髓系白血病
骨髓增生异常综合症
杂合子丢失
生物
等位基因
癌症研究
髓样
肿瘤科
遗传学
基因
医学
免疫学
骨髓
作者
Harrison Tsai,Christopher J. Gibson,H. Moses Murdock,Phani K. Davineni,Marian H. Harris,Eunice S. Wang,Lukasz P. Gondek,Annette S. Kim,Valentina Nardi,R. Coleman Lindsley
出处
期刊:Blood Advances
[American Society of Hematology]
日期:2022-07-21
卷期号:6 (14): 4236-4240
被引量:6
标识
DOI:10.1182/bloodadvances.2022007613
摘要
Abstract KMT2A partial tandem duplication (KMT2A-PTD) is an adverse risk factor in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), a potential therapeutic target, and an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. Although KMT2A-PTD has been reported to affect only a single allele, it has been theorized but not proven that genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including copy-neutral loss of heterozygosity and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML vs MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele.
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