Emerging Role of Podocalyxin in the Progression of Mature B-Cell Non-Hodgkin Lymphoma

Abstract

Mature B-cell non-Hodgkin lymphoma (B-NHL) constitutes a group of heterogeneous malignant lymphoproliferative diseases ranging from indolent to highly aggressive forms. Although the survival after chemo-immunotherapy treatment of mature B-NHL has increased over the last years, many patients relapse or remain refractory due to drug resistance, presenting an unfavorable prognosis. Hence, there is an urgent need to identify new prognostic markers and therapeutic targets. Podocalyxin (PODXL), a sialomucin overexpressed in a variety of tumor cell types and associated with their aggressiveness, has been implicated in multiple aspects of cancer progression, although its participation in hematological malignancies remains unexplored. New evidence points to a role for PODXL in mature B-NHL cell proliferation, survival, migration, drug resistance, and metabolic reprogramming, as well as enhanced levels of PODXL in mature B-NHL. Here, we review the current knowledge on the contribution of PODXL to tumorigenesis, highlighting and discussing its role in mature B-NHL progression.

Keywords: B-cell non-Hodgkin lymphoma; cancer progression; drug resistance; metabolic reprogramming; metastasis; podocalyxin.

Figure 1

Schematic representation of the potential role of podocalyxin (PODXL) in mature B-cell non-Hodgkin lymphoma (B-NHL) progression. PODXL induces cell survival, proliferation, and drug resistance in mature B- NHL cells, likely through the activation of activated phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways. Additionally, PODXL promotes glutaminolysis, lipogenesis, and pentose phosphate pathway via activation of glutaminase 1 (GLS1), fatty acid synthase (FASN), and glucose 6-phosphate dehydrogenase (G6PD), respectively, which would generate biomolecules and reducing agents necessary for tumor cell survival, proliferation, and drug resistance. This metabolic reprogramming may be mediated by PI3K/AKT and MAPK signaling pathways. The PODXL-induced B-NHL-resistance to obinutuzumab could be due to the capacity of PODXL to reorganize the actin cytoskeleton. In addition to this, PODXL favors cell-to-cell adhesion in B-NHL by a beta2-integrin-mediated process, which would lead to cell survival. PODXL also enhances chemotaxis of B-NHL cells towards C-X-C motif chemokine ligand 12 (CXCL12), which is released by stromal cells of distant sites and binds to C-X-C motif chemokine receptor 4 (CXCR4), a chemokine receptor that interacts with PODXL. NHERF1: Na⁺/H⁺-exchanger regulatory factor; PPP: pentose phosphate pathway.