成人 T 细胞白血病淋巴瘤 (ATLL) 是一种侵袭性人类 T 细胞白血病病毒 1 型 (HTLV-1) 驱动的恶性肿瘤。尽管西半球（非洲-加勒比海和南美）患者面临更差的预后，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，以阐明西方队列中 ATLL 的基因组图谱。涉及 FOXO3、ANKRD11、DGKZ 和 PTPN6 的反复缺失和/或破坏性突变表明这些基因是潜在的肿瘤抑制基因。 RNA-seq、已发表的功能数据和体外测定支持 ANKRD11 和 FOXO3 分别作为 ATLL 中 T 细胞增殖和凋亡的调节因子。生存数据表明 ANKRD11 突变可能会导致更差的预后。除了急性和淋巴瘤亚型之外，日本和西方队列还表现出不同的分子模式。 GATA3 缺失与不利的慢性病例相关。 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新的假定 ATLL 驱动基因以及日本和西方 ATLL 患者之间的临床相关差异。

Adult T-cell leukemia-lymphoma (ATLL) is an aggressive Human T-cell Leukemia Virus Type 1 (HTLV-1)-driven malignancy. Although Western hemisphere (Afro-Caribbean and South American) patients 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 deletion and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-seq, 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 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 unfavorable chronic cases. 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.