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Publications

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
Blood Cancer Discovery Dec 2023
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.

VIEW

Area

Heme

Institution Type

Academia

Indication / Modality

Myeloproliferative Neoplasms (MPN), Acute Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia (ALL)

Goal of Study

Clinical Profiling, CHIP

Key Genes

TP53

PAD Project

No

Analytes Assessed

CNV

Sample Type

Patient Material

Tissue / Organ

Bone Marrow Aspirates

Species

Human
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