticity of AML cells. While healthy human hematopoietic stem/progenitor cells robustly expressed ESAM, AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM(-) and ESAM(+) leukemia cells obtained from AML patients were mutually interconvertible in culture. KG1a and CMK, human AML clones, also represented the heterogeneity in terms of ESAM expression. Single cell culture with ESAM(-) or ESAM(+) AML clones recapitulated the phenotypic interconversion. The phenotypic alteration was regulated at the gene expression level, and RNA sequencing revealed activation of TGF beta signaling in these cells. AML cells secreted TGF beta 1, which autonomously activated TGF beta pathway and induced their phenotypic variation. Surprisingly, TGF beta signaling blockade inhibited not only the variation but also the proliferation of AML cells. Therefore, autonomous activation of TGF beta signaling underlies the LSC heterogeneity, which may be a promising therapeutic target for AML.