Details

Autor(en) / Beteiligte

• Chen, Jingyu
• Sathiaseelan, Vijitha
• Reddy Chilamakuri, Chandra Sekkar
• Roamio Franklin, Valar Nila
• Jakwerth, Constanze A.
• D’Santos, Clive
• Ringshausen, Ingo

Titel

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

Ist Teil von

• Blood advances, 2024-03, Vol.8 (5), p.1167-1178

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• •ZAP-70 enhances a tonic BCR-signal exclusively found in IGHV-unmutated CLL.•ZAP-70 augments CCR7-signaling and cell migration of unmutated CLL through activation of LCP-1. [Display omitted] 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.