GART promotes multiple myeloma malignancy via tumor stemness mediated by activating the HSP90α/CDK6/β-catenin axis

Tumor progression involves the acquisition of progenitor and stem cell-like characteristics. Glycinamide ribonucleotide transformylase (GART) has been studied in solid tumors for its role in promoting Cancer cell stemness, but its function in multiple myeloma (MM) remains unclear. This study aims to determine the impact of GART on MM cell proliferation and its potential as a therapeutic target. Elevated GART was associated with MM stem cell-like markers and unfavorable outcomes in MM patients. In vitro experiments using lentivirus-based overexpression and siRNA-mediated knockdown methods demonstrated that GART promoted MM cell proliferation, colony formation, and cell cycle progression. In vivo studies using a chemically induced plasmacytoma mouse model confirmed that GART accelerated MM malignancy. Mechanistic studies revealed that GART binds to and stabilizes the HSP90α protein, thereby upregulating its client protein CDK6. Additionally, GART activated the Wnt/β-catenin pathway, promoting cell proliferation and the expression of stemness genes in MM. Furthermore, a GART inhibitor, pemetrexed (PEM), effectively suppressed cell proliferation and tumor growth in a human cell line-derived xenograft model (CDX). In conclusion, our findings demonstrate that GART promotes MM cell proliferation and tumor stemness by activating the HSP90α/CDK6/β-catenin axis. Targeting GART may be a promising strategy for developing and improving MM treatments.

CDK6; Glycinamide ribonucleotide transformylase (GART); HSP90α; Multiple myeloma; Stemness; Wnt/β-catenin.