CD157 signaling promotes survival of acute myeloid leukemia cells and modulates sensitivity to cytarabine through regulation of anti-apoptotic Mcl-1

Yuliya Yakymiv,Semra Aydin,Massimo Massaia,Cristiano Bracci,Stefania Augeri,Enza Ferrero,Erika Ortolan,Sara Marchisio,Stefano D’Ardia,Ada Funaro

doi:10.1038/s41598-021-00733-5

Abstract

CD157/BST-1 (a member of the ADP-ribosyl cyclase family) is expressed at variable levels in 97% of patients with acute myeloid leukemia (AML), and is currently under investigation as a target for antibody-based immunotherapy. We used peripheral blood and bone marrow samples from patients with AML to analyse the impact of CD157-directed antibodies in AML survival and in response to cytarabine (AraC) ex vivo. The study was extended to the U937, THP1 and OCI-AML3 AML cell lines of which we engineered CD157-low versions by shRNA knockdown. CD157-targeting antibodies enhanced survival, decreased apoptosis and reduced AraC toxicity in AML blasts and cell lines. CD157 signaling activated the PI3K/AKT/mTOR and MAPK/ERK pathways and increased expression of Mcl-1 and Bcl-XL anti-apoptotic proteins, while decreasing expression of Bax pro-apoptotic protein, thus preventing Caspase-3 activation. The primary CD157-mediated anti-apoptotic mechanism was Bak sequestration by Mcl-1. Indeed, the Mcl-1-specific inhibitor S63845 restored apoptosis by disrupting the interaction of Mcl-1 with Bim and Bak and significantly increased AraC toxicity in CD157-high but not in CD157-low AML cells. This study provides a new role for CD157 in AML cell survival, and indicates a potential role of CD157 as a predictive marker of response to therapies exploiting Mcl-1 pharmacological inhibition.

Highlights

CD157/bone marrow stromal cell antigen 1 (BST-1) is expressed at variable levels in 97% of patients with acute myeloid leukemia (AML), and is currently under investigation as a target for antibody-based immunotherapy
In a clinical trial on relapsed and refractory AML, sensitivity to venetoclax increased with increased Bcl-2 expression; in contrast, sensitivity decreased with increased expression of myeloid cell leukemia-1 (Mcl-1)[14], a critical anti-apoptotic member of the Bcl-2 family and target of various inhibitors being used in clinical trials, such as S63845
We focused on PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK)/extracellular signal kinase (ERK) signal transduction pathways, known to be activated through CD157 targeting in monocytes[20] and frequently deregulated in AML29,30

Summary

Introduction

CD157/BST-1 (a member of the ADP-ribosyl cyclase family) is expressed at variable levels in 97% of patients with acute myeloid leukemia (AML), and is currently under investigation as a target for antibody-based immunotherapy. We used peripheral blood and bone marrow samples from patients with AML to analyse the impact of CD157-directed antibodies in AML survival and in response to cytarabine (AraC) ex vivo. Abbreviations AML Acute myeloid leukemia AraC Cytarabine BM Bone marrow ECM Extracellular matrix Mcl-1 Myeloid cell leukemia-1 FCS Fetal calf serum mAb Monoclonal antibody PI Propidium Iodide GSK-3β Glycogen synthase kinase 3 MFI Mean fluorescence intensity EC50 Half maximal effective concentration MAPK Mitogen-activated protein kinase ERK Extracellular signal kinase. In a clinical trial on relapsed and refractory AML, sensitivity to venetoclax increased with increased Bcl-2 expression; in contrast, sensitivity decreased with increased expression of myeloid cell leukemia-1 (Mcl-1)[14], a critical anti-apoptotic member of the Bcl-2 family and target of various inhibitors being used in clinical trials, such as S63845. CD157-directed agonistic antibodies are effective in mimicking the signaling effects of the myeloid cells/ ECM interaction[19,20,21]

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Results

Discussion

Conclusion