Autonomous TGFβ 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 TGFβ signaling in these cells. AML cells secreted TGFβ1, which autonomously activated TGFβ pathway and induced their phenotypic variation. Surprisingly, TGFβ signaling blockade inhibited the variation and proliferation of AML cells. Therefore, autonomous TGFβ signaling underlying LSC heterogeneity may be a promising therapeutic target. We conducted RNA sequencing on ESAM-Hi and ESAM-Neg KG1a fractions immediately after sorting.

白血病干细胞（leukemia stem cells, LSCs）的异质性与其集体化疗耐药密切相关。为根除白血病干细胞，亟需阐明其异质性背后的分子机制。本研究旨在鉴定人类急性髓系白血病（acute myeloid leukemia, AML）中驱动白血病干细胞异质性的信号调控因素。健康人造血干/祖细胞可稳定表达内皮细胞选择性黏附分子（endothelial cell-selective adhesion molecule, ESAM），而AML细胞的ESAM表达则呈现显著异质性。有趣的是，ESAM阴性与ESAM阳性的AML细胞可实现相互转化；RNA测序（RNA sequencing）结果显示，此类细胞中转化生长因子β（transforming growth factor β, TGFβ）信号通路处于激活状态。AML细胞可分泌TGFβ1，后者能够自主激活TGFβ通路并诱导细胞表型发生变异。令人意外的是，阻断TGFβ信号通路可抑制AML细胞的表型变异与增殖能力。综上，介导白血病干细胞异质性的自主TGFβ信号通路或可成为极具潜力的治疗靶点。本研究于分选后即刻，对ESAM高表达（ESAM-Hi）与ESAM阴性（ESAM-Neg）的KG1a细胞组分开展了RNA测序。