Acute lymphoblastic leukemia with myeloid mutations is a high-risk disease associated with clonal hematopoiesis
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- General Medicine
Abstract
Myeloid neoplasms arise from pre-existing clonal hematopoiesis (CH), however the role of CH in pathogenesis of 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.