| Autor: |
Fujisawa, M, Sakata-Yanagimoto, M, Nishizawa, S, Komori, D, Gershon, P, Kiryu, M, Tanzima, S, Fukumoto, K, Enami, T, Muratani, M, Yoshida, K, Ogawa, S, Matsue, K, Nakamura, N, Takeuchi, K, Izutsu, K, Fujimoto, K, Teshima, T, Miyoshi, H, Gaulard, P, Ohshima, K |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Zdroj: |
Leukemia. 32(3):694-702 |
| ISSN: |
0887-6924 |
| Popis: |
Somatic G17V RHOA mutations were found in 50–70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1–STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1–STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1–STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA–VAV1 axis may provide a new therapeutic target in AITL. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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