Open AccessAutonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia
Author(s) -
Shingai Yasuhiro,
Yokota Takafumi,
Okuzaki Daisuke,
Sudo Takao,
Ishibashi Tomohiko,
Doi Yukiko,
Ueda Tomoaki,
Ozawa Takayuki,
Nakai Ritsuko,
Tanimura Akira,
Ichii Michiko,
Shibayama Hirohiko,
Kanakura Yuzuru,
Hosen Naoki
Publication year - 2021
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.3348
Subject(s) - biology , haematopoiesis , myeloid leukemia , phenotype , leukemia , stem cell , progenitor cell , cancer research , signal transduction , cell culture , microbiology and biotechnology , gene , immunology , genetics
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 TGFβ signaling in these cells. AML cells secreted TGFβ1, which autonomously activated TGFβ pathway and induced their phenotypic variation. Surprisingly, TGFβ signaling blockade inhibited not only the variation but also the proliferation of AML cells. Therefore, autonomous activation of TGFβ signaling underlies the LSC heterogeneity, which may be a promising therapeutic target for AML.