Publication Date:
2019-11-13
Description:
Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy. Although more than half of these patients may achieve long-term remission, the majority of the remaining patients succumb to DLBCL.These patients relapse after conventional Rituximab (R)-based chemotherapy regimen, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) in association with drug resistance. Iron is essential for many fundamental cellular functions, including proliferation and DNA synthesis. Accumulating evidence reveals that abnormal iron metabolism plays an important role in carcinogenesis and in the progression of many tumors. In cancer cells, the demand for iron increases in response to sustained deregulation of cell proliferation and DNA synthesis. Based on these data, we searched to identify if iron metabolism pathway is deregulated in DLBCL and could be exploited to develop novel therapeutic strategies. A list of 63 genes related to iron metabolism in cancer was defined. Using Maxstat R function, we showed that 12 genes out of the 63 investigated have a prognostic value in two independent cohorts of DLBCL patients treated by R-CHOP (Melnick cohort, n=69 and Lenz cohort, n=233). Based on these prognostic genes, we created a gene expression profile (GEP)-based risk score as the sum of the beta coefficients weighted by ±1 according to the patient signal above or below the probe set Maxstat value as previously reported (Herviou L et al. Clinical epigenetics 2018). The iron score was significantly associated with high-risk DLBCL in 3 independent cohorts of patients. GSEA analysis revealed that high-risk DLBCL patients defined by iron score are significantly enriched in genes involved in MYC amplification and MYC targets (p〈 0.01). These data demonstrated that high iron score allows to identify DLBCL patients with a poor outcome and that could benefit from targeted therapy. We analyzed the therapeutic interest of Ironomycin, a new promising iron depleting molecule. Ironomycin is known to sequester iron in the lysosome and to induce ferroptosis (Mai TT et al. Nature Chemistry 2017). Ironomycin inhibits DLBCL cell proliferation in a panel of 16 DLBCL cell lines, at nanomolar concentrations (Median IC50: 30nM; range: 7.2 - 91.5 nM) compared to other iron chelators. Ironomycin induces significant cell growth inhibition, apoptosis of DLBCL cells and DNA double strand break accumulation. Furthermore, apoptosis induced by Ironomycin was not reversed by Iron supplementation. Caspase activation and apoptosis induction mediated by Ironomycin could be partially reversed by pan-caspase inhibitor QVD (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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