An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.

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Blood, ISSN: 1528-0020, Vol: 130, Issue: 19, Page: 2131-2145

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Poe, Jonathan C, Jia, Wei, Su, Hsuan, Anand, Sarah, Rose, Jeremy J, Tata, Prasanthi V, Suthers, Amy N, Jones, Corbin D, Kuan, Pei Fen, Vincent, Benjamin G, Serody, Jonathan S, Horwitz, Mitchell E, Ho, Vincent T, Pavletic, Steven Z, Hakim, Frances T, Owzar, Kouros, Zhang, Dadong, Blazar, Bruce R, Siebel, Christian W, Chao, Nelson J, Maillard, Ivan, Sarantopoulos, Stefanie Show More Hide
American Society of Hematology
Biochemistry, Genetics and Molecular Biology, Immunology and Microbiology, Medicine
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article description
B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors and , each critical to B-cell differentiation and fate. All- retinoic acid (ATRA) increased expression, restored the -to- ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated and , but not (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.

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