Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Sadras, Teresa; Martin, M.; Kume, Kohei; Robinson, Mark E.; Saravanakumar, Supraja; Lenz, Gal; Chen, Zhengshan; Song, Joo Y.; Siddiqi, Tanya; Oksa, Laura; Knapp, Anne‐Marie; Cutler, Jevon; Cosgun, Kadriye Nehir; Klemm, Lars; Ecker, Veronika; Winchester, Janet; Ghergus, Dana; Soulas-Sprauel, Pauline; Kiefer, Friedemann; Heisterkamp, Nora; Pandey, Akhilesh; Ngo, Vu N.; Wang, Lili; Jumaa, Hassan; Buchner, Maike; Ruland, Jürgen; Chan, Wing C.; Meffre, Eric; Martin, Thierry; Müschen, Markus

doi:10.1016/j.molcel.2021.03.043

Cited by 19 publications

(36 citation statements)

References 83 publications

(77 reference statements)

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“…To the best of our knowledge, the association of BEST2 gene and the prognosis of HNSCC was identified for the first time in our study. ZAP70 (Zeta chain of T cell receptor associated protein kinase 70) is expressed in a broad range of B cell malignancies ( Sadras et al, 2021 ). Chen et al demonstrated that ZAP70 could promote cell survival, microenvironment interactions, protein synthesis and further drive disease progression in chronic lymphocytic leukemia cells (Chen et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Prognostic Model Based on Fatty Acid Metabolism-Related Genes of Head and Neck Squamous Cell Carcinoma

Chai

Zong

et al. 2022

Front. Genet.

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The fatty acid metabolism (FAM) is known to impact tumorigenesis, tumor progression and treatment resistance via enhancing lipid synthesis, storage and catabolism. However, the role of FAM in head and neck squamous cell carcinoma (HNSCC) has remained elusive. In the present study, we obtained a total of 69 differentially expressed FAM-related genes between 502 HNSCC samples and 44 normal samples from The Cancer Genome Atlas (TCGA) database. The HNSCC samples were divided into 2 clusters according to 69 differentially expressed genes (DEGs) via cluster analysis. Then DEGs in the two clusters were found, and 137 prognostic DEGs were identified by univariate analysis. Subsequently, combined with the clinical information of 546 HNSCC patients from TCGA database, a 12-gene prognostic risk model was established (FEPHX3, SPINK7, FCRLA, MASP1, ZNF541, CD5, BEST2 and ZAP70 were down-regulation, ADPRHL1, DYNC1I1, KCNG1 and LINC00460 were up-regulation) using multivariate Cox regression and LASSO regression analysis. The risk scores of 546 HNSCC samples were calculated. According to the median risk score, 546 HNSCC patients were divided into the high- and low-risk (high- and low score) groups. The Kaplan-Meier survival analysis showed that the survival time of HNSCC patients was significantly shorter in the high-risk group than that in the low-risk group (p < 0.001). The same conclusion was obtained in the Gene Expression Omnibus (GEO) dataset. After that, the multivariate Cox regression analysis indicated that the risk score was an independent factor for patients with HNSCC in the TCGA cohort. In addition, single-sample gene set enrichment analysis (ssGSEA) indicated that the level of infiltrating immune cells was relatively low in the high-risk group compared with the low-risk group. In summary, FAM-related gene expression-based risk signature could predict the prognosis of HNSCC independently.

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Section: Discussionmentioning

confidence: 99%

Identification of a Prognostic Model Based on Fatty Acid Metabolism-Related Genes of Head and Neck Squamous Cell Carcinoma

Chai

Zong

et al. 2022

Front. Genet.

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“…The BCR connection to RAS is likely mainly through CD19 and PI3K. Hence, LYN, SYK and ZAP-70 have been shown to phosphorylate the YXXM motif in CD19, to which PI3K can tether (90)(91)(92). Moreover, generation of phosphatidylinositol (3-5)-trisphosphate (PIP3) by PI3K is essential for the activity of and membrane tethering of BTK (93)(94)(95).…”

Section: Lack Of Btki Resistance Mutations In the Pi3k-ras And Calcineurin Arms Of The Bcr Pathwaymentioning

confidence: 99%

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

Smith

Burger

2021

Front. Immunol.

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Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the BTK gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic BTK driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.

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“…However, although this study focused on monocytes/macrophages, the results suggest that B cells also could over-express this protein. Upon BCR signalling, SYK phosphorylates CD19, which promotes the recruitment of PI3K to the membrane and subsequently results in activation of AKT [ 114 , 124 , 125 , 126 , 127 ] ( Figure 2 ). AKT activation in turn leads to the phosphorylation of the transcription factor FOXO, preventing apoptosis [ 128 ] and promoting survival.…”

Section: Key Features Of B Lineage Cells In Aavmentioning

confidence: 99%

B Lineage Cells in ANCA-Associated Vasculitis

Merino-Vico

Hamburg

Tas

2021

IJMS

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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that affects small sized blood vessels and can lead to serious complications in the lungs and kidneys. The prominent presence of ANCA autoantibodies in this disease implicates B cells in its pathogenesis, as these are the precursors of the ANCA-producing plasma cells (PCs). Further evidence supporting the potential role of B lineage cells in vasculitis are the increased B cell cytokine levels and the dysregulated B cell populations in patients. Confirmation of the contribution of B cells to pathology arose from the beneficial effect of anti-CD20 therapy (i.e., rituximab) in AAV patients. These anti-CD20 antibodies deplete circulating B cells, which results in amelioration of disease. However, not all patients respond completely, and this treatment does not target PCs, which can maintain ANCA production. Hence, it is important to develop more specific therapies for AAV patients. Intracellular signalling pathways may be potential therapeutic targets as they can show (disease-specific) alterations in certain B lineage cells, including pathogenic B cells, and contribute to differentiation and survival of PCs. Preliminary data on the inhibition of certain signalling molecules downstream of receptors specific for B lineage cells show promising therapeutic effects. In this narrative review, B cell specific receptors and their downstream signalling molecules that may contribute to pathology in AAV are discussed, including the potential to therapeutically target these pathways.

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Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Cited by 19 publications

References 83 publications

Identification of a Prognostic Model Based on Fatty Acid Metabolism-Related Genes of Head and Neck Squamous Cell Carcinoma

Identification of a Prognostic Model Based on Fatty Acid Metabolism-Related Genes of Head and Neck Squamous Cell Carcinoma

Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway

B Lineage Cells in ANCA-Associated Vasculitis

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