Chen, Jingyu;
Sathiaseelan, Vijitha;
Reddy Chilamakuri, Chandra Sekkar;
Roamio Franklin, Valar Nila;
Jakwerth, Constanze A;
D'Santos, Clive;
Ringshausen, Ingo;
(2024)
ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV–unmutated chronic lymphocytic leukemia.
Blood Advances
, 8
(5)
pp. 1167-1178.
10.1182/bloodadvances.2022009557.
Preview |
Text
blooda_adv-2022-009557-main.pdf - Published Version Download (1MB) | Preview |
Abstract
Expression of ZAP-70 in a subset of patients with chronic lymphocytic leukemia (CLL) positively correlates with the absence of immunoglobulin heavy-chain gene (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 B-cell receptor (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 GSK-3β. 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. Results of 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.
| Type: | Article |
|---|---|
| Title: | ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV–unmutated chronic lymphocytic leukemia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/bloodadvances.2022009557 |
| Publisher version: | http://dx.doi.org/10.1182/bloodadvances.2022009557 |
| Language: | English |
| Additional information: | Copyright © 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode, permitting only noncommercial, nonderivative use with attribution. All other rights reserved. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10188682 |
Archive Staff Only
 |
View Item |
