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Chai, Li

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Chai

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Li

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Chai, Li

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2008 - 200922010 - 201611

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Author's Publications: search.filters.isAuthorOfPublication.6328a814-0f39-4a47-bfdb-4853f00f4af1

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Now showing 1 - 10 of 13
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    Targeting SALL4 by entinostat in lung cancer
    (Impact Journals LLC, 2016) Yong, Kol Jia; Li, Ailing; Ou, Wen-Bin; Hong, Clarice Kit Yee; Zhao, Wenxiu; Wang, Fei; Tatetsu, Hiro; Yan, Benedict; Qi, Lihua; Fletcher, Jonathan; Yang, Henry; Soo, Ross; Tenen, Daniel; Chai, Li
    The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling of SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Connectivity Map analysis revealed the HDAC inhibitor entinostat as a potential drug in treating SALL4-expressing cancers, and this was confirmed in 17 lung cancer cell lines. In summary, we report for the first time that entinostat can target SALL4-positive lung cancer. This lays the foundation for future clinical studies evaluating the therapeutic efficacy of entinostat in SALL4-positive lung cancer patients.
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    Stem cell factor SALL4, a potential prognostic marker for myelodysplastic syndromes
    (BioMed Central, 2013) Wang, Fei; Guo, Ye; Chen, Qian; Yang, Zhuo; Ning, Ning; Zhang, Yujuan; Xu, Yonggang; Xu, Xiaodong; Tong, Chunrong; Chai, Li; Cui, Wei
    Background: Myelodysplastic syndromes (MDS) are a group of heterogeneous diseases with variable clinical course. Predicting disease progression is difficult due to lack of specific molecular marker(s). SALL4 plays important roles in normal hematopoiesis and leukemogenesis. SALL4 transgenic mice develop MDS prior to acute myeloid leukemia (AML) transformation. However, the role of SALL4 in human MDS has not been extensively investigated. In this study, we evaluate the diagnostic/prognostic value of SALL4 in MDS by examining its expression levels in a cohort of MDS patients. Methods: Fifty-five newly diagnosed MDS, twenty MDS-AML, and sixteen post-treatment MDS patients were selected for our study along with ten healthy donors. Results: We demonstrated that SALL4 was over-expressed in MDS patients and proportionally increased in MDS patients with high grade/IPSS scores. This expression pattern was similar to that of Bmi-1, an important marker in predicting MDS/AML progression. In addition, the level of SALL4 was positively correlated with increased blast counts, high-risk keryotypes and increased significantly in MDS-AML transformation. Furthermore, higher level of SALL4 expression was associated with worse survival rates and SALL4 level decreased following effective therapy. Conclusions: To the best of our knowledge, this is the largest series and the first to report the expression pattern of SALL4 in detail in various subtypes of MDS in comparison to that of Bmi-1. We conclude that SALL4 is a potential molecular marker in predicting the prognosis of MDS.
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    Leukemic survival factor SALL4 contributes to defective DNA damage repair
    (2016) Wang, Fei; Gao, Chong; Lu, Jiayun; Tatetsu, Hiro; Williams, David; Müller, Lars U; Cui, Wei; Chai, Li
    SALL4 is aberrantly expressed in human myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We have generated a SALL4 transgenic (SALL4B Tg) mouse model with pre-leukemic MDS-like symptoms that transform to AML over time. This makes our mouse model applicable for studying human MDS/AML diseases. Characterization of the leukemic initiation population in this model leads to the discovery that Fancl (Fanconi anemia, complementation group L) is down-regulated in SALL4B Tg leukemic and pre-leukemic cells. Similar to the reported Fanconi anemia (FA) mouse model, chromosomal instability with radial changes that can be detected in pre-leukemic SALL4B Tg bone marrow (BM) cells after DNA damage challenge. Results from additional studies using DNA damage repair reporter assays support a role of SALL4 in inhibiting the homologous recombination pathway. Intriguingly, unlike the FA mouse model, after DNA damage challenge, SALL4B Tg BM cells can survive and generate hematopoietic colonies. We further elucidated that the mechanism by which SALL4 promotes cell survival is through Bcl2 activation. Overall, our studies demonstrate for the first time that SALL4 has a negative impact in DNA damage repair, and support the model of dual functional properties of SALL4 in leukemogenesis through inhibiting DNA damage repair and promoting cell survival.
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    Targeting Transcription Factor SALL4 in Acute Myeloid Leukemia by Interrupting Its Interaction with an Epigenetic Complex
    (American Society of Hematology, 2013) Gao, Chong; Dimitrov, Todor; Yong, Kol Jia; Tatetsu, Hiro; Jeong, Ha-Won; Luo, Hongbo; Bradner, James E; Tenen, Daniel; Chai, Li
    An exciting recent approach to targeting transcription factors in cancer is to block formation of oncogenic complexes. We investigated whether interfering with the interaction of the transcription factor SALL4, which is critical for leukemic cell survival, and its epigenetic partner complex represents a novel therapeutic approach. The mechanism of SALL4 in promoting leukemogenesis is at least in part mediated by its repression of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through its interaction with a histone deacetylase (HDAC) complex. In this study, we demonstrate that a peptide can compete with SALL4 in interacting with the HDAC complex and reverse its effect on PTEN repression. Treating SALL4-expressing malignant cells with this peptide leads to cell death that can be rescued by a PTEN inhibitor. The antileukemic effect of this peptide can be confirmed on primary human leukemia cells in culture and in vivo, and is identical to that of down-regulation of SALL4 in these cells using an RNAi approach. In summary, our results demonstrate a novel peptide that can block the specific interaction between SALL4 and its epigenetic HDAC complex in regulating its target gene, PTEN. Furthermore, targeting SALL4 with this approach could be an innovative approach in treating leukemia.
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    Fak Depletion in Both Hematopoietic and Nonhematopoietic Niche Cells Leads to Hematopoietic Stem Cell Expansion
    (Elsevier BV, 2012) Lu, Jiayun; Sun, Yan; Nombela-Arrieta, Cesar; Du, Karrie P.; Park, Shin-Young; Chai, Li; Walkley, Carl; Luo, Hongbo; Silberstein, Leslie
    Hematopoietic stem cells (HSCs) reside in complex bone marrow microenvironments, where niche-induced signals regulate hematopoiesis. Focal adhesion kinase (Fak) is a nonreceptor protein tyrosine kinase that plays an essential role in many cell types, where its activation controls adhesion, motility, and survival. Fak expression is relatively increased in HSCs compared to progenitors and mature blood cells. Therefore, we explored its role in HSC homeostasis. We have used the Mx1-CreLinducible conditional knockout mouse model to investigate the effects of Fak deletion in bone marrow compartments. The total number as well as the fraction of cycling \(Lin^-Sca-1^+c-kit^+\) (LSK) cells is increased in \(Fak^{-/-}\) mice compared to controls, while hematopoietic progenitors and mature blood cells are unaffected. Bone marrow cells from \(Fak^{-/-}\) mice exhibit enhanced, long-term (i.e., 20-week duration) engraftment in competitive transplantation assays. Intrinsic Fak function was assessed in serial transplantation assays, which showed that HSCs (\(Lin^-Sca-1^+c-kit^+CD34^-Flk-2^-\) cells) sorted from \(Fak^{-/-}\) mice have similar self-renewal and engraftment ability on a per-cell basis as wild-type HSCs. When Fak deletion is induced after engraftment of \(Fak^{fl/fl}Mx1-Cre^+\) bone marrow cells into wild-type recipient mice, the number of LSKs is unchanged. In conclusion, Fak inactivation does not intrinsically regulate HSC behavior and is not essential for steady- state hematopoiesis. However, widespread Fak inactivation in the hematopoietic system induces an increased and activated HSC pool size, potentially as a result of altered reciprocal interactions between HSCs and their microenvironment.
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    Deficiency of Lipid Phosphatase SHIP Enables Long-Term Reconstitution of Hematopoietic Inductive Bone Marrow Microenvironment
    (Elsevier BV, 2013) Liang, Olin Dehui; Lu, Jiayun; Nombela-Arrieta, César; Zhong, Jia; Zhao, Li; Pivarnik, Gregory; Mondal, Subhanjan; Chai, Li; Silberstein, Leslie; Luo, Hongbo
    A dysfunctional bone marrow (BM) microenvironment is thought to contribute to the development of hematologic diseases. However, functional replacement of pathologic BM microenvironment through BM transplantation has not been possible. Furthermore, the study of hematopoietic inductive BM microenvironment is hampered by the lack of a functional nonhematopoietic reconstitution system. Here, we show that a deficiency of SH2-containing inositol-5'-phosphatase-1 (SHIP) in a nonhematopoietic host microenvironment enables its functional reconstitution by wild-type donor cells. This microenvironment reconstitution normalizes hematopoiesis in peripheral blood and BM and alleviates pathology of spleen and lung in the SHIP-deficient recipients. SHIP-deficient BM contains a significantly smaller population of multipotent stromal cells with distinct properties, which may contribute to the reconstitution by wild-type cells. We further demonstrate that it is the nonhematopoietic donor cells that are responsible for the reconstitution. Thus, we have established a nonhematopoietic BM microenvironment reconstitution system to functionally study specific cell types in hematopoietic niches.
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    Inositol Trisphosphate 3-Kinase B (InsP3KB) as a Physiological Modulator of Myelopoiesis
    (Proceedings of the National Academy of Sciences, 2008) Jia, Yonghui; Loison, Fabien; Hattori, Hidenori; Li, Yitang; Erneux, Christophe; Park, Shin-Young; Gao, Chong; Chai, Li; Silberstein, Leslie; Schurmans, Stephane; Luo, Hongbo
    Inositol trisphosphate 3-kinase B (InsP3KB) belongs to a family of kinases that convert inositol 1,4,5-trisphosphate (Ins(1,4,5)P3 or IP3) to inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4). Previous studies have shown that disruption of InsP3KB leads to impaired T cell and B cell development as well as hyperactivation of neutrophils. Here, we demonstrate that InsP3KB is also a physiological modulator of myelopoiesis. The InsP3KB gene is expressed in all hematopoietic stem/progenitor cell populations. In InsP3KB null mice, the bone marrow granulocyte monocyte progenitor (GMP) population was expanded, and GMP cells proliferated significantly faster. Consequently, neutrophil production in the bone marrow was enhanced, and the peripheral blood neutrophil count was also substantially elevated in these mice. These effects might be due to enhancement of PtdIns(3,4,5)P3/Akt signaling in the InsP3KB null cells. Phosphorylation of cell cycle-inhibitory protein \(p21^{cip1}\), one of the downstream targets of Akt, was augmented, which can lead to the suppression of the cell cycle-inhibitory effect of p21.
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    Relevant Mouse Model for Human Monocytic Leukemia through Cre/lox-Controlled Myeloid-Specific Deletion of PTEN
    (Nature Publishing Group, 2010) Yu, H.; Li, Yili; Gao, Chuanyun; Fabien, L.; Jia, Y.; Lu, Junjie; Silberstein, Leslie; Pinkus, Geraldine; Ye, K.; Chai, Li; Luo, Hongbo
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    The next new target in leukemia: The embryonic stem cell gene SALL4
    (2015) Wang, Fei; Zhao, Wenxiu; Kong, Nikki; Cui, Wei; Chai, Li
    The embryonic stem (ES) cell gene SALL4 has recently been identified as a new target for cancer therapy, including leukemia. SALL4 is expressed in ES cells and during embryonic development, but is absent in most adult tissues. It is, however, aberrantly expressed in various solid tumors and hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Aberrant expression of SALL4 is frequently associated with a more aggressive cancer phenotype, which includes high-risk MDS and its progression to AML. SALL4 contributes to leukemogenesis through multiple pathways including the repression of PTEN and the activation of HOXA9 expression. Targeting the SALL4/PTEN pathway by blocking the protein–protein interaction of SALL4 and its associated epigenetic complex, nucleosome remodeling and deacetylase complex (NuRD), might be a novel approach to treating AML and holds great potential for the treatment of other SALL4-mediated oncogenic processes such as high-risk MDS and solid tumors.
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    SALL4 is a new target in endometrial cancer
    (2014) Li, Ailing; Jiao, Yisheng; Yong, Kol Jia; Wang, Fei; Gao, Chong; Yan, Benedict; Srivastava, Supriya; Lim, Gkeok Stzuan Diana; Tang, Ping; Yang, Henry; Tenen, Daniel; Chai, Li
    Aggressive cancers and embryonic stem (ES) cells share a common gene expression signature. Identifying the key factors/pathway(s) within this ES signature responsible for the aggressiveness of cancers can lead to a potential cure. In this study, we find that SALL4, a gene involved in the maintenance of ES cell self-renewal, is aberrantly expressed in 47.7% of primary human endometrial cancer samples. It is not expressed in normal or hyperplastic endometrial. More importantly, SALL4 expression is positively correlated with worse patient survival and aggressive features such as metastasis in endometrial carcinoma. Further functional studies have shown that loss of SALL4 inhibits endometrial cancer cell growth in vitro and tumorigenicity in vivo, as a result of inhibition of cell proliferation and increased apoptosis. In addition, down-regulation of SALL4 significantly impedes the migration and invasion properties of endometrial cancer cells in vitro and their metastatic potential in vivo. Furthermore, manipulation of SALL4 expression can affect drug sensitivity of endometrial cancer cells to carboplatin. Moreover, we show that SALL4 specifically binds to the c-Myc promoter region in endometrial cancer cells. While down-regulation of SALL4 leads to a decreased expression of c-Myc at both protein and mRNA levels, ectopic SALL4 overexpression causes increased c-Myc protein and mRNA expression, indicating that c-Myc is one of the SALL4 downstream targets in endometrial tumorigenesis. In summary, we are the first to demonstrate that SALL4 plays functional role(s) in metastasis and drug resistance in aggressive endometrial cancer. As a consequence of its functional roles in cancer cell and absence in normal tissue, SALL4 is a potential novel therapeutic target for the high risk endometrial cancer patient population.