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Letters to the Editor
cells express TGFBR and associated proteins (ACVR1, ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, AMHR2, BMPR2, TGFBR1, TGFBR2, TGFBR3, TGF- BRAP1). The classic HL cell line KMH-2 contained rele- vant transcript levels of all TGFBR types, HDLM-2 expressed TGFBR1 and TGFBR3, and the NLPHL cell line DEV expressed TGFBR1; the classic HL cell lines L1236 and L428 exhibited TGBRAP1 transcripts. In all these cell lines SMAD1 transcripts were decreased.
In summary, our data suggest a likely important, not yet described role of SMAD1 hypermethylation in HL, potentially causing an imbalance of TGF-β signaling axis responses in involved tissues. SMAD1 has been demon- strated to be part of the TGF-β-mediated anti-prolifera- tive pathway in different B-cell lymphomas. Intriguingly, lymphomas with mutated or knocked-out SMAD1 were protected from the tumor-suppressive effects of TGF-β.13
Lack of SMAD1 expression in HRS and LP cells due to promoter hypermethylation or gene mutation may anal- ogously contribute to their resistance towards the pro- apoptotic and anti-proliferative effects of TGF-β, despite the presence of TGFBR transcripts. This hypothesis is fur- ther supported by observations in EBV-positive classic HL, in which decreased SMAD2 levels due to EBNA1- mediated increased protein turnover14 disable TGF-β sig- naling, being congruent with our data regarding SMAD1 downregulation in HRS cells.
In contrast, retained SMAD1 expression in surround- ing TIL may contribute to immune escape, as intact TGF-β signaling promotes T-cell differentiation into tumor-supporting Treg,2 which is reflected by the observed correlation between higher numbers of FOXP3- positive Treg and expression of SMAD1 in TIL. The tumor-suppressive effects of TGF-β on TIL have recently been challenged by a promising clinical study in which the infusion of TGF-β-insensitive T cells was successfully used in patients with EBV-positive relapsed classic HL.15
Our data suggest a possible rationale for the applica- tion of a more tailored treatment with hypomethylating agents in HL, which may be worth of prospective inves- tigations, as agents such as decitabine have already shown promising results in SMAD1 hypermethylated DLBCL5 and in classic HL cell lines.10
Magdalena M. Gerlach,1 Anna Stelling-Germani,2 Cheuk Ting Wu,2 Sebastian Newrzela,3 Claudia Döring,3 Visar Vela,1 Anne Müller,2 Sylvia Hartmann3
and Alexandar Tzankov1
1Institute of Medical Genetics and Pathology, University of Basel, Basel, Switzerland; 2Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland and 3Institute of Pathology, Department of Pathology, Goethe University Frankfurt on Main, Germany
Correspondence:
ALEXANDAR TZANKOV - alexandar.tzankov@usb.ch
doi:10.3324/haematol.2020.249276
Disclosures: no conflicts of interests to disclose.
Contributions: MMG wrote the manuscript and evaluated the histology and immunohistochemical stains; AS-G supervised the
SMAD1 promoter methylation assessment, performed cell line viability experiments, corrected the manuscript and wrote the legend to Figure 2; CTW assessed SMAD1 promoter methylation; SN provided gene expression data of Hodgkin lymphoma cell lines; CD provided and analyzed gene expression data of Hodgkin lymphoma cell lines; VV enriched Hodgkin and Reed-Sternberg cells from archived clinical sam- ples and isolated DNA from them; AM supervised SMAD1 promoter methylation assessment; SH provided cell lines; AT designed the study, supervised histopathological assessment, performed statistics, analyzed gene expression data of Hodgkin lymphoma cell lines, partially wrote and completely edited the manuscript
Funding: this study was supported by the Swiss National Science Foundation.
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