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Browsing by Author "Gao, Rui"
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Item Access provided by IUPUI University Library, Indiana (Ruth Lilly) Altmetric: 0Citations: 2More detail Letter to the Editor Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia(Nature, 2017) Kobayashi, Michihiro; Chen, Sisi; Bai, Yunpeng; Yao, Chonghua; Gao, Rui; Sun, Xiao-Jian; Mu, Chen; Twiggs, Taylor A.; Yu, Zhi-Hong; Boswell, H. Scott; Yoder, Mervin C.; Kapur, Reuben; Mulloy, James C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of MedicineItem 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 Bmi1 maintains the self-renewal property of innate-like B lymphocytes(American Association of Immunologists, 2020-06-15) Kobayashi, Michihiro; Lin, Yang; Mishra, Akansha; Shelly, Chris; Gao, Rui; Reeh, Colton W; Wang, Paul Zhiping; Xi, Rongwen; Liu, Yunlong; Wenzel, Pamela; Ghosn, Eliver; Liu, Yan; Yoshimoto, Momoko; Pediatrics, School of MedicineThe self-renewal ability is a unique property of fetal-derived innate-like B-1a lymphocytes, which survive and function without being replenished by bone marrow (BM) progenitors. However, the mechanism by which IgM-secreting mature B-1a lymphocytes self-renew is poorly understood. In this study, we showed that Bmi1 was critically involved in this process. Although Bmi1 is considered essential for lymphopoiesis, the number of mature conventional B cells was not altered when Bmi1 was deleted in the B cell lineage. In contrast, the number of peritoneal B-1a cells was significantly reduced. Peritoneal cell transfer assays revealed diminished self-renewal ability of Bmi1-deleted B-1a cells, which was restored by additional deletion of Ink4-Arf, the well-known target of Bmi1 Fetal liver cells with B cell-specific Bmi1 deletion failed to repopulate peritoneal B-1a cells, but not other B-2 lymphocytes after transplantation assays, suggesting that Bmi1 may be involved in the developmental process of B-1 progenitors to mature B-1a cells. Although Bmi1 deletion has also been shown to alter the microenvironment for hematopoietic stem cells, fat-associated lymphoid clusters, the reported niche for B-1a cells, were not impaired in Bmi1 -/- mice. RNA expression profiling suggested lysine demethylase 5B (Kdm5b) as another possible target of Bmi1, which was elevated in Bmi1-/- B-1a cells in a stress setting and might repress B-1a cell proliferation. Our work has indicated that Bmi1 plays pivotal roles in self-renewal and maintenance of fetal-derived B-1a cells.Item Bmi1 promotes erythroid development through regulating ribosome biogenesis(Wiley, 2015-03) Gao, Rui; Chen, Sisi; Kobayashi, Michihiro; Yu, Hao; Zhang, Yingchi; Wan, Yang; Young, Sara K.; Soltis, Anthony; Yu, Ming; Vemula, Sasidhar; Fraenkel, Ernest; Cantor, Alan; Antipin, Yevgeniy; Xu, Yang; Yoder, Mervin C.; Wek, Ronald C.; Ellis, Steven R.; Kapur, Reuben; Zhu, Xiaofan; Liu, Yan; Department of Pediatrics, Indiana University School of MedicineWhile Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including Diamond-Blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies.Item Bmi1 Regulates Wnt Signaling in Hematopoietic Stem and Progenitor Cells(Springer, 2021) Yu, Hao; Gao, Rui; Chen, Sisi; Liu, Xicheng; Wang, Qiang; Cai, Wenjie; Vemula, Sasidhar; Fahey, Aidan C.; Henley, Danielle; Kobayashi, Michihiro; Liu, Stephen Z.; Qian, Zhijian; Kapur, Reuben; Broxmeyer, Hal E.; Gao, Zhonghua; Xi, Rongwen; Liu, Yan; Pediatrics, School of MedicinePolycomb group protein Bmi1 is essential for hematopoietic stem cell (HSC) self-renewal and terminal differentiation. However, its target genes in hematopoietic stem and progenitor cells are largely unknown. We performed gene expression profiling assays and found that genes of the Wnt signaling pathway are significantly elevated in Bmi1 null hematopoietic stem and progenitor cells (HSPCs). Bmi1 is associated with several genes of the Wnt signaling pathway in hematopoietic cells. Further, we found that Bmi1 represses Wnt gene expression in HSPCs. Importantly, loss of β-catenin, which reduces Wnt activation, partially rescues the HSC self-renewal and differentiation defects seen in the Bmi1 null mice. Thus, we have identified Bmi1 as a novel regulator of Wnt signaling pathway in HSPCs. Given that Wnt signaling pathway plays an important role in hematopoiesis, our studies suggest that modulating Wnt signaling may hold potential for enhancing HSC self-renewal, thereby improving the outcomes of HSC transplantation.Item Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML(Impact Journals, 2017-12-25) Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry D.; Weisenbach, Jill; Sargent, Katie J.; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Boswell, H. Scott; Medicine, School of MedicineCo-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.Item Genotoxic stresses promote clonal expansion of hematopoietic stem cells expressing mutant p53(Nature, 2018) Chen, Sisi; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Liu, Stephen Z.; Yoder, Mervin C.; Broxmeyer, Hal; Kapur, Reuben; Boswell, H. Scott; Mayo, Lindsey D.; Liu, Yan; Pediatrics, School of MedicineItem 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 Mutant p53 enhances leukemia-initiating cell self-renewal to promote leukemia development(Nature, 2019-06) Nabinger, Sarah C.; Chen, Sisi; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Vemula, Sasidhar; Fahey, Aidan C.; Wang, Christine; Daniels, Cecil; Boswell, H. Scott; Sandusky, George E.; Mayo, Lindsey D.; Kapur, Reuben; Liu, Yan; Pediatrics, School of MedicineItem Necdin modulates leukemia-initiating cell quiescence and chemotherapy response(Impact Journals, 2017-09-18) Yao, Chonghua; Kobayashi, Michihiro; Chen, Sisi; Nabinger, Sarah C.; Gao, Rui; Liu, Stephen Z.; Asai, Takashi; Liu, Yan; Pediatrics, School of MedicineAcute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.