Identification of CD105 (endoglin) as novel risk marker in CLL

Sarah M Greiner,Melanie Märklin,Joseph Kauer,Jonas S Heitmann,Clemens Hinterleitner,Gundram Jung,Ilona Hagelstein,Helmut R Salih,Sophie Meyer,Samuel Holzmayer,Kübra Kaban,Claudia Tandler

doi:10.1007/s00277-022-04756-4

Abstract

Several genetic and clinical markers are established as prognostic factors in chronic lymphocytic leukemia (CLL). However, additional markers are needed for risk stratification. Flow cytometric analysis is a mainstay of CLL diagnostics, thus identification of novel prognostic surface markers can improve risk assessment without increasing burden for patients and physicians. Furthermore, surface molecules preferentially expressed in high-risk cases could serve as therapeutic targets for immunotherapy. CD105 (endoglin) is a TGF-beta coreceptor and activates endothelial cells in healthy tissues and cancer. In addition, it is expressed on healthy hematopoietic precursors as well as lymphoid and myeloid leukemias. In acute myeloid leukemia (AML), a CD105 antibody is successfully applied in clinical studies. In CLL, mRNA expression of the CD105 gene ENG reportedly correlates with other risk factors but failed to show significant correlation with overall survival. However, CD105 protein expression in CLL has never been studied. We here analyzed CD105 surface expression on CLL cells from 71 patients by flow cytometry and report for the first time that substantial levels of CD105 are detectable on CLL cells in 70.4% of patients. Using receiver operating characteristics, we established a cutoff of 5.99% positive cells to distinguish between low and high CD105 levels, the latter correlating with decreased time to first treatment and overall survival. High CD105 expression further correlates with CD38 expression. Our study identified membrane expression of CD105 as a potential risk marker and therapeutic target in high-risk CLL. However, multivariant analyses of large cohorts should be performed in confirmatory studies.

Highlights

Chronic lymphocytic leukemia (CLL) is a malignant disorder with a highly variable course and prognosis [1]
Summary: We report for the first time that CD105 is expressed on CLL cells, and high levels correlate with shorter time to first-line therapy and overall survival
CD105 expression has been reported for healthy hematopoietic stem cells [23,24,25] and neoplasias like myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) [26, 27]

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a malignant disorder with a highly variable course and prognosis [1]. CD105 (endoglin) is an accessory molecule within the transforming growth factor (TGF) beta receptor signaling complex [12, 13] and mediates activation of endothelial cells [14,15,16] It is expressed on the neovasculature of many solid tumor entities where expression correlates with poor prognosis [17,18,19,20,21,22]. CD105 expression has been reported for healthy hematopoietic stem cells [23,24,25] and neoplasias like myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) [26, 27] In the latter, CD105 expression correlates with poor outcome [28] and is increasingly evaluated as therapeutic target. We report on CD105 levels on CLL cells and their association with disease outcome in 71 patients

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Results

Conclusion