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Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia. | LitMetric

AI Article Synopsis

  • The study investigates the diversity of leukemia stem cells (LSCs) in human acute myeloid leukemia (AML) and how this diversity contributes to their resistance to chemotherapy.
  • Researchers focused on the endothelial cell-selective adhesion molecule (ESAM) as a marker to monitor LSC variation and found that ESAM expression was heterogeneous among AML cells compared to healthy cells.
  • The results indicated that TGFβ signaling plays a crucial role in this heterogeneity, as AML cells secrete TGFβ1, which promotes their variation and growth, suggesting that targeting this signaling pathway could be a potential treatment strategy for AML.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248163PMC
http://dx.doi.org/10.1002/stem.3348DOI Listing

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