Browsing by Author "Jiang, Li"

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    BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection
    (National Academy of Sciences, 2019-06-11) Zhu, Bibo; Zhang, Ruixuan; Li, Chaofan; Jiang, Li; Xiang, Min; Ye, Zhenqing; Kita, Hirohito; Melnick, Ari M.; Dent, Alexander L.; Sun, Jie; Pediatrics, School of Medicine
    Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.
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    BCL6 represses antiviral resistance in follicular T helper cells
    (Wiley, 2017-08) Amet, Tohti; Son, Young Min; Jiang, Li; Cheon, In Su; Huang, Su; Gupta, Samir K.; Dent, Alexander L.; Montaner, Luis J.; Yu, Qigui; Sun, Jie; Microbiology and Immunology, School of Medicine
    Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells. A lower antiviral resistance in Tfh was consistent with a higher susceptibility to retroviral infections. Mechanistically, we found that BCL6, a master regulator of Tfh cell development, binds to ISG loci and inhibits the expression of MX2 and IFITM3 in Tfh cells. We demonstrate further that inhibition of the BCL6 BR-C, ttk, and bab (BTB) domain function increases the expression of ISGs and suppresses HIV infection and replication in Tfh cells. Our data reveal a regulatory role of BCL6 in inhibiting antiviral resistance factors in Tfh cells, thereby promoting the susceptibility Tfh cells to viral infections. Our results indicate that the modulation of BCL6 function in Tfh cells could be a potential strategy to enhance Tfh cell resistance to retroviral infections and potentially decrease cellular reservoirs of HIV infection.
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    Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK
    (PLOS, 2021-07-15) Chang, Long-Sheng; Oblinger, Janet L.; Smith, Abbi E.; Ferrer, Marc; Angus, Steven P.; Hawley, Eric; Petrilli, Alejandra M.; Beauchamp, Roberta L.; Riecken, Lars Björn; Erdin, Serkan; Poi, Ming; Huang, Jie; Bessler, Waylan K.; Zhang, Xiaohu; Guha, Rajarshi; Thomas, Craig; Burns, Sarah S.; Gilbert, Thomas S.K.; Jiang, Li; Li, Xiaohong; Lu, Qingbo; Yuan, Jin; He, Yongzheng; Dixon, Shelley A.H.; Masters, Andrea; Jones, David R.; Yates, Charles W.; Haggarty, Stephen J.; La Rosa, Salvatore; Welling, D. Bradley; Stemmer-Rachamimov, Anat O.; Plotkin, Scott R.; Gusella, James F.; Guinney, Justin; Morrison, Helen; Ramesh, Vijaya; Fernandez-Valle, Cristina; Johnson, Gary L.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.
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    Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial
    (Springer Nature, 2021-01) Fisher, Michael J.; Shih, Chie-Schin; Rhodes, Steven D.; Armstrong, Amy E.; Wolters, Pamela L.; Dombi, Eva; Zhang, Chi; Angus, Steven P.; Johnson, Gary L.; Packer, Roger J.; Allen, Jeffrey C.; Ullrich, Nicole J.; Goldman, Stewart; Gutmann, David H.; Plotkin, Scott R.; Rosser, Tena; Robertson, Kent A.; Widemann, Brigitte C.; Smith, Abbi E.; Bessler, Waylan K.; He, Yongzheng; Park, Su-Jung; Mund, Julie A.; Jiang, Li; Bijangi-Vishehsaraei, Khadijeh; Robinson, Coretta Thomas; Cutter, Gary R.; Korf, Bruce R.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
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    Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation
    (Oxford, 2019-08) Rhodes, Steven D.; He, Yongzheng; Smith, Abbi; Jiang, Li; Lu, Qingbo; Mund, Julie; Li, Xiaohong; Bessler, Waylan; Qian, Shaomin; Dyer, William; Sandusky, George E.; Horvai, Andrew E.; Armstrong, Amy E.; Clapp, D. Wade; Pediatrics, School of Medicine
    Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1−/− SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
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    Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma
    (American Association for Cancer Research, 2023) Flint, Alyssa C.; Mitchell, Dana K.; Angus, Steven P.; Smith, Abbi E.; Bessler, Waylan; Jiang, Li; Mang, Henry; Li, Xiaohong; Lu, Qingbo; Rodriguez, Brooke; Sandusky, George E.; Masters, Andi R.; Zhang, Chi; Dang, Pengtao; Koenig, Jenna; Johnson, Gary L.; Shen, Weihua; Liu, Jiangang; Aggarwal, Amit; Donoho, Gregory P.; Willard, Melinda D.; Bhagwat, Shripad V.; Clapp, D. Wade; Rhodes, Steven D.; Pediatrics, School of Medicine
    Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusions: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
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    Early administration of imatinib mesylate reduces plexiform neurofibroma tumor burden with durable results after drug discontinuation in a mouse model of neurofibromatosis type 1
    (Wiley, 2020-05-27) Armstrong, Amy E.; Rhodes, Steven D.; Smith, Abbi; Chen, Shi; Bessler, Waylan; Ferguson, Michael J.; Jiang, Li; Li, Xiaohong; Yuan, Jin; Yang, Xianlin; Yang, Feng-Chun; Robertson, Kent A.; Ingram, David A.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of Medicine
    BACKGROUND Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of pre-existing pNF, however imatinib’s role on preventing pNF development has yet to be explored. PROCEDURE We evaluated the effect of imatinib dosed at 10–100 mg/kg/day for 12 weeks to 1-month old Nf1flox/flox;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib to vehicle treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared to age-matched littermates that received vehicle control. CONCLUSIONS Early administration of imatinib inhibits pNF genesis in vivo and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to substantial development of pNF.
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    Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 1
    (Elsevier, 2020-07-17) Mund, Julie A.; Park, SuJung; Smith, Abbi E.; He, Yongzheng; Jiang, Li; Hawley, Eric; Roberson, Michelle J.; Mitchell, Dana K.; Abu-Sultanah, Mohannad; Yuan, Jin; Bessler, Waylan K.; Sandusky, George; Chen, Shi; Zhang, Chi; Rhodes, Steven D.; Clapp, D. Wade; Pediatrics, School of Medicine
    Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene. NF1 encodes neurofibromin, a GTPase-activating protein for RAS proto-oncogene GTPase (RAS). Plexiform neurofibromas are a hallmark of NF1 and result from loss of heterozygosity of NF1 in Schwann cells, leading to constitutively activated p21RAS. Given the inability to target p21RAS directly, here we performed an shRNA library screen of all human kinases and Rho-GTPases in a patient-derived NF1-/- Schwann cell line to identify novel therapeutic targets to disrupt PN formation and progression. Rho family members, including Rac family small GTPase 1 (RAC1), were identified as candidates. Corroborating these findings, we observed that shRNA-mediated knockdown of RAC1 reduces cell proliferation and phosphorylation of extracellular signal-regulated kinase (ERK) in NF1-/- Schwann cells. Genetically engineered Nf1flox/flox;PostnCre+ mice, which develop multiple PNs, also exhibited increased RAC1-GTP and phospho-ERK levels compared with Nf1flox/flox;PostnCre- littermates. Notably, mice in which both Nf1 and Rac1 loci were disrupted (Nf1flox/floxRac1flox/flox;PostnCre+) were completely free of tumors and had normal phospho-ERK activity compared with Nf1flox/flox ;PostnCre+ mice. We conclude that the RAC1-GTPase is a key downstream node of RAS and that genetic disruption of the Rac1 allele completely prevents PN tumor formation in vivo in mice.
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    Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice
    (Oxford University Press, 2013-12-01) Sharma, Richa; Wu, Xiaohua; Rhodes, Steven D.; Chen, Shi; He, Yongzheng; Yuan, Jin; Li, Jiliang; Yang, Xianlin; Li, Xiaohong; Jiang, Li; Kim, Edward T.; Stevenson, David A.; Viskochil, David; Xu, Mingjiang; Yang, Feng-Chun; Department of Pediatrics, IU School of Medicine
    Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to debilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseudarthrosis (nonunion fracture). Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progenitors and mesenchymal stem cells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPK as a critical pathway underlying the pathogenesis of NF1-associated fracture repair deficits. Nf1-deficient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase activating-related domain (NF1 GAP-related domain) in vitro is sufficient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1−/− pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-deficient murine pro-OBLs. Similarly, MEK inhibition enhances OBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclast maturation in Nf1 haploinsufficient bone marrow mononuclear cells (BMMNCs). Importantly, MEK inhibitor significantly improves fracture healing in an NF1 murine model, Col2.3Cre
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    Interferon regulatory factor 4 sustains CD8+ T cell expansion and effector differentiation
    (Elsevier, 2013-11-14) Yao, Shuyu; Buzo, Bruno Fernando d.; Pham, Duy; Jiang, Li; Taparowsky, Elizabeth J.; Kaplan, Mark H.; Sun, Jie; Pediatrics, School of Medicine
    Upon infection, CD8(+) T cells undergo a stepwise process of early activation, expansion, and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8(+) T cell activation, was vital for sustaining the expansion and effector differentiation of CD8(+) T cells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8(+) T cell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8(+) T cells impaired antiviral CD8(+) T cell responses, viral clearance, and CD8(+) T cell-mediated host recovery from influenza infection. IRF4 expression was regulated by T cell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR signaling into different quantitative and qualitative CD8(+) T cell response