Browsing by Author "Yao, Chonghua"

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    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 Medicine
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    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 Medicine
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    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 Medicine
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    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 Medicine
    Clonal 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.
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    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 Medicine
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    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 Medicine
    Acute 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.
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    Pharmacological inhibition of AKT activity in human CD34+ cells enhances their ability to engraft immunodeficient mice
    (Elsevier, 2017-01) Chen, Sisi; Gao, Rui; Kobayashi, Michihiro; Yu, Hao; Yao, Chonghua; Kapur, Reuben; Yoder, Mervin C.; Liu, Yan; Biochemistry and Molecular Biology, School of Medicine
    Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplantation remains limited by the inability to expand functional HSCs ex vivo. To determine the role of phosphoinositide 3-kinase (PI3K)/AKT signaling in human hematopoietic stem and progenitor cell (HSPC) maintenance, we examined the effect of genetic and pharmacological inhibition of AKT on human umbilical cord blood (UCB) CD34+ cells. We found that knock-down of AKT1 in human UCB CD34+ cells using short interfering RNAs targeting AKT1 enhances their quiescence and colony formation potential in vitro. We treated human UCB CD34+ cells with an AKT-specific inhibitor (AKTi) and performed both in vitro and in vivo stem and progenitor cell assays. We found that ex vivo treatment of human HSPCs maintains CD34 expression and enhances colony formation in serial replating assays. Moreover, pharmacological inhibition of AKT enhances the short-term repopulating potential of human UCB CD34+ cells in immunodeficient mice. Mechanistically, genetic and pharmacological inhibition of AKT activity promotes human HSPC quiescence. These preclinical results suggest a positive role for AKTi during ex vivo culture of human UCB HSPCs.
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    Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia
    (Nature Publishing group, 2017-06) 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 Medicine
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    Phosphatase PRL2 promotes oncogenic NOTCH1-Induced T-cell leukemia
    (Nature, 2017) Kobayashi, Michihiro; Bai, Yunpeng; Chen, Sisi; Gao, Rui; Yao, Chonghua; Cai, Wenjing; Cardoso, Angelo A.; Croop, James; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
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    PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation
    (American Association for Cancer Research, 2024) Chen, Hongxia; Bai, Yunpeng; Kobayashi, Michihiro; Xiao, Shiyu; Barajas, Sergio; Cai, Wenjie; Chen, Sisi; Miao, Jinmin; Meke, Frederick Nguele; Yao, Chonghua; Yang, Yuxia; Strube, Katherine; Satchivi, Odelia; Sun, Jianmin; Rönnstrand, Lars; Croop, James M.; Boswell, H. Scott; Jia, Yuzhi; Liu, Huiping; Li, Loretta S.; Altman, Jessica K.; Eklund, Elizabeth A.; Sukhanova, Madina; Ji, Peng; Tong, Wei; Band, Hamid; Huang, Danny T.; Platanias, Leonidas C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
    Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. Implications: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.