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Ringshausen, I.* ; Chen, J.* ; Sathiaseelan, V.* ; Chilamakuri, C.S.* ; Jakwerth, C.A. ; D'Santos, C.S.* ; Roamio Franklin, V.N.*

ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV unmutated chronic lymphocytic leukemia.

Blood Adv. 8, 1167-1178 (2023)
Publ. Version/Full Text DOI PMC
Free journal
Expression of ZAP-70 in a subset of CLL patients positively correlates with the absence of IGHV mutations and is indicative of a more active disease and shorter treatment free survival. We recently demonstrated that ZAP-70 regulates the constitutive expression of CCL3 and CCL4, activation of AKT and expression of MYC in the absence of an overt BCR signal, bona fide functions of BCR activation. We here provide evidence that these features relate to the presence of a constitutive tonic BCR signal, exclusively found in IGHV unmutated CLL and dependent on the ZAP-70 mediated activation of AKT and its downstream target GSK3b. These findings are associated with increased steady state activation of CD19 and SRC. Notably this tonic BCR signal is not present in IGHV mutated CLL cells, discordantly expressing ZAP-70. Quantitative mass spectrometry and phosphoprotein-analyses indicate that this ZAP-70-dependent, tonic BCR-signal regulates CLL cell migration through phosphorylation of LCP1 on serine-5. Indeed, we show that CCL19- and CCL21-induced chemotaxis is regulated by and dependent on the expression of ZAP-70 through its function to enhance CCR7 signaling to LCP1. Thus, our data demonstrate that ZAP-70 converges a tonic BCR signal, exclusively present in IGHV unmutated CLL, and CCR7-mediated chemotaxis.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Tyrosine Kinase; Constitutive Activation; Immunological-synapse; Gene-expression; L-plastin; Actin; Cll; Wasp; Recruitment; Inhibition
ISSN (print) / ISBN 2473-9529
e-ISSN 2473-9537
Journal Blood advances
Quellenangaben Volume: 8, Issue: 5, Pages: 1167-1178 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place Washington, DC
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Grants Natural Science Foundation of China
Cancer Research UK
Kay Kendell Foundation