CD99 antibody disrupts T-cell acute lymphoblastic leukemia adhesion to meningeal cells and attenuates chemoresistance

Maryam Ebadi,Leslie M Jonart,Peter M Gordon,Jason Ostergaard

doi:10.1038/s41598-021-03929-x

Maryam Ebadi, Leslie M Jonart + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-03929-x

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Abstract

Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia. In prior work we found that the meninges, the thin layer of tissue that covers the brain and spinal cord, harbor leukemia cells in the CNS. Importantly, direct interactions between leukemia and meningeal cells enabled leukemia chemoresistance. Herein, we show that an antibody targeting CD99, a transmembrane protein expressed on meningeal cells and many leukemia cells, disrupts adhesion between leukemia and meningeal cells and restores sensitivity of the leukemia cells to chemotherapy. This work identifies a mechanism regulating critical intercellular interactions within the CNS leukemia niche and may lead to novel therapeutic approaches for overcoming niche-mediated chemoresistance.

Highlights

Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia
We previously showed that direct interactions between leukemia and meningeal cells in the CNS enhance leukemia chemotherapy resistance through effects on leukemia apoptosis balance and cell cycle[5,6]
We showed that Me6TREN (Tris[2-(dimethylamino) ethyl] amine), a small molecule drug initially identified as a hematopoietic stem cell (HSC) mobilizing c ompound[7,8], disrupts leukemia-meningeal cell adhesion and significantly overcomes leukemia chemotherapy resistance both in vitro and in vivo

Summary

Introduction

Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia. We showed that CD99 is expressed on meningeal cells and that CD99 ligation with a monoclonal antibody disrupts adhesion between leukemia and meningeal cells and restores sensitivity of the leukemia cells to chemotherapy. We selected the CD99 antibody clone 0662 for further testing in leukemia-meningeal adhesion assays.

Results

Conclusion