Autonomous TGF β signaling induces phenotypic variation in human acute myeloid leukemia

Leukemic stem cells (LSCs) in human acute myeloid leukemia (AML) represent phenotypic variability, which is delineated by endothelial cell ‐selective adhesion molecule (ESAM) expression. The variable ESAM levels reflect fluctuating transcriptome in LSCs that is at least partly regulated by autocrine/paracrine cytokine signals. While autonomous TGFβ1 signaling promotes the phenotypic variability of LSCs, blocking the signaling inhibi ts not only their variability but also their growth by inducing apoptosis. AbstractHeterogeneity 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 regul...

Source: Stem Cells - February 15, 2021 Category: Stem Cells Authors: Yasuhiro Shingai, Takafumi Yokota, Daisuke Okuzaki, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi, Tomoaki Ueda, Takayuki Ozawa, Ritsuko Nakai, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama, Yuzuru Kanakura, Naoki Hosen Tags: ORIGINAL RESEARCH Source Type: research