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Browsing by Author "Cai, Zhigang"
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Item Author Correction: Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway(Nature Publishing Group, 2020-07-28) Chen, Sisi; Wang, Qiang; Yu, Hao; Capitano, Maegan L.; Vemula, Sasidhar; Nabinger, Sarah C.; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Geng, Zhuangzhuang; Fahey, Aidan; Henley, Danielle; Liu, Stephen Z.; Barajas, Sergio; Cai, Wenjie; Wolf, Eric R.; Ramdas, Baskar; Cai, Zhigang; Gao, Hongyu; Luo, Na; Sun, Yang; Wong, Terrence N.; Link, Daniel C.; Liu, Yunlong; Boswell, H. Scott; Mayo, Lindsey D.; Huang, Gang; Kapur, Reuben; Yoder, Mervin C.; Broxmeyer, Hal E.; Gao, Zhonghua; Liu, Yan; Biochemistry and Molecular Biology, School of MedicineItem Driver Mutations in Leukemia Promote Disease Pathogenesis through a Combination of Cell-Autonomous and Niche Modulation(Elsevier, 2020-07-14) Ramdas, Baskar; Mali, Raghuveer Singh; Palam, Lakshmi Reddy; Pandey, Ruchi; Cai, Zhigang; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Kapur, Reuben; Pediatrics, School of MedicineStudies of patients with acute myeloid leukemia (AML) have led to the identification of mutations that affect different cellular pathways. Some of these have been classified as preleukemic, and a stepwise evolution program whereby cells acquire additional mutations has been proposed in the development of AML. How the timing of acquisition of these mutations and their impact on transformation and the bone marrow (BM) microenvironment occurs has only recently begun to be investigated. We show that constitutive and early loss of the epigenetic regulator, TET2, when combined with constitutive activation of FLT3, results in transformation of chronic myelomonocytic leukemia-like or myeloproliferative neoplasm-like phenotype to AML, which is more pronounced in double-mutant mice relative to mice carrying mutations in single genes. Furthermore, we show that in preleukemic and leukemic mice there are alterations in the BM niche and secreted cytokines, which creates a permissive environment for the growth of mutation-bearing cells relative to normal cells.Item Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development(Company of Biologists, 2014-02-01) Li, Hongge; Tao, Chenqi; Cai, Zhigang; Hertzler-Schaefer, Kristina; Collins, Tamica N.; Wang, Fen; Feng, Gen-Sheng; Gotoh, Noriko; Zhang, Xin; Department of Medical and Molecular Genetics, IU School of MedicineFibroblast growth factor (FGF) signaling requires a plethora of adaptor proteins to elicit downstream responses, but the functional significances of these docking proteins remain controversial. In this study, we used lens development as a model to investigate Frs2α and its structurally related scaffolding proteins, Gab1 and Gab2, in FGF signaling. We show that genetic ablation of Frs2α alone has a modest effect, but additional deletion of tyrosine phosphatase Shp2 causes a complete arrest of lens vesicle development. Biochemical evidence suggests that this Frs2α-Shp2 synergy reflects their epistatic relationship in the FGF signaling cascade, as opposed to compensatory or parallel functions of these two proteins. Genetic interaction experiments further demonstrate that direct binding of Shp2 to Frs2α is necessary for activation of ERK signaling, whereas constitutive activation of either Shp2 or Kras signaling can compensate for the absence of Frs2α in lens development. By contrast, knockout of Gab1 and Gab2 failed to disrupt FGF signaling in vitro and lens development in vivo. These results establish the Frs2α-Shp2 complex as the key mediator of FGF signaling in lens development.Item Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid(American Society for Clinical Investigation, 2021-01-04) Cai, Zhigang; Lu, Xiaoyu; Zhang, Chi; Nelanuthala, Sai; Aguilera, Fabiola; Hadley, Abigail; Ramdas, Baskar; Fang, Fang; Nephew, Kenneth; Kotzin, Jonathan J.; Williams, Adam; Henao-Mejia, Jorge; Haneline, Laura; Kapur, Reuben; Microbiology and Immunology, School of MedicineDiabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.Item Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis(Elsevier, 2018-12-06) Cai, Zhigang; Kotzin, Jonathan J.; Ramdas, Baskar; Chen, Sisi; Nelanuthala, Sai; Palam, Lakshmi Reddy; Pandey, Ruchi; Mali, Raghuveer Singh; Liu, Yan; Kelley, Mark R.; Sandusky, George; Mohseni, Morvarid; Williams, Adam; Henao-Mejia, Jorge; Kapur, Reuben; Pediatrics, School of MedicineInflammation is a risk factor for cancer development. Individuals with preleukemic TET2 mutations manifest clonal hematopoiesis and are at a higher risk of developing leukemia. How inflammatory signals influence the survival of preleukemic hematopoietic stem and progenitor cells (HSPCs) is unclear. We show a rapid increase in the frequency and absolute number of Tet2-KO mature myeloid cells and HSPCs in response to inflammatory stress, which results in enhanced production of inflammatory cytokines, including interleukin-6 (IL-6), and resistance to apoptosis. IL-6 induces hyperactivation of the Shp2-Stat3 signaling axis, resulting in increased expression of a novel anti-apoptotic long non-coding RNA (lncRNAs), Morrbid, in Tet2-KO myeloid cells and HSPCs. Expression of activated Shp2 in HSPCs phenocopies Tet2 loss with regard to hyperactivation of Stat3 and Morrbid. In vivo, pharmacologic inhibition of Shp2 or Stat3 or genetic loss of Morrbid in Tet2 mutant mice rescues inflammatory-stress-induced abnormalities in HSPCs and mature myeloid cells, including clonal hematopoiesis.Item Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway(Nature Research, 2019-12-11) Chen, Sisi; Wang, Qiang; Yu, Hao; Capitano, Maegan L.; Vemula, Sasidhar; Nabinger, Sarah C.; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Geng, Zhuangzhuang; Fahey, Aidan; Henley, Danielle; Liu, Stephen Z.; Barajas, Sergio; Sergio, Wenjie; Wolf, Eric R.; Ramdas, Baskar; Cai, Zhigang; Gao, Hongyu; Luo, Na; Sun, Yang; Wong, Terrence N.; Link, Daniel C.; Liu, Yunlong; Boswell, H. Scott; Mayo, Lindsey D.; Huang, Gang; Kapur, Reuben; Yoder, Mervin C.; Broxmeyer, Hal E.; Gao, Zhonghua; Liu, Yan; Biochemistry and Molecular Biology, School of MedicineClonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.Item Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis(Wiley Online Library, 2014-10) Cai, Zhigang; Grobe, Kay; Zhang, Xin; Department of Ophthalmology, IU School of MedicineBackground Heparan sulfate proteoglycans (HSPG) are important for embryonic development via the regulation of gradient formation and signaling of multiple growth factors and morphogens. Previous studies have shown that Bmp/Shh/Fgf signaling are required for the regionalization of the optic vesicle (OV) and for the closure of the optic fissure (OF), the disturbance of which underlie ocular anomalies such as microphthalmia, coloboma and optic nerve hypoplasia. Results To study HSPG-dependent coordination of these signaling pathways during mammalian visual system development, we have generated a series of OV-specific mutations in the heparan sulfate (HS) N-sulfotransferase genes (Ndst1 and Ndst2) and HS O-sulfotransferase genes (Hs2st, Hs6st1 and Hs6st2) in mice. Interestingly, the resulting HS undersulfation still allowed for normal retinal neurogenesis and optic fissure closure, but led to defective optic disc and stalk development. The adult mutant animals further developed optic nerve aplasia/hypoplasia and displayed retinal degeneration. We observed that MAPK/ERK signaling was down-regulated in Ndst mutants, and consistent with this, HS-related optic nerve morphogenesis defects in mutant mice could partially be rescued by constitutive Kras activation. Conclusions These results suggest that HSPGs, depending on their HS sulfation pattern, regulate multiple signaling pathways in optic disc and stalk morphogenesis.Item Role of lncRNA Morrbid in PTPN11(Shp2)E76K-driven juvenile myelomonocytic leukemia(American Society of Hematology, 2020-07-22) Cai, Zhigang; Zhang, Chi; Kotzin, Jonathan J.; Williams, Adam; Henao-Mejia, Jorge; Kapur, Reuben; Pediatrics, School of MedicineMutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, contribute to ∼35% of cases of juvenile myelomonocytic leukemia (JMML). A common clinical picture in children with JMML is that it presents as a constitutive hyperinflammatory syndrome, partially reminiscent of chronic myelomonocytic leukemia in adults. Thus, a component of JMML is associated with a hyperinflammatory state and abundant innate immune cells such as neutrophils and monocytes. Recently, we showed that the evolutionarily conserved mouse lncRNA Morrbid is specifically expressed in myeloid cells and uniquely represses the expression of the proapoptotic gene Bim to regulate the lifespan of myeloid cells. However, its role in JMML has not been investigated. In this study, we characterized the role of Morrbid and its target Bim, which are significantly dysregulated in Shp2E76K/+-bearing myeloid cells, in driving JMML. Loss of Morrbid in a mouse model of JMML driven by the Shp2E76K/+ mutation resulted in a significant correction of myeloid and erythroid cell abnormalities associated with JMML, including overall survival. Consistently, patients with JMML who had PTPN11, KRAS, and NRAS mutations and high expression of MORRBID manifested poor overall survival. Our results suggest that Morrbid contributes to JMML pathogenesis.Item Targeting Bim via a lncRNA Morrbid Regulates the Survival of Preleukemic and Leukemic Cells(Elsevier, 2020-06-23) Cai, Zhigang; Aguilera, Fabiola; Ramdas, Baskar; Daulatabad, Swapna Vidhur; Srivastava, Rajneesh; Kotzin, Jonathan J.; Carroll, Martin; Wertheim, Gerald; Williams, Adam; Janga, Sarath Chandra; Zhang, Chi; Henao-Mejia, Jorge; Kapur, Reuben; Pediatrics, School of MedicineInhibition of anti-apoptotic proteins BCL-2 and MCL-1 to release pro-apoptotic protein BIM and reactivate cell death could potentially be an efficient strategy for the treatment of leukemia. Here, we show that a lncRNA, MORRBID, a selective transcriptional repressor of BIM, is overexpressed in human acute myeloid leukemia (AML), which is associated with poor overall survival. In both human and animal models, MORRBID hyperactivation correlates with two recurrent AML drivers, TET2 and FLT3ITD. Mice with individual mutations of Tet2 or Flt3ITD develop features of chronic myelomonocytic leukemia (CMML) and myeloproliferative neoplasm (MPN), respectively, and combined presence results in AML. We observe increased levels of Morrbid in murine models of CMML, MPN, and AML. Functionally, loss of Morrbid in these models induces increased expression of Bim and cell death in immature and mature myeloid cells, which results in reduced infiltration of leukemic cells in tissues and prolongs the survival of AML mice.