Orally Available Decitabine Prodrug OR-2100 induces Mitotic Perturbation for The Treatment Of Double-Hit Lymphoma Open Access

• Orally available decitabine prodrug OR-2100, inhibits proliferation of double hit lymphoma via the mitotic perturbation.

• The combination of OR-2100 and CHOP might be an effective and feasible treatment for double hit lymphoma

Double hit lymphoma (DHL), an aggressive B cell lymphoma with a poor prognosis, harbors rearrangement of MYC and BCL2. Standard chemoimmunotherapy comprising rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) yields an unsatisfactory treatment response. Hypomethylating agents increase susceptibility to malignant lymphoma via the restoration of tumor suppressor genes. Decitabine not only inhibits DNA methylation but also causes mitotic disruption leading to anti-leukemia effects through the covalent binding of DNA-methyltransferase 1 to DNA. Previously, we developed an orally bioavailable prodrug of decitabine (OR-2100). Here, we investigated the efficacy and underlying mechanism of OR-2100 as a treatment of DHL. OR-2100 alone or in combination with key anti-lymphoma drugs, including doxorubicin and vincristine, suppressed the in vitro proliferation of DHL cell lines, particularly those with wild-type TP53. OR-2100 induced downregulation of CDCA8 and BIRC5, the knockdown of which suppressed the proliferation of DHL cell lines. Both OR-2100 treatment and CDCA8 knockdown led to mitotic perturbation, suggesting that disruption of mitosis may underlie the antitumor mechanism of OR-2100. Given that the efficacy of OR-2100 was dependent on TP53 status, and that CDCA8 and BIRC5 are downstream targets of the E2F1 pathway. These findings suggest that the antitumor activity of OR-2100 may be mediated through inhibition of the E2F1 pathway. Combination of CHOP and OR-2100 reduced tumor weight significantly in a xenograft mouse model without increased toxicities. Induction of mitotic perturbation might be a key anti-lymphoma mechanism by OR-2100 and the combination of OR-2100 and CHOP might be a promising treatment strategy for DHL.