Hui Cheng

Peking Union Medical College Hospital, Peping, Beijing, China

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Publications (27)101.88 Total impact

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    ABSTRACT: Neuroguidin (NGDN) is a eukaryotic translation initiation factor 4E binding protein. The purpose of this study was to clarify the function of NGDN and its possible mechanism of action in human myeloid leukemia cells. Proliferation inhibition and apoptosis in NGDN over-expressing myeloid multidrug-resistant leukemia cells (K562/A02-NGDN) was significantly higher than in control K562/A02 cells following treatment with vincristine, etoposide, and epirubicin, indicating that NGDN over-expression can increase the sensitivity of multidrug-resistant leukemia cells to chemotherapeutic drugs. Furthermore, NGDN knock-down in K562/A02 cells resulted in the activation of multiple tumor-related signaling pathways, especially the mammalian target of rapamycin (mTOR) pathway. Electronic supplementary material The online version of this article (doi:10.1186/s13045-015-0108-6) contains supplementary material, which is available to authorized users.
    Journal of Hematology & Oncology 12/2015; 8(1). DOI:10.1186/s13045-015-0108-6 · 4.93 Impact Factor
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    ABSTRACT: Cytopenias resulting from the impaired generation of normal blood cells from hematopoietic precursors are important contributors to morbidity and mortality in patients with leukemia. However, the process by which normal hematopoietic cells are overtaken by emerging leukemia cells and how different subsets of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) are distinctly influenced during leukemic cell infiltration is poorly understood. To investigate these important questions, we used a robust non-irradiated mouse model of human MLL-AF9 leukemia to examine the suppression of HSCs and HPCs during leukemia cell expansion in vivo. Among all the hematopoietic subsets, long-term repopulating HSCs were the least reduced whereas megakaryocytic-erythroid progenitors (MEPs) were the most significantly suppressed. Notably, nearly all of HSCs were forced into a non-cycling state in leukemic marrow at late stages, but their reconstitution potential appeared to be intact upon transplantation into non-leukemic hosts. Gene expression profiling and further functional validation revealed that Egr3 was a strong limiting factor for the proliferative potential of HSCs. Therefore, this study provides not only a molecular basis for the more tightened quiescence of HSCs in leukemia but also a novel approach for defining functional regulators of HSCs in disease. Copyright © 2015 American Society of Hematology.
    Blood 07/2015; DOI:10.1182/blood-2015-01-623645 · 10.43 Impact Factor
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    ABSTRACT: In clinic settings, rel apsed leukemic patients are found to be more fragile to chemotherapy due to delayed or incomplete hematopoietic recovery, and hematopoiesis of these patients seem to be impaired. We established a leukemia therapy model with a non-irradiated T cell acute lymphoblastic leukemia mouse model combined with cytarabine and cyclophosphamide. Dynamic kinetics and functional status of both primitive hematopoietic cells and leukemic cells in a leukemia host under the chemotherapy stress were comprehensively investigated. We successfully established the leukemia therapy model with T lymphoblastic phenotype. After treatment with cytarabine and cyclophosphamide, the frequency of L − K + S + hematopoietic cells tides with the therapy, and stabled when the disease remission, then reduced when relapsed, while leukemic cells showed a delayed but consistent regeneration. Combination of chemotherapy significantly promote an early and transient entrance of L − K + S + hematopoietic cells into active proliferation and induction of apoptosis on L − K + S + cells in vivo. Moreover, in the competitive bone marrow transplantation assays, hematopoietic cells showed gradually diminished regenerative capacity. Testing of senescence-associated beta-galactosidase (SA-β gal) status showed higher levels in L − K + S + hematopoietic cells post therapy when compared with the control. Gene expression analysis of hematopoietic primitive cells revealed up-regulated p16, p21, and down-regulated egr1 and fos. We conclude that primitive hematopoietic cells in bone marrow enter proliferation earlier than leukemic cells after chemotherapy, and gradually lost their regenerative capacity partly by senescence due to accelerated cycling.
    Journal of Translational Medicine 07/2015; 13(1). DOI:10.1186/s12967-015-0543-8 · 3.99 Impact Factor
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    ABSTRACT: The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft‑versus‑host disease (aGVHD). However, the role of MSCs in graft‑versus‑leukemia remains to be determined. In the present study, we co‑cultured C57BL/6 mouse bone marrow (BM)‑derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.
    International Journal of Molecular Medicine 04/2015; DOI:10.3892/ijmm.2015.2191 · 1.88 Impact Factor
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    ABSTRACT: To improve the MigR1-CD19-CAR (chimeric antigen receptor) that contains a single chain variable region (scFv) which targeted to CD19 through a retroviral vector transduction efficiency of T-lymphocytes. Insert the CD19-CAR fragment into the retroviral vector (MigR1) through recombinant DNA technology, after transfecting plat-A packaging cell lines, viral supernatant was collected to transduce K562 cell line and activated human T-lymphocytes. We used flow cytometry to determine the transduction efficiency and RT-PCR to confirm the transcription of CD19-CAR gene. The ability of the transduced T cells to produce IFN-γ and TNF-α in a CD19-specific manner was measured in an enzyme-linked immunosorbent (ELISA) assay. (1)Using MigR1-CD19-CAR retroviral vector to produce the high titer retrovirus. (2)MigR1-CD19-CAR transduction efficiency of K562 cell line was significantly higher than human T-lymphocytes (P<0.01). (3)120 min centrifugation could significantly improve transduction efficiency of T-lymphocytes to (54.5±14.6)%. (4)Transduction efficiency could be improved by deciding transduce time according to T-lymphocytes proliferation fold in vitro individually, and the highest transduction efficiency in the study was 69.3%. The CD19-CAR gene sequence was transcripted specificly with high efficiency. (5) IFN-γ and TNF-α released by CD19-CAR transduced T-lymphocytes significantly increased to (13 230±1 543) pg/ml and (4 217±211) pg/ml when coculture with CD19-K562 cells. We have successfully constructed a second generation CAR which targeted to CD19 through a retroviral vector called MigR1 (MigR1-CD19-CAR). Deciding transduce time according to T-lymphocytes proliferation fold in vitro individually and 120 min centrifugation could improve the CAR transduction efficiency of T-lymphocytes. RT-PCR confirmed that the CD19-CAR gene was specificly transcripted with high efficiency. IFN-γ and TNF-α released by CD19-CAR transduced T-lymphocytes significantly increased when activated by target cells.
    Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 04/2015; 36(4):331-336. DOI:10.3760/cma.j.issn.0253-2727.2015.04.016
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    ABSTRACT: Backgrownd: Macrophage inflammatory protein-1α (MIP-l α/CCL3) belongs to the C-C chemokine family (CCL3), which can be secreted by macrophages, other types of hematopoietic cells and bone marrow stromal cells. Higher levels of MIP-1α were found to be associated with several kinds of hematologic malignancies, including multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Moreover, MIP-1α has been reported to be an adverse prognostic factor for CLL. However, the impact of MIP-1α on acute myeloid leukemia (AML) has been poorly investigated. To investigate the influence of MIP-1α on proliferction of AML cells. Using MLL-AF9 induced AML mouse model, the expression of MIP-1α was measured by real time quantitative RT-PCR. AML cell proliferation was examined by cell counting and colony forming assay (CFC). The influence of blocking the MIP-1α action on the growth and pathogenic ability of AML cells was explored by using the small molecule antagonist for interfering interaction of MIP-1α with its receptor CCR1. The MIP-1α could promote the proliferation and colony formation of AML cells, the blocking MIP-1a could inhibit the growth of AML cells and delay onset of AML. The MIP-1a promotes the occurence and progression of AML, therefore blocking the MIP-1α signal pathway may be served as a strategy to inhibit the growth of AML cells, and MIP-1α can be a potential target for treatment of AML.
    Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 04/2015; 23(2):306-11.
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    ABSTRACT: Although great efforts have been made to improve available therapies, the mortality rate of acute myeloid leukemia (AML) remains high due to poor treatment response and frequent relapse after chemotherapy. Leukemia stem cells (LSCs) are thought to account for this poor prognosis and relapse. Phosphoinositide-dependent kinase 1 (PDK1) is a critical regulator of the PI3K/Akt pathway and has been shown to be frequently activated in leukemia. However, the role of PDK1 in the regulation of LSCs in AML is still not clear. Using a PDK1 conditional deletion MLL-AF9 murine AML model, we revealed that the deletion of PDK1 prolonged the survival of AML mice by inducing LSC apoptosis. This was accompanied by the increased expression of the pro-apoptotic genes Bax and p53 and the reduced expression of Stat5, which has been shown to be constitutively activated in leukemia. Thus, our findings suggest that PDK1 plays an essential role in maintaining LSCs. Further delineating the function of PDK1 in LSCs may provide a new strategy for the improved treatment of AML relapse. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 03/2015; 459(4). DOI:10.1016/j.bbrc.2015.03.007 · 2.28 Impact Factor
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    ABSTRACT: To explore the effects and possible mechanisms of decitabine on Molt4 in vitro. Effects of decitabine on cells proliferation were detected by using CCK-8, the apoptosis by Annexin V-FITC, cell cycles by propidium iodide-FACS. Discrepancy genes were screened by RNA-seq technique. The CpG methylation of lactoferrin (LTF) gene in Molt4 cells were identified by Bisulfite sequencing PCR (BSP). The expression of LTF mRNA in Molt4 by RT-PCR and LTF protein expression were analyzed by Western blot. Decitabine effectively inhibited proliferation and induced apoptosis for Molt4 cells by an time- and dose-dependent manners. Cell cycles were arrested at the G₀/G₁ phase. The promoter methylation degree of LTF gene in Molt4 cells was 72.3% before decitabine treatment and decreased to 45.0% after treatment with 0.50 μmol/L decitabine for 72 h. After the reduction of methylation, expression of its mRNA and protein increased, meanwhile caspase 3 and caspase 9 protein expression levels increased. The demethylating drug decitabine can induce apoptosis, detain cell cycle at phase G₀/G₁, inhibit proliferation and up-regulate LTF gene expression in Molt4 cells. LTF may become a new target for acute T lymphoblastic leukemia.
    Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 03/2015; 36(3):230-4. DOI:10.3760/cma.j.issn.0253-2727.2015.03.012
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    ABSTRACT: Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel small-molecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.
    Nature Communications 02/2015; 6. DOI:10.1038/ncomms7328 · 10.74 Impact Factor
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    ABSTRACT: To report an acute promyelocytic leukaemia (APL) case with translocation of rob (13;21) t(15;17)(q22;q21) and review its clinical and laboratory characteristics. Based on routine karyotype analysis and bone marrow morphology, we further used double color double fluorescent in situ hybridization (DCDF-FISH) and reverse transcriptase PCR (RT-PCR) to examine the patient's abnormities on cytogenetic and molecular biology, and reveal the clinical characteristics of this rare translocation also from the related literatures. The clinical manifestation and bone marrow morphology examination of this patient were in accordance with pathologic feature of APL. On first visit, immunophenotyping analysis showed positive myeloid markers. Through R-banding, the patient's karyotype was confirmed as 45,XX,rob(13;21)t(15;17)(q22;q21)[6]/45,XX,rob(13;21)[14]. FISH results showed that 68.9% cells were typical t(15;17) pattern. The positive rates of fusion gene of PML-RARα detected by RT-PCR was 25.8%. Patient was treated by induction and consolidation therapy, the karyotype was 45,XX,rob(13;21)[20] after complete remission. The positive rate of fusion gene of PML-RARα by FISH and its level were 2.5% and 0.003% respectively. APL with rob (13;21) t(15;17)(q22;q21) was very rare, which was accorded with clinical and laboratory characteristics of APL. The value of chromosome abnormality as a prognostic marker in APL needs to be further observed..
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    ABSTRACT: To investigate the patients' characteristics and efficacy of prognosis evaluation by International Prognosis Scoring System (IPSS) and Revised International Prognosis Scoring System (IPSS-R) in patients with myelodysplastic syndrome (MDS). Prognostic value of IPSS and IPSS-R was evaluated on clinical data from 159 MDS patients, according to WHO classification. With a median age of 44 years (range:15-80 years), MDS patients had the frequency of 38.56% with abnormal karyotype, including the most common abnormality +8 (20/153, 12.6%). 34 of 142 patients transformed into leukemia. Age and the level of β2 micro-globulin were the prognostic factors by multivariate analysis and IPSS-R had a better prognostic significance. The differences in cumulative survival between IPSS subgroups were significant (P<0.05) except that between low- and intermediate I-risk group (P>0.05). There were statistical differences for IPSS-R low risk group vs high or very high risk group, and intermediate risk group vs high or very high risk group (P<0.05). IPSS-R enables IPSS subgroups re-stratification and split IPSS intermediate I-risk group into two subgroups with different prognosis. There were significant differences in age of onset, distribution of prognosis scoring system subgroups and abnormal karyotype compared with those in Europe and America. The proportion of higher risk (worse than good karyotype) in IPSS-R was higher than that in Europe and America. Age and the level of β2 micro-globulin were prognostic factors. Both IPSS and IPSS-R were applicable in Chinese MDS patients and the latter performed better. Applying IPSS-R to re-stratify IPSS subgroups helps evaluate prognosis more accurately and improve treatment outcomes.
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    ABSTRACT: Background Leukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed.MethodsA Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice.ResultsMore leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3ß was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3ß recruits T-ALL cells which express a high level of MIP-3ß receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3ß, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice.Conclusions Our study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia.
    Journal of Hematology & Oncology 11/2014; 7(1):71. DOI:10.1186/s13045-014-0071-7 · 4.93 Impact Factor
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    ABSTRACT: Immuno-compromised mice, such as the non-obese diabetic/severe combined immune-deficient (NOD/SCID) mice, have been widely used to examine the in vivo self-renewal and differentiation of human hematopoietic stem cells (HSCs). However, the efficiency of human HSC engraftment remains very low. Here, we report that NOD/SCID mice had higher levels of reactive oxygen species (ROS) in their bone marrow (BM) than other commonly used mouse strains (C57BL/6 and BALB/C). Treatment with the antioxidant N-acetyl-L-cysteine (NAC) decreased ROS levels in the BM of NOD/SCID mice. Furthermore, the NAC-treated mice displayed a significant increase in human HSC engraftment and multi-lineage differentiation compared with the controls. In comparison with the control mice, NAC-treated recipients displayed a 10.8-fold increase in engraftment in the injected tibiae. A beneficial effect of NAC for human hematopoietic engraftment was also observed in an additional immune-deficient mouse strain, namely NOD.Cg-Prkdc(scid)I12rg(tm1Wjl)/SzJ (NOD/SCID/γc(-/-) or NSG). Therefore, our current study uncovers a previously unappreciated negative effect of ROS on human stem cell engraftment in immune-deficient mouse models.
    Blood 10/2014; 124(20). DOI:10.1182/blood-2014-03-559369 · 10.43 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (aGvHD) is the most common complication of allogeneic hematopoietic stem cell transplantation (HSCT), which is often accompanied by impaired hematopoietic reconstitution. Sinusoidal endothelial cells (SECs) constitute bone marrow (BM) vascular niche that plays an important role in supporting self-renewal capacity and maintaining the stability of HSC pool. Here we provide evidences that vascular niche is a target of aGvHD in a major histocompatibility complex (MHC)-haploidentical matched murine HSCT model. The results demonstrated that hematopoietic cells derived from GvHD mice had the capacity to reconstitute hematopoiesis in healthy recipient mice. However, hematopoietic cells from healthy donor mice failed to reconstitute hematopoiesis in GvHD recipient mice, indicating that the BM niche was impaired by aGvHD in this model. We further demonstrated that SECs were markedly reduced in the BM of aGvHD mice. High level of Fas and caspase-3 expression and high rate of apoptosis were identified in SECs, indicating that SECs were destroyed by aGvHD in this murine HSCT model. Furthermore, high Fas ligand expression on engrafted donor CD4+, but not CD8+ T cells, and high level MHC-II but not MHC-I expression on SECs, suggested that SECs apoptosis was mediated by CD4+ donor T cells through the Fas/FasL pathway.
    PLoS ONE 08/2014; 9(8):e104607. DOI:10.1371/journal.pone.0104607 · 3.23 Impact Factor
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    ABSTRACT: Cytopenia and delayed immune reconstitution with acute graft-versus-host disease (aGvHD) indicate a poor prognosis. However, how donor-derived cell hematopoiesis is impaired in aGvHD is not well understood. We addressed this issue by studying the kinetics of hematopoiesis and the functions of hematopoietic stem and progenitor cells (HSPCs) in an aGvHD model with haplo-MHC-matched murine bone marrow transplantation (BMT). Although hematopoiesis was progressively suppressed during aGvHD, the hematopoietic regenerative potential of donor-derived HSCs remains intact. There was a dramatic reduction in primitive hematopoietic cells and a defect in the ability of these cells to generate common myeloid progenitors (CMPs) and megakaryocyte/erythrocyte progenitors (MEPs). These effects were observed along with a concomitant increase in granulocyte/macrophage progenitors (GMPs), suggesting that differentiation into MEPs is blocked during aGvHD. Interestingly, cyclosporine A (CsA) was able to partially reverse the hematopoietic suppression as well as the differentiation blockage of CMPs. These data provide new insights into the pathogenesis of aGvHD and may improve the clinical management of aGvHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2014; 20(9). DOI:10.1016/j.bbmt.2014.05.009 · 3.35 Impact Factor
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    ABSTRACT: To analyze the impact of the occurrence and severity of acute and chronic graft versus host disease (GVHD) on the long-term outcome of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for leukemia.
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    ABSTRACT: Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.
    Nature Genetics 02/2014; 46(3). DOI:10.1038/ng.2894 · 29.65 Impact Factor
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    ABSTRACT: Mammalian target of rapamycin (mTOR) is composed of two distinct biochemical complexes, mTORC1 and mTORC2. mTORC1 is known to control cellular growth in response to nutrients and growth factors by regulating the translational regulators S6K1 and 4E-BP1, whereas mTORC2 mediates cell proliferation and survival by activating AKT through phosphorylation at Ser473. Studies have shown that the deregulation of mTORC2 leads to the development of myeloproliferative disorder and leukemia in the PTEN-deleted mouse model. However, the mechanism by which mTORC2 specifically affects leukemogenesis is still not fully understood. Here, we investigated the role of mTORC2 in NOTCH1-driven T-ALL in a Rictor deficient mouse model. We found that by deleting Rictor, an essential component of mTORC2, leukemia progression was significantly suppressed by arresting a greater proportion of Rictor△/△ leukemic cells at the G0 phase of the cell cycle. Furthermore, the absence of Rictor led to the overexpression of chemotaxis-related genes, such as CCR2, CCR4 and CXCR4, which contributed to the homing and migration of Rictor deficient T-ALL cells to the spleen but not the bone marrow. In addition, we demonstrated that inactivation of mTORC2 caused the overexpression of FoxO3a and its downstream effectors and eased the progression of leukemia in T-ALL mice. Our study thus indicates that FoxO3a could be a potential drug target for the treatment of T-ALL leukemia.
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    ABSTRACT: The Notch1 signaling pathway plays an essential role in cell growth and differentiation. Over-expression of the intracellular Notch1 domain (ICN1) in murine hematopoietic cells is able to induce robust T-cell acute lymphoblastic leukemia (T-ALL) in mice. Here we explored the drug sensitivity of T-ALL cells in two subpopulations of CD8(+)CD4(+) and CD8(+)CD4(-) cells in Notch1-induced T-ALL mice. We found that Notch1 induced T-ALL cells could be decreased by chemotherapeutic drug cyclophosphamide (CTX). CD8(+)CD4(-) T-ALL cells were more sensitive to CTX treatment than CD8(+)CD4(+) T-ALL cells. The percentage of apoptotic cells induced by CTX treatment was higher in CD8(+)CD4(-) T-ALL cells. T-ALL cells were also inhibited by inhibitor of mTORC1 rapamycin. CD8(+)CD4(+) T-ALL cells were more susceptible to rapamycin treatment than CD8(+)CD4(-) T-ALL cells. Rapamycin treatment selectively arrested more CD8(+)CD4(+) T-ALL cells at G0 phase of cell cycle. A combination of the two drugs significantly improved overall survival of T-ALL bearing mice when compared with CTX or rapamycin alone. These results indicated that CD8(+)CD4(+) and CD8(+)CD4(-) leukemia cell populations had distinct drug sensitivity.
    Leukemia research 09/2013; 37(11). DOI:10.1016/j.leukres.2013.09.007 · 2.69 Impact Factor

Publication Stats

32 Citations
101.88 Total Impact Points

Institutions

  • 2014–2015
    • Peking Union Medical College Hospital
      Peping, Beijing, China
  • 2013–2015
    • China Academy of Chinese Medical Sciences
      Peping, Beijing, China
    • Chinese Academy of Medical Sciences
      Peping, Beijing, China
  • 2012–2015
    • Changhai Hospital, Shanghai
      Shanghai, Shanghai Shi, China
  • 2011–2015
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China