Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.

IF 11.5 Q1 HEMATOLOGY
Caner Saygin, Pu Zhang, Jacob Stauber, Ibrahim Aldoss, Adam S Sperling, Lachelle D Weeks, Marlise R Luskin, Todd C Knepper, Pankhuri Wanjari, Peng Wang, Angela M Lager, Carrie Fitzpatrick, Jeremy P Segal, Mehdi Gharghabi, Sandeep Gurbuxani, Girish Venkataraman, Jason X Cheng, Bart J Eisfelder, Oliver Bohorquez, Anand A Patel, Sheethal Umesh Nagalakshmi, Savita Jayaram, Olatoyosi M Odenike, Richard A Larson, Lucy A Godley, Daniel A Arber, Christopher J Gibson, Nikhil C Munshi, Guido Marcucci, Benjamin L Ebert, John M Greally, Ulrich Steidl, Rosa Lapalombella, Bijal D Shah, Wendy Stock
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引用次数: 0

Abstract

Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies.

Significance: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142.

髓系突变的急性淋巴细胞白血病是一种与克隆性造血相关的高危疾病。
髓系肿瘤产生于原有的克隆性造血(CH),但CH在ALL发病机制中的作用尚不清楚。我们发现18%的成人ALL病例携带TP53,16%携带髓系CH相关基因突变。具有髓系基因突变(MyM)的ALL具有独特的遗传和临床特征,且存活率较低。通过使用单细胞蛋白基因组分析,我们证明髓系突变在ALL确诊前数年就已存在,这些克隆的一个子集随着时间的推移不断扩大,在ALL中表现为显性克隆。单细胞RNA测序显示,在有MyM的B-ALL中,与细胞存活和抗凋亡相关的基因上调,这对较新的免疫治疗方法反应更好。这些发现将伴有MyM的ALL定义为一种可由先兆CH引起的高危疾病,并为开发更好的治疗和预防策略提供了新的机理认识。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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