Kim TaeHyung, Lee Hyewon, Capo-Chichi Jose-Mario, Chang Myung Hee, Yoo Young Seok, Basi Gurbaksh, Ketela Troy, Smith Adam C, Tierens Anne, Zhang Zhaolei, Minden Mark D, Kim Dennis Dong Hwan
Division of Medical Oncology and Hematology Princess Margaret Cancer Centre Toronto Ontario Canada.
Department of Computer Science University of Toronto Toronto Ontario Canada.
EJHaem. 2022 Feb 24;3(2):426-433. doi: 10.1002/jha2.390. eCollection 2022 May.
Internal tandem duplication of the Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (-ITD) is one of the most clinically relevant mutations in acute myeloid leukemia (AML), with a high -ITD allelic ratio (AR) (≥0.5) being strongly associated with poor prognosis. -ITDs are heterogeneous, varying in size and location, with some patients having multiple -ITDs. Bulk cell-based approaches are limited in their ability to reveal the clonal structure in such cases. Using single-cell proteogenomic sequencing (ScPGseq), we attempted to identify a relapse-fated subclone in an AML case with mutations in , , and tyrosine kinase domain and two -ITDs (21 bp and 39 bp) (low AR) at presentation, then relapsed only with and mutations and one -ITD (high AR). This relapse-fated subclone at presentation (∼2.1% of sequenced cells) was characterized by the presence of a homozygous 21 bp -ITD resulting from copy neutral loss of heterozygosity (CN-LOH) of chr13q and an aberrant, immature myeloid cell surface signature, contrast to the cell surface phenotype at presentation. In contrast to results from multicolor flow-cytometry, ScPGseq not only enabled the early detection of rare relapse-fated subclone showing immature myeloid signature but also highlighted the presence of homozygous 21 bp -ITDs in the clone at presentation.
猫 McDonough 肉瘤（FMS）样酪氨酸激酶 3 的内部串联重复（-ITD）是急性髓系白血病（AML）中最具临床相关性的突变之一，高 -ITD 等位基因比例（AR）（≥0.5）与不良预后密切相关。-ITD 具有异质性，大小和位置各不相同，一些患者有多个 -ITD。基于群体细胞的方法在揭示此类病例的克隆结构方面能力有限。我们使用单细胞蛋白质基因组测序（ScPGseq），试图在一例 AML 病例中鉴定出一个注定复发的亚克隆，该病例初诊时 、 和 酪氨酸激酶结构域存在突变，并有两个 -ITD（21bp 和 39bp）（AR 低），复发时仅出现 和 突变以及一个 -ITD（AR 高）。初诊时这个注定复发的亚克隆（约占测序细胞的 2.1%）的特征是存在一个纯合的 21bp -ITD，它是由 13 号染色体长臂的杂合性拷贝中性缺失（CN-LOH）导致的，并且具有异常的、不成熟的髓系细胞表面特征，与初诊时的细胞表面表型不同。与多色流式细胞术的结果不同，ScPGseq 不仅能够早期检测到显示不成熟髓系特征的罕见的注定复发亚克隆，还突出显示了初诊时该克隆中纯合 21bp -ITD 的存在。
