Adult T-cell leukemia-lymphoma (ATL) is a highly aggressive T cell malignancy with dismal prognosis caused by the human T-cell leukemia virus, type 1 (HTLV-1), which is prevalent in Japan, South America, and the Caribbean. Because of our geographic proximity to HTLV-1 endemic regions, ATL patients are commonly encountered in south Florida and northeast U.S.A. At least four clinical ATL subtypes have been recognized. The acute and lymphomatous lethal forms are by far the most common variants. The 4-year survival rates for lymphomatous and acute type ATL are less than 20%, with median survival less than 11 months. First-line treatment options include multi-agent cytotoxic chemotherapy and interferon-a (IFNa)-based therapy. We recently published a large genomic study of ATL found in the Western hemisphere (W-ATLL) and discovered mutational patterns that differed from Japanese patients [Myers and Choi group, Gru, and Ramos et al. Haematologica. 2024 Dec 1;109(12):4021-4039]. A notorious finding was the recurrence of novel FOXO3 mutations (R177W and D199N) mapping to the DNA binding domain in 10% of patients (17% of African-descent cases) with acute type ATL suggesting that the possible tumor suppressive function of FOXO3 in ATL requires DNA binding. In total, FOXO3 mutations or genomic deletions occurred at a frequency of ~20%. FOXO3 is a transcriptional activator, whose function is known to induce the expression of pro-apoptotic genes (i.e., BIM and FasL) and to promote drug-induced autophagy. FOXO3 protein has been demonstrated to be inactivated by phosphorylation via AKT and targeted by HTLV-1 bZip (HBZ) protein, which sequesters it in the nucleus while attenuating its pro-apoptotic function. W-ATL tumors analyzed from our cohort generally showed reduced FOXO3 protein expression, suggesting that dysregulated FOXO3 function could be an important oncogenic event in ATL development. Our preliminary in vitro studies using our patient derived ATL cell lines showed that overexpression of FOXO3 increased antineoplastic drug-induced apoptosis in ATL cells, while overexpression of R177W and D199N mutant forms and FOXO3 knock-out (KO) conferred resistance to anti-neoplastic drugs. More recently, our ATL cell lines were engineered to overexpress FOXO3 via more efficient transduction of tetracycline-inducible pRetroX vectors demonstrating FOXO3 slow the proliferation of ATL cells in vitro. We also correlated our published exome sequencing with patient outcomes (treatment response rates and survival) using our existing well-annotated database. Surprisingly, W-ATLL patients carrying mutated FOXO3 responded better to IFNa-based therapies after achieving a significantly higher complete response rate (37% vs. 16%) and longer progression-free survival (7 months vs. 0.9 months, p= 0.0172) (unpublished data). Thus, FOXO3 mutations may result in ATL forms that are perhaps more susceptible to immune-based therapies such as IFN which depend less on direct drug-induced apoptosis. Our current studies aim to confirm and define the functional role of FOXO3 in ATL and to evaluate the clinical implications of altered FOXO3 in this disease. Given our preliminary findings, we are investigating FOXO3 as a predictive biomarker in prospective ATL samples and characterizing its functional using our preclinical models.

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2025
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