Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy driven by human T-cell leukemia virus type 1 (HTLV-1). Although patients from the Western hemisphere (Afro-Caribbean and South American) face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletions and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-sequencing, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest that ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with chronic cases with unfavorable outcomes. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.

中文翻译：

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西方人群中人类嗜 T 淋巴细胞病毒 1 型相关成人 T 细胞白血病淋巴瘤的独特基因组特征。


成人 T 细胞白血病淋巴瘤 （ATLL） 是一种由人类 T 细胞白血病病毒 1 型 （HTLV-1） 驱动的侵袭性恶性肿瘤。尽管来自西半球（非裔加勒比和南美洲）的患者预后较差，但我们对 ATLL 分子驱动因素的理解主要来自日本的研究。我们进行了多组学分析，以阐明 ATLL 在西方队列中的基因组景观。涉及 FOXO3 、 ANKRD11 、 DGKZ 和 PTPN6 的复发性缺失和/或破坏性突变表明这些基因是潜在的肿瘤抑制因子。RNA 测序、已发表的功能数据和体外检测支持 ANKRD11 和 FOXO3 分别作为 ATLL 中 T 细胞增殖和细胞凋亡的调节因子。生存数据表明，ANKRD11突变可能使预后更差。日本和西方队列，除了急性和淋巴瘤亚型外，还表现出不同的分子模式。GATA3 缺失与预后不良的慢性病例相关。IRF4 和 CARD11 突变经常出现在干扰素治疗后的复发中。我们的研究结果揭示了日本和西方 ATLL 患者之间新的推定 ATLL 驱动基因和临床相关差异。