Multiple myeloma (MM) is the second most common hematological malignancy, with its global incidence on the rise. Despite significant improvements in the survival rate of MM patients, there is still considerable variation in prognosis, with some patients experiencing rapid progression and short survival periods. Therefore, identifying specific markers for highly malignant plasma cell subgroups with poor prognosis is crucial.

To address this, we conducted single-cell transcriptome sequencing across the entire disease progression spectrum, including MGUS, MGRS, SMM, and MM. We identified highly malignant plasma cell subgroups (clusters 5 and 17) based on copy number variations and malignant plasma cell subgroup (MPCS) scores. Using a malignant metabolic pathway scoring method (MPAS), we discovered that abnormalities in the alanine, aspartate, and glutamate metabolic pathways significantly impacted the poor prognosis of patients in these subgroups. Notably, within these pathways, adenylosuccinase (Adsl) was significantly overexpressed. Data from the GEO (GSE6477) and MMRF databases revealed that Adsl was significantly associated with poor clinical stages (R-ISS) and survival prognosis of patients. Knockdown of Adsl significantly promoted apoptosis and reduced the proliferation index, as evidenced by TUNEL, cell cycle assay and expression levels of classic apoptotic proteins (cleaved Caspase-3 and cleaved PARP). Further research showed that Adsl knockdown led to a significant reduction in AMP production, which was the main downstream product of Adsl. This reduction inhibited AMP from directly binding to the γ subunit of AMPK, thereby inhibiting phosphorylation at the Thr172 site and suppressing AMPK pathway activation. Mitochondrial fission factor (MFF), a core member of the mitochondrial fission process, is a phosphorylation substrate of AMPK at Ser172. After Adsl knockdown, MFF Ser172 phosphorylation was significantly reduced, leading to decreased mitochondrial fission. Reduced mitochondrial fission weakened glycolysis, enhanced oxidative phosphorylation, and increased ROS production. Consequently, increased ROS inhibited myeloma cell proliferation and promoted apoptosis.

In summary, Adsl acts as a bridge linking amino acid metabolism and glucose metabolism and serves as a specific marker for highly malignant plasma cell subgroups. This finding provides a novel therapeutic target for improving the prognosis of MM patients.

Disclosures

No relevant conflicts of interest to declare.

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