Iron chelation and 2‐oxoglutarate‐dependent dioxygenase inhibition suppress mantle cell lymphoma's cyclin D1

Abstract

The patients with mantle cell lymphoma (MCL) have translocation t(11;14) associated with cyclin D1 overexpression. We observed that iron (an essential cofactor of dioxygenases including prolyl hydroxylases [PHDs]) depletion by deferoxamine blocked MCL cells’ proliferation, increased expression of DNA damage marker γH2AX, induced cell cycle arrest and decreased cyclin D1 level. Treatment of MCL cell lines with dimethyloxalylglycine, which blocks dioxygenases involving PHDs by competing with their substrate 2‐oxoglutarate, leads to their decreased proliferation and the decrease of cyclin D1 level. We then postulated that loss of EGLN2/PHD1 in MCL cells may lead to down‐regulation of cyclin D1 by blocking the degradation of FOXO3A, a cyclin D1 suppressor. However, the CRISPR/Cas9‐based loss‐of‐function of EGLN2/PHD1 did not affect cyclin D1 expression and the loss of FOXO3A did not restore cyclin D1 levels after iron chelation. These data suggest that expression of cyclin D1 in MCL is not controlled by ENGL2/PHD1‐FOXO3A pathway and that chelation‐ and 2‐oxoglutarate competition‐mediated down‐regulation of cyclin D1 in MCL cells is driven by yet unknown mechanism involving iron‐ and 2‐oxoglutarate‐dependent dioxygenases other than PHD1. These data support further exploration of the use of iron chelation and 2‐oxoglutarate‐dependent dioxygenase inhibitors as a novel therapy of MCL.

Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies

“…DFX has also been reported to inhibit mantle cell lymphoma cell proliferation [230,231], and iron deprivation is cytotoxic to malignant B-and T-cells [232,233]. Moreover, in ALL and T-cell lymphoma, DFX displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase.…”

Amino acid influx via LAT1 regulates iron demand and sensitivity to PPMX-T003 of aggressive natural killer cell leukemia

“…Since accumulated studies have reported that the antineoplastic efficacy of iron chelators, such as deferoxamine and deferasirox, is caused by G1 arrest followed by p21-triggered apoptosis [30][31][32][33][34][35][36][37][38][39], the cell death induced by PPMX-T003-mediated specific TfR1 blockage in ANKL is unique. Further investigation of the mechanisms, including iron sensing, iron metabolism, and iron cellular distribution, is needed to clarify the differences in cell cycle regulation between iron chelation and specific TfR1 inhibition.…”