Uncovering Ferroptosis-Mediated Immune Escape in del(17p) Multiple Myeloma

Description

Deletion of the short arm of chromosome 17 (del(17p)) defines a high-risk multiple myeloma (MM) subtype with poor prognosis and therapy resistance, yet its impact on tumor–immune interactions and specific vulnerabilities remain understood. Using a novel isogenic del(17p) MM model generated by Dr Fulciniti´s laboratory at Dana-Farber Cancer Institute, we identified broad transcriptomic reprogramming including altered immune-related pathways. Moreover, del(17p) MM cells exhibited dysregulation of the ferroptosis axis—an iron dependent form of regulated cell death driven by lipid peroxidation and linked to impaired immune cell function—and were selectively vulnerable to GPX4 inhibitors.

We therefore hypothesize that del(17p) MM cells exhibit intrinsic ferroptosis deregulation that promotes an immunosuppressive tumor microenvironment, facilitating immune escape and contributing to the poor prognosis of del(17p) patients. To test this hypothesis, we will define how 17p loss rewires ferroptosis and impacts MM cell growth and immune interactions, and exploit these vulnerabilities by testing ferroptosis modulators in combination with standard‑of‑care and immune‑based therapies.
This project will elucidate how 17p loss drives ferroptosis dysregulation and immune escape in MM and will identify actionable, biomarker‑guided therapeutic strategies for patients with high‑risk del(17p) disease.