B cell receptor signaling drives APOBEC3 expression via direct enhancer regulation in chronic lymphocytic leukemia B cells

Zhiquan Wang, Huihuang Yan, Justin C. Boysen, Charla R. Secreto, Renee C. Tschumper, Dania Ali, Qianqian Guo, Jian Zhong, Jiaqi Zhou, Haiyun Gan, Chuanhe Yu, Diane F. Jelinek, Susan L. Slager, Sameer A. Parikh, Esteban Braggio, Neil E. Kay

Research output: Contribution to journalArticlepeer-review

Abstract

Constitutively activated B cell receptor (BCR) signaling is a primary biological feature of chronic lymphocytic leukemia (CLL). The biological events controlled by BCR signaling in CLL are not fully understood and need investigation. Here, by analysis of the chromatin states and gene expression profiles of CLL B cells from patients before and after Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib treatment, we show that BTKi treatment leads to a decreased expression of APOBEC3 family genes by regulating the activity of their enhancers. BTKi treatment reduces enrichment of enhancer marks (H3K4me1 and H3K27ac) and chromatin accessibility at putative APOBEC3 enhancers. CRISPR-Cas9 directed deletion or inhibition of the putative APOBEC3 enhancers leads to reduced APOBEC3 expression. We further find that transcription factor NFATc1 couples BCR signaling with the APOBEC3 enhancer activity to control APOBEC3 expression. We also find that enhancer-regulated APOBEC3 expression contributes to replication stress in malignant B cells. In total we demonstrate a novel mechanism for BTKi suppression of APOBEC3 expression via direct enhancer regulation in an NFATc1-dependent manner, implicating BCR signaling as a potential regulator of leukemic genomic instability.

Original languageEnglish (US)
Article number99
JournalBlood cancer journal
Volume12
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
The authors thank all the members of the Mayo Stabile CLL Research group for helpful discussions of the work; and Dr. Rentian Wu for helpful insights and technique supports of the enhancer deletion assays; and Dr. Steven Offer for strategic discussions. We thank the Henry J. Predolin Foundation for the support for the Mayo Clinic CLL Tissue Bank. The work was supported by a Hematology research merit grant, Hematological Malignancies Program (P30CA015083), Hollis Brownstein Research Grants Program from Leukemia Research Foundation, the Mayo Clinic Center for Individualized Medicine (ZW); R01 GM130588 from National Institutes of Health (CY).

Funding Information:
The authors thank all the members of the Mayo Stabile CLL Research group for helpful discussions of the work; and Dr. Rentian Wu for helpful insights and technique supports of the enhancer deletion assays; and Dr. Steven Offer for strategic discussions. We thank the Henry J. Predolin Foundation for the support for the Mayo Clinic CLL Tissue Bank. The work was supported by a Hematology research merit grant, Hematological Malignancies Program (P30CA015083), Hollis Brownstein Research Grants Program from Leukemia Research Foundation, the Mayo Clinic Center for Individualized Medicine (ZW); R01 GM130588 from National Institutes of Health (CY).

Funding Information:
NEK Advisory Board for Abbvie, AstraZeneca, BeiGene, Behring, Cytomx Therapy, Dava Oncology, Janssen, Juno Therapeutics, Oncotracker, Pharmacyclics and Targeted Oncology. DSMC (Data Safety Monitoring Committee) for Agios Pharm, AstraZeneca, BMS/Celgene, Cytomx Therapeutics, Janssen, Morpho-sys, Rigel. Research funding from Abbvie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, MEI Pharma, Pharmacyclics, Sunesis, TG Therapeutics, and Tolero Pharmaceuticals. SAP: Research funding has been provided to the institution from Pharmacyclics, Janssen, AstraZeneca, TG Therapeutics, Merck, AbbVie, and Ascentage Pharma for clinical studies in which SAP is a principal investigator. SAP has also participated in Advisory Board meetings of Pharmacyclics, AstraZeneca, Genentech, GlaxoSmithKline, Adaptive Health, Adaptive Biotechnologies, and AbbVie (he was not personally compensated for his participation).

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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