Increased AID results in mutations at the CRLF2 locus implicated in Latin American ALL health disparities

Sep 21, 2026

Uploaded by Liam

Activation-induced cytidine deaminase (AID) drives antibody diversification but also contributes to B cell malignancies. The study quantifies AID-related mutation load and DNA double-strand break formation and repair using a digital PCR assay at DSB-prone sites. Increased AID levels in immature B cells promote genome instability at loci involved in chromosomal translocations, including CRLF2. Using dPCR on B cell-derived DNA from Hispanic ALL patients and healthy Hispanic donors, the work detects elevated CRLF2 mutations in both groups, suggesting heightened vulnerability to DNA damage may underlie observed health disparities. Quantification enables improved risk identification, early detection, and disparity reduction.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Immunological background and AID function

Digital PCR assay and quantification strategy

Findings at the CRLF2 locus and links to translocations

Implications for risk identification and health disparity reduction

Article [https://doi.org/10.1038/s41467-024-50537-0](https://doi.org/10.1038/s41467-024-50537-0) Increased AID results in mutations at the CRLF2 locus implicated in Latin American ALL health disparities Received: 6 September 2023 | Accepted: 10 July 2024 | | --- | | | | Check for updates | Valeria Rangel1,2,12, Jason N. Sterrenberg1,12, Aya Garawi3, Vyanka Mezcord4, Melissa L. Folkerts 1,2, Sabrina E. Calderon3, Yadhira E. Garcia5, Jinglong Wang6, Eli M. Soyfer 1,2, Oliver S. Eng 7,8, Jennifer B. Valerin1,8, Sora Park Tanjasiri8,9, Fabiola Quintero-Rivera10,11, Marcus M. Seldin 2,8, Selma Masri 2,8, Richard L. Frock 6, Angela G. Fleischman 1,2,8 & Nicholas R. Pannunzio 1,2,8 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 cellderived genomic DNA from both Hispanic ALL patients and healthy Hispanic donorsand found increased mutations in both, suggesting that vulnerability to DNA damage atCRLF2maybe 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. Diversiﬁcation of the immunoglobulin heavy chain (IGH) locus in B cells is a form ofphysiological genome editing that has been conserved over 500 million years of evolution1,2. As B cells mature, DNA doublestrand breaks (DSBs) are generated at two different points by two distinct mechanisms to modify the region oftheIGHgene that encodes for either the antibody variable region or the antibody constant region3. In pro-B/pre-B cells, the recombination activating gene (RAG) complex is expressed to generate DSBs at the variable (V), diversity 1Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA. 2Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. 3School of Biological Sciences, University of California, Irvine, Irvine, CA, USA. 4Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA, USA. 5Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, CA, USA. 6Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. 7Division of Surgical Oncology, Department of Surgery, University of California, Irvine, Irvine, CA, USA. 8Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA. 9Department of Health, Society and Behavior, University of California, Irvine, Irvine, CA, USA. 10Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA. 11Department of Pediatrics, University of California, Irvine, Irvine, CA, USA. 12These authors contributed equally: Valeria Rangel, Jason N. Sterrenberg. e-mail: [nrpann@hs.uci.edu](nrpann@hs.uci.edu) (D), and joining (J) gene segments during V(D)J recombination4. In mature B cells, activation-induced

FAQs

What role does AID play in B cells and why is it important for cancer risk?

AID is a B cell-specific mutator required for antibody diversification, but aberrant or off-target activity can contribute to several B cell malignancies. Its dysregulation can lead to genome-wide mutations and increase cancer risk.

How does the study measure AID-induced mutations and DNA break repair?

The researchers develop a digital PCR (dPCR) assay to quantify mutations generated by AID modification and by DNA double-strand break formation and subsequent repair at DSB-prone sites.

What did dPCR show about the CRLF2 locus in Hispanic ALL patients versus healthy donors?

dPCR identified increased mutations at the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors, indicating vulnerability to DNA damage at CRLF2 may contribute to health disparities.

Sep 21, 2026

Uploaded by Liam