Caroline S Myers, Eli Williams, Carlos Barrionuevo Cornejo, Georgios Pongas, Ngoc L Toomey, Jose A Sanches, Maxime Battistella, Samuel Mo, Melissa Pulitzer, Cristopher A Moskaluk, Govind Bhagat, Kenneth Ofori, Jonathan J Davick, Octavio Servitje, Denis Miyashiro, Fina Climent, Kimberley Ringbloom, Daniela Duenas, Calvin Law, Sandro Casavilca Zambrano, Luis Malpica, Brady E Beltran, Denisse Castro, Luciana Barreto, Carlos Brites, Jennifer R Chapman, Jaehyuk Choi, Alejandro A Gru, Juan C Ramos
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引用次数: 0
摘要
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。虽然西半球(非洲-加勒比海和南美洲)患者的预后较差,但我们对 ATLL 分子驱动因素的了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 的基因组状况。涉及 FOXO3、ANKRD11、DGKZ 和 PTPN6 的反复缺失和/或损伤性突变使这些基因成为潜在的肿瘤抑制因子。RNA-seq、已发表的功能数据和体外实验支持 ANKRD11 和 FOXO3 在 ATLL 中分别作为 T 细胞增殖和凋亡的调节因子。生存数据表明,ANKRD11突变可能会导致预后恶化。除了急性亚型和淋巴瘤亚型外,日本和西方队列也显示出不同的分子模式。GATA3缺失与不利的慢性病例有关。IRF4和CARD11突变经常出现在干扰素治疗后的复发病例中。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 患者在临床上的相关差异。
Distinctive genomic features of human T-lymphotropic virus type 1-related adult T-cell leukemia-lymphoma in Western populations.
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.
期刊介绍:
Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research.
Scope:
The scope of the journal includes reporting novel research results that:
Have a significant impact on understanding normal hematology or the development of hematological diseases.
Are likely to bring important changes to the diagnosis or treatment of hematological diseases.