Person: Wang, Qi
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Publication Phosphatidylinositol 3-Kinase (PI3K) δ blockade increases genomic instability in B cells(2017) Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Meng, Fei-Long; Poggio, Teresa; Yeap, Leng-Siew; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Ambrogio, Chiara; Voena, Claudia; Wiestner, Adrian; Kasar, Siddha N.; Brown, Jennifer; Sun, Jing; Wu, Catherine; Gostissa, Monica; Alt, Frederick; Chiarle, RobertoActivation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM)1. Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression2. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells4. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib block PI3Kδ activity directly or indirectly5–8, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both these effects were completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism, an effect that should be carefully considered as such inhibitors are administered for years to patients.Publication Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1(Impact Journals LLC, 2016) Voena, Claudia; Varesio, Lydia M.; Zhang, Liye; Menotti, Matteo; Poggio, Teresa; Panizza, Elena; Wang, Qi; Minero, Valerio G.; Fagoonee, Sharmila; Compagno, Mara; Altruda, Fiorella; Monti, Stefano; Chiarle, RobertoA subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. ALK-rearranged NSCLC are typically adenocarcinoma characterized by a solid signet-ring cell pattern that is frequently associated with a metastatic phenotype. Recent reports linked the presence of ALK rearrangement to an epithelial-mesenchymal transition (EMT) phenotype in NSCLC, but the extent and the mechanisms of an ALK-mediated EMT in ALK-rearranged NSCLC are largely unknown. We found that the ALK-rearranged H2228 and DFCI032, but not the H3122, cell lines displayed a mesenchymal phenotype. In these cell lines, oncogenic ALK activity dictated an EMT phenotype by directly suppressing E-cadherin and up-regulating vimentin expression, as well as expression of other genes involved in EMT. We found that the epithelial splicing regulatory protein 1 (ESRP1), a key regulator of the splicing switch during EMT, was repressed by EML4-ALK activity. The treatment of NSCLC cells with ALK tyrosine kinase inhibitors (TKIs) led to up-regulation of ESRP1 and E-cadherin, thus reverting the phenotype from mesenchymal to epithelial (MET). Consistently, ESRP1 knock-down impaired E-cadherin up-regulation upon ALK inhibition, whereas enforced expression of ESRP1 was sufficient to increase E-cadherin expression. These findings demonstrate an ALK oncogenic activity in the regulation of an EMT phenotype in a subset of NSCLC with potential implications for the biology of ALK-rearranged NSCLC in terms of metastatic propensity and resistance to therapy.Publication Preoperative Neutrophil-to-Lymphocyte Ratio and Neutrophilia Are Independent Predictors of Recurrence in Patients with Localized Papillary Renal Cell Carcinoma(Hindawi Publishing Corporation, 2015) Huang, Jiwei; Dahl, Douglas; Dong, Liang; Liu, Qiang; Cornejo, Kristine; Wang, Qi; Wu, Shulin; Feldman, Adam; Huang, Yiran; Xue, Wei; Wu, Chin-LeeObjective:. To evaluate the role of preoperative neutrophil-to-lymphocyte ratio (NLR) and absolute neutrophil count (ANC) in patients' prognosis with localized papillary renal cell carcinoma (pRCC). Methods:. Data from 218 localized pRCC patients (T1-3 N0/+ M0), operated between 1991 and 2011 at two centers, were evaluated retrospectively. Univariable and multivariable analyses using the Cox regression model were performed to determine the associations of NLR and ANC with recurrence-free survival (RFS). Prognostic accuracy was evaluated with the Harrell concordance index. Results:. The 5-year RFS rate was 87.0%. Multivariable analysis identified increased NLR (≥3.6) and ANC (≥5300/μL) as independent prognostic factors for RFS (hazard ratio (HR) = 4.01, P = 0.018) and (HR = 4.71, P = 0.045). The final model built by the addition of NLR or ANC improved predictive accuracy (c-index: 0.824, 0.842) compared with the clinicopathological base model (c-index: 0.800), which included TNM stage and tumor necrosis. Conclusions:. The NLR and ANC appear to be independent prognostic factors for RFS after surgery for localized pRCC. They significantly increase the accuracy of established prognostic factors. Therefore, we recommend adding NLR and ANC to traditional prognostic model, which may improve its predictive accuracy.