Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis by using the new oral demethylating agent OR-2100

Abstract

Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T-cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1-infected individuals are asymptomatic and only 3-5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1-infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV-infected T-cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes down-regulated due to promoter hypermethylation in HTLV-1-infected T-cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1-infected cell lines but was normalized by re-expression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1-infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1-infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the two compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.

Recent Advancement in Atypical Lipomatous Tumor Research

“…These environmental stimuli provoke epigenetic changes, which regulate the biological modification of DNA without changing the sequences and subsequently influence the degree of gene expression [98]. The importance of epigenetic modification has been observed in various cutaneous skin malignancies, such as squamous cell carcinoma [99], melanoma [100], and lymphomas [101].…”

Comprehensive genomic analysis identifying heterogeneity in peripheral T‐cell lymphoma

“…A recent study investigating ATLL in Japanese subjects identified the accumulation of aberrant DNA methylation, which was correlated with development and progression. 28 Based on genomic findings from Japanese subjects with ATLL, it is believed that DNA hypermethylation status in ATLL cells is not related to genetic events. 10 Although the methylation pattern of ATLL in North American subjects remains unclear, gene expression profiling distinguished North American and Japanese cases, suggesting that they have different properties.…”

Titans awake: HMAs for virus-driven ATL

“…They observed tumor reduction by all three HMAs, albeit with variable hematopoietic toxicity (least to most; AZA, OR21, DAC) and hypomethylation of THEMIS TSS200 (least to most; AZA, OR21, DAC) at the doses used. With a view to potential long-term oral therapy, OR-21 was used (intraperitoneally, twice weekly for 100 days) to treat mice bearing peritoneal hCD45 1 / CADM1 1 xenografts established by inoculating peripheral blood mononuclear cells from a patient with chronic ATL. OR21 produced a striking improvement in morbidity and mortality (see figure panel B).…”

“…10 OR-21 was shown to be bioavailable following intraduodenal administration to macaques and is potentially another oral HMA. 1 The cell death can be overcome in vitro and in vivo by interleukin-2 (IL-2) supplementation. This work builds on the previous observation of the same group, which showed 2 subpopulations of Tregs with distinct phenotypes in AA: Treg A, with a naive phenotype (low proliferative index), and Treg B, with a memory phenotype (moderate/high proliferative index) that correlated with response to immunosuppressive therapy (IST).…”

“…1,9 Despite the limitations of their xenograft model, Watanabe et al demonstrate that a slumbering Themis can be roused to restore her natural law. Their data are a compelling precursor for clinical evaluation of HMAs in ATL.…”