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
{"title":"Acute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.","authors":"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","doi":"10.1158/2643-3230.BCD-23-0106","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p><p><strong>Significance: </strong>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.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"164-179"},"PeriodicalIF":11.5000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061587/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cancer Discovery","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2643-3230.BCD-23-0106","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
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.
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.