Increased AID results in mutations at the CRLF2 locus implicated in Latin American ALL health disparities
Year: 2024
Type: article
Abstract: Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.
Source: Nature Communications
Authors: Valeria Rangel, Jason N. Sterrenberg, Aya Garawi, Vyanka Mezcord, Melissa L. Folkerts, Sabrina E. Calderon, Yadhira E. Garcia, Jinglong Wang, Eli M. Soyfer, Oliver S. Eng, Jennifer B. Valerin, Sora Park Tanjasiri, Fabiola Quintero-Rivera, Marcus M. Seldin, Selma Masri, Richard L. Frock, Angela G. Fleischman, Nicholas R. Pannunzio
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Health and Human Services, American Cancer Society, National Institutes of Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Chao Family Comprehensive Cancer Center
Awards: G1169025721, G1680621539, Circadian Clock Disruption and Colorectal Cancer, Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations, G2048011311, G239270354, G2856648956, G3342084782, G3736823865, G426636197, G4410599597, G4874248554, Aberrant V(D)J recombination in B cells initiates lymphoid malignancy, G7177441555, G7212969016, G7745993534, G9000102675, G9000110427, G9000213965, Cancer Center Support Grant, A Training Program for Interdisciplinary Cancer Research, Circadian Clock and Myc-dependent Regulation of Cellular Transformation, G925540568, G950807186
OpenAlex ID: W4401048917