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Review
. 2023 May 3:25:e16.
doi: 10.1017/erm.2023.13.

Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia

Jessica Parker  1 , Sean Hockney  1 , Orest W Blaschuk  2 , Deepali Pal  1   3
Affiliations
Review

Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia

Jessica Parker et al. Expert Rev Mol Med. .

Abstract

This review discusses current research on acute paediatric leukaemia, the leukaemic bone marrow (BM) microenvironment and recently discovered therapeutic opportunities to target leukaemia-niche interactions. The tumour microenvironment plays an integral role in conferring treatment resistance to leukaemia cells, this poses as a key clinical challenge that hinders management of this disease. Here we focus on the role of the cell adhesion molecule N-cadherin (CDH2) within the malignant BM microenvironment and associated signalling pathways that may bear promise as therapeutic targets. Additionally, we discuss microenvironment-driven treatment resistance and relapse, and elaborate the role of CDH2-mediated cancer cell protection from chemotherapy. Finally, we review emerging therapeutic approaches that directly target CDH2-mediated adhesive interactions between the BM cells and leukaemia cells.

Keywords: Anti-cancer drugs; CDH2; cancer microenvironment; leukaemia; treatment resistance.

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Conflict of interest statement

OWB holds shares in Zonula Incorporated. The company is developing N-cadherin antagonists (such as Compound 15) for the treatment of fibroblast-associated diseases. DP and her team which includes JP and SH, are collaborating in studies investigating the ability of Compound 15 to act as a therapeutic for the treatment of ALL.

Figures

Figure 1.
Figure 1.
Schematic diagram of the BM microenvironment under normal conditions and following leukaemogenesis and treatment in AML (top right) and ALL (top left). After leukaemogenesis and treatment, the microenvironment is remodelled, pro-inflammatory and anti-angiogenic cytokines are produced resulting in the loss of vasculature in the endosteal and osteoblastic cells. Adapted from Refs , , , , , , , , , , , , .
Figure 2.
Figure 2.
Schematic diagram of the pathways and transcription factors associated with CDH2, including the PI3K/Akt/mTOR pathway and the Wnt/β-catenin pathway. Arrows represent activation; bars represent inhibition, double-ended arrows in the pathway indicate upregulation of a molecule results in downregulation of the other and vice versa. Adapted from Refs , , , , .
Figure 3.
Figure 3.
ADH-1 competitively binds to CDH2 on BM cells, preventing leukaemia–niche cell binding of leukaemia cells within the BM microenvironment. Adapted from Refs , .
See this image and copyright information in PMC

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