ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV-unmutated chronic lymphocytic leukemia.
Jingyu ChenVijitha SathiaseelanChandra Sekkar Reddy ChilamakuriValar Nila Roamio FranklinConstanze A JakwerthClive D'SantosIngo RingshausenPublished in: Blood advances (2024)
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.
Keyphrases
- chronic lymphocytic leukemia
- acute lymphoblastic leukemia
- tyrosine kinase
- poor prognosis
- chronic myeloid leukemia
- mass spectrometry
- cell migration
- liver injury
- binding protein
- free survival
- signaling pathway
- liver fibrosis
- dendritic cells
- drug induced
- regulatory t cells
- cell proliferation
- liquid chromatography
- machine learning
- oxidative stress
- immune response
- diabetic rats
- big data
- high performance liquid chromatography
- high glucose
- smoking cessation
- replacement therapy