Chao Niu - Academia.edu (original) (raw)

Papers by Chao Niu

Blood

It has been found that c-Myc protein plays a critical role in controlling self-renewal versus dif... more It has been found that c-Myc protein plays a critical role in controlling self-renewal versus differentiation in hematopoietic stem cells. We report that c-Myc also controls the fate of megakaryocyte-erythrocyte progenitors through regulating the differentiation of erythroid and megakaryocytic progenitors. In addition to the significant reduction of granulocytes/macrophages and B and T lymphocytes because of the reduction of their corresponding progenitors, we found significantly increased numbers of megakaryocytic progenitors and mature megakaryocytes in bone marrow and spleens of c-Myc-knockout (c-Myc(-/-)) mice. Differentiation of erythrocytes was blocked at the erythroid progenitor stage. This increased megakaryocytopoiesis is a cell-intrinsic defect of c-Myc-mutant hematopoietic stem cells, as shown by transplantation studies. Furthermore, we found that c-Myc is required for polyploidy formation but not for cytoplasmic maturation of megakaryocytes. Megakaryocytes from c-Myc(-/-...

American journal of physiology. Gastrointestinal and liver physiology, Jan 16, 2015

The pathophysiology of esophageal injury, repair, and inflammation in gastro-esophageal reflux di... more The pathophysiology of esophageal injury, repair, and inflammation in gastro-esophageal reflux disease (GERD) is complex. While most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that sub-epithelial esophageal myofibroblasts in GERD secrete pro-inflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts (α-SMA+ vimentin+ CD31-) in the sub-epithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed α-SMA co-immunostaining with IL-6 and p65. We established and characterized primary cultures of α-SMA+, vimentin+, CD31-, CD45- human esophageal myofibroblasts. We modeled GERD by treatment with pH 4.5 acidified media and TLR4 ligands LPS and HMGB1 and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate spindle-shap...

The Hematology Journal, 2000

To address the molecular regulation of hematopoiesis and the complex mechanism in leukemogenesis,... more To address the molecular regulation of hematopoiesis and the complex mechanism in leukemogenesis, we established the first catalogs of genes expressed in normal bone marrow and leukemia CD34(+) cells. CD34(+) cell cDNA libraries were constructed using mRNA from adult bone marrow and from a case of acute myeloid leukemia-M5 transformed from myelodysplastic syndrome (MDS-AML). Expressed sequence tags (ESTs) and full-length cDNAs were generated by sequencing and were annotated using bioinformatic tools. From a total of 4142 ESTs obtained from normal bone marrow, 3424 meaningful tags were integrated into 1630 clusters, representing 622 known genes, 522 dbEST entries and 486 novel sequences. Out of 5382 ESTs from MDS-AML, 1985 clusters were produced based on the analysis of 4321 useful ESTs, including 711 known genes, 657 known ESTs and 617 novel sequences. Among 251 transcripts found in both bone marrow and MDS-AML EST datasets and those present in only one dataset, 58 showed statistically significant differences in EST copy numbers between the two tissues (P<0.05). Twenty putative full-length cDNAs for novel genes were also cloned from the MDS-AML library. The distinct gene expression patterns in MDS-AML-CD34(+) cells as compared to normal control cells may contribute to the development and/or maintenance of the malignant phenotypes of leukemia cells.

The Hematology Journal, 2001

Introduction: To study the relationship between the expression level of the PML-RARa fusion trans... more Introduction: To study the relationship between the expression level of the PML-RARa fusion transcripts and the clinical status and eciency of the therapy in acute promyelocytic leukemia (APL) patients, we applied a very sensitive and speci®c real-time Reverse Transcription Polymerase Chain Reaction (RT ± PCR) system to quantify the dose of PML-RARa fusion transcripts in a series of APL patients at distinct disease stages. Materials and methods: A total of 31 APL patients (19 males and 12 females; aged from 8 to 74 years) from eight hospitals in Shanghai were analysed. Real-time Quantitative RT ± PCR was used to measure the normalized dose (Dose N ) of PML-RARa fusion transcripts. Results: A wide range of PML-RARa Dose N above 1610 3 was noted in 25 newly diagnosed patients. PML-RARa Dose N was signi®cantly decreased after remission induction with ATRA, ATRA/chemotherapy or As 2 O 3 and further reduced after consolidation. The fact that all patients with long disease free survival had a constantly low PML-RARa Dose N below 2610 2 and a higher level predicted impending relapse suggests that this value could serve as à threshold' for molecular remission. PML-RARa Dose N was also of prognostic value in a group of relapsed patients, since good response to As 2 O 3 reinduction was accompanied by a remarkable reduction of fusion transcript level, whereas patients with high PML-RARa Dose N after the second CR tended to relapse again rapidly. Conclusion: These results con®rm that real-time RT ± PCR assay for PML-RARa transcripts in APL patients is useful in re¯ecting leukemic burden, assessing response to treatment and indicating the ultimate clinical outcome or curability of disease.

Nature, 2003

run in TBE £ 0.5 at room temperature for 2 h at 150 V. The following two ( Q/q) 27-bp unmethylate... more run in TBE £ 0.5 at room temperature for 2 h at 150 V. The following two ( Q/q) 27-bp unmethylated oligonucleotides were used: 5 0 -GATCCTTCGCCTAGGCTC(A/G)CAGCG CGGGAGCGA-3 0 . A methylatedq probe (q*) was generated by incorporating a methylated cytosine at the mutated CpG site during oligonucleotide synthesis.

Molecular and Cellular Biology, 2007

RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leuke... more RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leukemia. To understand the role of the RBM15-MKL1 fusion protein in leukemia, we must understand the normal functions of RBM15 and MKL. Here, we show a role for Rbm15 in myelopoiesis. Rbm15 is expressed at highest levels in hematopoietic stem cells and at more moderate levels during myelopoiesis of murine cell lines and primary murine cells. Decreasing Rbm15 levels with RNA interference enhances differentiation of the 32DWT18 myeloid precursor cell line. Conversely, enforced expression of Rbm15 inhibits 32DWT18 differentiation. We show that Rbm15 alters Notch-induced HES1 promoter activity in a cell type-specific manner. Rbm15 inhibits Notch-induced HES1 transcription in nonhematopoietic cells but stimulates this activity in hematopoietic cell lines, including 32DWT18 and human erythroleukemia cells. Moreover, the N terminus of Rbm15 coimmunoprecipitates with RBPJ, a critical factor in Notch signaling, and the Rbm15 N terminus has a dominant negative effect, impairing activation of HES1 promoter activity by full-length-Rbm15. Thus, Rbm15 is differentially expressed during hematopoiesis and may act to inhibit myeloid differentiation in hematopoietic cells via a mechanism that is mediated by stimulation of Notch signaling via RBPJ.

Journal of Experimental & Clinical Cancer Research, 2010

To investigate the effect of all-trans retinoic acid(ATRA) on the proliferation and differentiati... more To investigate the effect of all-trans retinoic acid(ATRA) on the proliferation and differentiation of brain tumor stem cells(BTSCs) in vitro. Limiting dilution and clonogenic assay were used to isolate and screen BTSCs from the fresh specimen of human brain glioblastoma. The obtained BTSCs, which were cultured in serum-free medium, were classified into four groups in accordance with the composition of the different treatments. The proliferation of the BTSCs was evaluated by MTT assay. The BTSCs were induced to differentiate in serum-containing medium, and classified into the ATRA group and control group. On the 10th day of induction, the expressions of CD133 and glial fibrillary acidic protein (GFAP) in the differentiated BTSCs were detected by immunofluorescence. The differentiated BTSCs were cultured in serum-free medium, the percentage and the time required for formation of brain tumor spheres (BTS) were observed. BTSCs obtained by limiting dilution were all identified as CD133-positive by immunofluorescence. In serum-free medium, the proliferation of BTSCs in the ATRA group was observed significantly faster than that in the control group, but slower than that in the growth factor group and ATRA/growth factor group, and the size of the BTS in the ATRA group was smaller than that in the latter two groups(P < 0.01). In serum-containing medium, the expression percentages of CD133 and GFAP in the differentiated BTSCs were (2.29% +/- 0.27%) and (75.60% +/- 4.03%) respectively in the ATRA group, and (7.05% +/- 0.49%) and (12.51% +/- 0.77%) respectively in the control group. The differentiation rate of BTSCs in the ATRA group was significantly higher than that in the control group (P < 0.05), but there was still CD133 expressed in the ATRA group. The differentiated BTSCs could re-form BTSs in serum-free medium. The percentage of BTS formation in the ATRA group was(4.84% +/- 0.32%), significantly lower than that in the control group (17.71% +/- 0.78%) (P < 0.05), and the time required for BTS formation in the ATRA group was (10.07 +/- 1.03)d, significantly longer than that in the control group (4.08 +/- 0.35)d (P < 0.05). ATRA can promote the proliferation and induce the differentiation of BTSCs, but the differentiation is incomplete, terminal differentiation cannot be achieved and BTSs can be formed again.

Cancer Research, 2006

The formation of fusion genes between NUP98 and members of the HOX family represents a critical f... more The formation of fusion genes between NUP98 and members of the HOX family represents a critical factor for the genesis of acute leukemia or acute transformation of chronic myeloid leukemia (CML). To gain insights into the molecular mechanisms underlying the leukemogenesis of NUP98-HOX fusion products, we cloned NUP98-PMX1 from a CML-blast crisis patient with t(1;11) as a secondary chromosomal translocation, and functionally studied the fusion products in detail through various molecular and protein biochemical assays. In addition to many interesting features, we have found that the NUP98-PMX1 fusion protein exerts a repressive effect on PMX1 or serum response factor-mediated c-FOS activation, probably through the recruitment of a common corepressor histone deacetylase 1 by FG domains of the NUP98-PMX1 fusion protein. Moreover, we have provided evidence that the FG domains of NUP98-PMX1 and two other NUP98-containing fusion proteins, i.e., NUP98-HOXA9 and NUP98-HOXC11, all exhibit dual binding ability to both CREB binding protein, a coactivator, and histone deacetylase 1, a corepressor. Accordingly, we have hypothesized that this dual binding activity is shared by most, if not all, NUP98-HOX-involved fusion proteins, enabling these fusion proteins to act as both trans-activators and trans-repressors, and contributing to the genesis of acute leukemia or acute transformation of CML.

Cancer Genetics and Cytogenetics, 2000

ABSTRACT “Simple” variants of the t(8;21) translocation involving chromosome 8 and a chromosome o... more ABSTRACT “Simple” variants of the t(8;21) translocation involving chromosome 8 and a chromosome other than number 21 are rare. To our knowledge, only t(3;8)(q29;q22), t(8;11)(q22;q13), t(8;16)(q22;q24), t(8;20)(q22;p13), and t(8;22) have been reported in the literature. This paper describes for the first time two patients with acute myelogenous leukemia with a consistent t(8;19)(q22;q13) translocation. Their myelograms were compatible with the FAB-M2 subtype. The blasts from case 2 expressed CD34, CD33, CD13, and CD19. Karyotype analyses were performed on bone marrow cells using R- and G-banding at presentation. A t(8;19)(q22;q13) translocation was found in 28/30 metaphases for case 1 and in 23/25 metaphases for case 2. The latter case also had a deletion of chromosome 9, del(9)(q12q22) as an additional abnormality. Reverse transcriptase-polymerase chain reaction study revealed no AML1/ETO fusion transcript in case 2. Dual-color fluorescence in situ hybridization (FISH) assay using two probes (BAC92 and YAC412A4) convincingly demonstrated that the chromosomal material from 8q was translocated onto 19q rather than 19p in case 2. Thus, we consider t(8;19)(q22;q13) a true “simple” variant of t(8;21), and assume that a fusion gene resulting from the t(8;19) may contain the ETO gene located at 8q22 and an unknown partner gene from 19q13, which probably is a new transcription factor, whose molecular entity warrants further study.

Cancer Genetics and Cytogenetics, 1998

Chromosomal analysis of acute lymphoblastic leukemia (ALL) is often difficult because of the subo... more Chromosomal analysis of acute lymphoblastic leukemia (ALL) is often difficult because of the suboptimal in vitro growth of the immature lymphoid cell and the poor morphology obtained. In this study, we describe the application of comparative genomic hybridization (CGH) to investigate the genomic abnormalities in 14 patients with ALL, all of whom had cytogenetically identified numerical aberrations or gross chromosomal structural alteration. With the use of CGH, regional or whole chromosome overrepresentation or both were found to be more frequent than underrepresentation (52 gains vs. 6 losses), the most common gains being chromosomes 21 and X. The results of the comparison between CGH and conventional R-banding analysis could be classified into three categories: (1) in three cases, including two with trisomy, CGH and banding analysis gave identical results; (2) in six cases with hyperdiploidy and two cases presenting chromosome structural abnormalities, the results were consistent but with minor discrepancies; (3) in three cases, including two with triploidy and tetraploidy and one with chimeric karyotype together with +22, the data from CGH and cytogenetical analysis were discrepant. CGH could not find the triploidy and tetraploidy. Our results suggest that CGH has certain value in the detection of gains or losses of chromosome materials in hyperdiploid ALL. Nevertheless, the combination of CGH and conventional karyotyping provides more precise information on the genomic imbalance in ALL.

Cancer Genetics and Cytogenetics, 1999

To study the genomic abnormality underlying the acute transformation of chronic myeloid leukemia ... more To study the genomic abnormality underlying the acute transformation of chronic myeloid leukemia (CML), 15 CML patients in blast crisis (BC), 3 in accelerated phase (AP), and 20 in chronic phase (CP) were analyzed by conventional cytogenetics, comparative genomic hybridization (CGH), and dual-color chromosomal painting. Philadelphia (Ph) chromosome was identified in every case studied. Only 5 among 20 CP patients had additional abnormalities while 13 of 18 patients with disease progression (BC + AP) showed extra numerical and/or structural chromosomal aberrations. Cytogenetically, the most common chromosome gains during BC and AP were double or triple Ph chromosomes (5 of 14 cases) and trisomy 8 (5 of 14 cases). Trisomies 7 and 17 (1 of 14 cases each) were also observed. CGH analysis detected genetic imbalances in eight cases. Gains of chromosome 20 (3 cases) and 17q (2 cases) were observed, respectively. The recurrent chromosome loss was the deletion of the short arm of chromosome 17, seen in one case with i(17)(q10) and one case with an unbalanced translocation (1;17). In one case, a very complex chromosomal rearrangement, del(3),del(6),der(6)t(17;3;6),der(17)t(6;17), was seen. A novel finding of this work is the involvement of chromosome 1(q12-21qter) in CML disease progression. Overrepresentation of 1(q12-21qter) region was detected by CGH in one case which had a derivative chromosome 17. This abnormal chromosome was later confirmed by fluorescence in situ hybridization (FISH) painting to be a fusion between chromosome 1 and 17 to form the der(17)t(1;17) (q12-21;p11). Two other cases showed the same region being involved in translocations, t(1;10)(q12-21;q26) and t(1;11)(q12-21;p15). It is possible that one or more genes residing on chromosome 1q12-21 may be important in the acute transformation of CML. In conclusion, we find that the combined use of CGH, chromosome painting, and classic cytogenetic analysis allows a better evaluation of the genomic aberration involved in CML blastic transformation, and offers new directions for its further molecular investigations.

Cancer Genetics and Cytogenetics, 2001

Blood, 2009

RNA-binding motif protein 15 (RBM15) is involved in the RBM15-megakaryoblastic leukemia 1 fusion ... more RNA-binding motif protein 15 (RBM15) is involved in the RBM15-megakaryoblastic leukemia 1 fusion in acute megakaryoblastic leukemia. Although Rbm15 has been reported to be required for B-cell differentiation and to inhibit myeloid and megakaryocytic expansion, it is not clear what the normal functions of Rbm15 are in the regulation of hematopoietic stem cell (HSC) and megakaryocyte development. In this study, we report that Rbm15 may function in part through regulation of expression of the proto-oncogene c-Myc. Similar to c-Myc knockout (c-Myc-KO) mice, long-term (LT) HSCs are significantly increased in Rbm15-KO mice due to an apparent LT-HSC to short-term HSC differentiation defect associated with abnormal HSC-niche interactions caused by increased N-cadherin and beta(1) integrin expression on mutant HSCs. Both serial transplantation and competitive reconstitution capabilities of Rbm15-KO LT-HSCs are greatly compromised. Rbm15-KO and c-Myc-KO mice also share related abnormalities in megakaryocyte development, with mutant progenitors producing increased, abnormally small low-ploidy megakaryocytes. Consistent with a possible functional interplay between Rbm15 and c-Myc, the megakaryocyte increase in Rbm15-KO mice could be partially reversed by ectopic c-Myc. Thus, Rbm15 appears to be required for normal HSC-niche interactions, for the ability of HSCs to contribute normally to adult hematopoiesis, and for normal megakaryocyte development; these effects of Rbm15 on hematopoiesis may be mediated at least in part by c-Myc.

Biochemical Systematics and Ecology, 2010

In the present phytochemical study on the leaves of Crataegus pinnatifida, a new monoterpene glyc... more In the present phytochemical study on the leaves of Crataegus pinnatifida, a new monoterpene glycoside, (3S,5R,6R,7E,9R)-3,6-epoxy-7-megastigmen-5,9-diol-9-O-β-Dglucopyranoside(6) and a new sesquilignan glycoside, acernikol-4’’-O-β-D-glucopyranoside (15), together with thirteen known compounds were isolated.

Blood

It has been found that c-Myc protein plays a critical role in controlling self-renewal versus dif... more It has been found that c-Myc protein plays a critical role in controlling self-renewal versus differentiation in hematopoietic stem cells. We report that c-Myc also controls the fate of megakaryocyte-erythrocyte progenitors through regulating the differentiation of erythroid and megakaryocytic progenitors. In addition to the significant reduction of granulocytes/macrophages and B and T lymphocytes because of the reduction of their corresponding progenitors, we found significantly increased numbers of megakaryocytic progenitors and mature megakaryocytes in bone marrow and spleens of c-Myc-knockout (c-Myc(-/-)) mice. Differentiation of erythrocytes was blocked at the erythroid progenitor stage. This increased megakaryocytopoiesis is a cell-intrinsic defect of c-Myc-mutant hematopoietic stem cells, as shown by transplantation studies. Furthermore, we found that c-Myc is required for polyploidy formation but not for cytoplasmic maturation of megakaryocytes. Megakaryocytes from c-Myc(-/-...

American journal of physiology. Gastrointestinal and liver physiology, Jan 16, 2015

The pathophysiology of esophageal injury, repair, and inflammation in gastro-esophageal reflux di... more The pathophysiology of esophageal injury, repair, and inflammation in gastro-esophageal reflux disease (GERD) is complex. While most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that sub-epithelial esophageal myofibroblasts in GERD secrete pro-inflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts (α-SMA+ vimentin+ CD31-) in the sub-epithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed α-SMA co-immunostaining with IL-6 and p65. We established and characterized primary cultures of α-SMA+, vimentin+, CD31-, CD45- human esophageal myofibroblasts. We modeled GERD by treatment with pH 4.5 acidified media and TLR4 ligands LPS and HMGB1 and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate spindle-shap...

The Hematology Journal, 2000

To address the molecular regulation of hematopoiesis and the complex mechanism in leukemogenesis,... more To address the molecular regulation of hematopoiesis and the complex mechanism in leukemogenesis, we established the first catalogs of genes expressed in normal bone marrow and leukemia CD34(+) cells. CD34(+) cell cDNA libraries were constructed using mRNA from adult bone marrow and from a case of acute myeloid leukemia-M5 transformed from myelodysplastic syndrome (MDS-AML). Expressed sequence tags (ESTs) and full-length cDNAs were generated by sequencing and were annotated using bioinformatic tools. From a total of 4142 ESTs obtained from normal bone marrow, 3424 meaningful tags were integrated into 1630 clusters, representing 622 known genes, 522 dbEST entries and 486 novel sequences. Out of 5382 ESTs from MDS-AML, 1985 clusters were produced based on the analysis of 4321 useful ESTs, including 711 known genes, 657 known ESTs and 617 novel sequences. Among 251 transcripts found in both bone marrow and MDS-AML EST datasets and those present in only one dataset, 58 showed statistically significant differences in EST copy numbers between the two tissues (P<0.05). Twenty putative full-length cDNAs for novel genes were also cloned from the MDS-AML library. The distinct gene expression patterns in MDS-AML-CD34(+) cells as compared to normal control cells may contribute to the development and/or maintenance of the malignant phenotypes of leukemia cells.

The Hematology Journal, 2001

Introduction: To study the relationship between the expression level of the PML-RARa fusion trans... more Introduction: To study the relationship between the expression level of the PML-RARa fusion transcripts and the clinical status and eciency of the therapy in acute promyelocytic leukemia (APL) patients, we applied a very sensitive and speci®c real-time Reverse Transcription Polymerase Chain Reaction (RT ± PCR) system to quantify the dose of PML-RARa fusion transcripts in a series of APL patients at distinct disease stages. Materials and methods: A total of 31 APL patients (19 males and 12 females; aged from 8 to 74 years) from eight hospitals in Shanghai were analysed. Real-time Quantitative RT ± PCR was used to measure the normalized dose (Dose N ) of PML-RARa fusion transcripts. Results: A wide range of PML-RARa Dose N above 1610 3 was noted in 25 newly diagnosed patients. PML-RARa Dose N was signi®cantly decreased after remission induction with ATRA, ATRA/chemotherapy or As 2 O 3 and further reduced after consolidation. The fact that all patients with long disease free survival had a constantly low PML-RARa Dose N below 2610 2 and a higher level predicted impending relapse suggests that this value could serve as à threshold' for molecular remission. PML-RARa Dose N was also of prognostic value in a group of relapsed patients, since good response to As 2 O 3 reinduction was accompanied by a remarkable reduction of fusion transcript level, whereas patients with high PML-RARa Dose N after the second CR tended to relapse again rapidly. Conclusion: These results con®rm that real-time RT ± PCR assay for PML-RARa transcripts in APL patients is useful in re¯ecting leukemic burden, assessing response to treatment and indicating the ultimate clinical outcome or curability of disease.

Nature, 2003

run in TBE £ 0.5 at room temperature for 2 h at 150 V. The following two ( Q/q) 27-bp unmethylate... more run in TBE £ 0.5 at room temperature for 2 h at 150 V. The following two ( Q/q) 27-bp unmethylated oligonucleotides were used: 5 0 -GATCCTTCGCCTAGGCTC(A/G)CAGCG CGGGAGCGA-3 0 . A methylatedq probe (q*) was generated by incorporating a methylated cytosine at the mutated CpG site during oligonucleotide synthesis.

Molecular and Cellular Biology, 2007

RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leuke... more RBM15 is the fusion partner with MKL in the t(1;22) translocation of acute megakaryoblastic leukemia. To understand the role of the RBM15-MKL1 fusion protein in leukemia, we must understand the normal functions of RBM15 and MKL. Here, we show a role for Rbm15 in myelopoiesis. Rbm15 is expressed at highest levels in hematopoietic stem cells and at more moderate levels during myelopoiesis of murine cell lines and primary murine cells. Decreasing Rbm15 levels with RNA interference enhances differentiation of the 32DWT18 myeloid precursor cell line. Conversely, enforced expression of Rbm15 inhibits 32DWT18 differentiation. We show that Rbm15 alters Notch-induced HES1 promoter activity in a cell type-specific manner. Rbm15 inhibits Notch-induced HES1 transcription in nonhematopoietic cells but stimulates this activity in hematopoietic cell lines, including 32DWT18 and human erythroleukemia cells. Moreover, the N terminus of Rbm15 coimmunoprecipitates with RBPJ, a critical factor in Notch signaling, and the Rbm15 N terminus has a dominant negative effect, impairing activation of HES1 promoter activity by full-length-Rbm15. Thus, Rbm15 is differentially expressed during hematopoiesis and may act to inhibit myeloid differentiation in hematopoietic cells via a mechanism that is mediated by stimulation of Notch signaling via RBPJ.

Journal of Experimental & Clinical Cancer Research, 2010

To investigate the effect of all-trans retinoic acid(ATRA) on the proliferation and differentiati... more To investigate the effect of all-trans retinoic acid(ATRA) on the proliferation and differentiation of brain tumor stem cells(BTSCs) in vitro. Limiting dilution and clonogenic assay were used to isolate and screen BTSCs from the fresh specimen of human brain glioblastoma. The obtained BTSCs, which were cultured in serum-free medium, were classified into four groups in accordance with the composition of the different treatments. The proliferation of the BTSCs was evaluated by MTT assay. The BTSCs were induced to differentiate in serum-containing medium, and classified into the ATRA group and control group. On the 10th day of induction, the expressions of CD133 and glial fibrillary acidic protein (GFAP) in the differentiated BTSCs were detected by immunofluorescence. The differentiated BTSCs were cultured in serum-free medium, the percentage and the time required for formation of brain tumor spheres (BTS) were observed. BTSCs obtained by limiting dilution were all identified as CD133-positive by immunofluorescence. In serum-free medium, the proliferation of BTSCs in the ATRA group was observed significantly faster than that in the control group, but slower than that in the growth factor group and ATRA/growth factor group, and the size of the BTS in the ATRA group was smaller than that in the latter two groups(P < 0.01). In serum-containing medium, the expression percentages of CD133 and GFAP in the differentiated BTSCs were (2.29% +/- 0.27%) and (75.60% +/- 4.03%) respectively in the ATRA group, and (7.05% +/- 0.49%) and (12.51% +/- 0.77%) respectively in the control group. The differentiation rate of BTSCs in the ATRA group was significantly higher than that in the control group (P < 0.05), but there was still CD133 expressed in the ATRA group. The differentiated BTSCs could re-form BTSs in serum-free medium. The percentage of BTS formation in the ATRA group was(4.84% +/- 0.32%), significantly lower than that in the control group (17.71% +/- 0.78%) (P < 0.05), and the time required for BTS formation in the ATRA group was (10.07 +/- 1.03)d, significantly longer than that in the control group (4.08 +/- 0.35)d (P < 0.05). ATRA can promote the proliferation and induce the differentiation of BTSCs, but the differentiation is incomplete, terminal differentiation cannot be achieved and BTSs can be formed again.

Cancer Research, 2006

The formation of fusion genes between NUP98 and members of the HOX family represents a critical f... more The formation of fusion genes between NUP98 and members of the HOX family represents a critical factor for the genesis of acute leukemia or acute transformation of chronic myeloid leukemia (CML). To gain insights into the molecular mechanisms underlying the leukemogenesis of NUP98-HOX fusion products, we cloned NUP98-PMX1 from a CML-blast crisis patient with t(1;11) as a secondary chromosomal translocation, and functionally studied the fusion products in detail through various molecular and protein biochemical assays. In addition to many interesting features, we have found that the NUP98-PMX1 fusion protein exerts a repressive effect on PMX1 or serum response factor-mediated c-FOS activation, probably through the recruitment of a common corepressor histone deacetylase 1 by FG domains of the NUP98-PMX1 fusion protein. Moreover, we have provided evidence that the FG domains of NUP98-PMX1 and two other NUP98-containing fusion proteins, i.e., NUP98-HOXA9 and NUP98-HOXC11, all exhibit dual binding ability to both CREB binding protein, a coactivator, and histone deacetylase 1, a corepressor. Accordingly, we have hypothesized that this dual binding activity is shared by most, if not all, NUP98-HOX-involved fusion proteins, enabling these fusion proteins to act as both trans-activators and trans-repressors, and contributing to the genesis of acute leukemia or acute transformation of CML.

Cancer Genetics and Cytogenetics, 2000

ABSTRACT “Simple” variants of the t(8;21) translocation involving chromosome 8 and a chromosome o... more ABSTRACT “Simple” variants of the t(8;21) translocation involving chromosome 8 and a chromosome other than number 21 are rare. To our knowledge, only t(3;8)(q29;q22), t(8;11)(q22;q13), t(8;16)(q22;q24), t(8;20)(q22;p13), and t(8;22) have been reported in the literature. This paper describes for the first time two patients with acute myelogenous leukemia with a consistent t(8;19)(q22;q13) translocation. Their myelograms were compatible with the FAB-M2 subtype. The blasts from case 2 expressed CD34, CD33, CD13, and CD19. Karyotype analyses were performed on bone marrow cells using R- and G-banding at presentation. A t(8;19)(q22;q13) translocation was found in 28/30 metaphases for case 1 and in 23/25 metaphases for case 2. The latter case also had a deletion of chromosome 9, del(9)(q12q22) as an additional abnormality. Reverse transcriptase-polymerase chain reaction study revealed no AML1/ETO fusion transcript in case 2. Dual-color fluorescence in situ hybridization (FISH) assay using two probes (BAC92 and YAC412A4) convincingly demonstrated that the chromosomal material from 8q was translocated onto 19q rather than 19p in case 2. Thus, we consider t(8;19)(q22;q13) a true “simple” variant of t(8;21), and assume that a fusion gene resulting from the t(8;19) may contain the ETO gene located at 8q22 and an unknown partner gene from 19q13, which probably is a new transcription factor, whose molecular entity warrants further study.

Cancer Genetics and Cytogenetics, 1998

Chromosomal analysis of acute lymphoblastic leukemia (ALL) is often difficult because of the subo... more Chromosomal analysis of acute lymphoblastic leukemia (ALL) is often difficult because of the suboptimal in vitro growth of the immature lymphoid cell and the poor morphology obtained. In this study, we describe the application of comparative genomic hybridization (CGH) to investigate the genomic abnormalities in 14 patients with ALL, all of whom had cytogenetically identified numerical aberrations or gross chromosomal structural alteration. With the use of CGH, regional or whole chromosome overrepresentation or both were found to be more frequent than underrepresentation (52 gains vs. 6 losses), the most common gains being chromosomes 21 and X. The results of the comparison between CGH and conventional R-banding analysis could be classified into three categories: (1) in three cases, including two with trisomy, CGH and banding analysis gave identical results; (2) in six cases with hyperdiploidy and two cases presenting chromosome structural abnormalities, the results were consistent but with minor discrepancies; (3) in three cases, including two with triploidy and tetraploidy and one with chimeric karyotype together with +22, the data from CGH and cytogenetical analysis were discrepant. CGH could not find the triploidy and tetraploidy. Our results suggest that CGH has certain value in the detection of gains or losses of chromosome materials in hyperdiploid ALL. Nevertheless, the combination of CGH and conventional karyotyping provides more precise information on the genomic imbalance in ALL.

Cancer Genetics and Cytogenetics, 1999

To study the genomic abnormality underlying the acute transformation of chronic myeloid leukemia ... more To study the genomic abnormality underlying the acute transformation of chronic myeloid leukemia (CML), 15 CML patients in blast crisis (BC), 3 in accelerated phase (AP), and 20 in chronic phase (CP) were analyzed by conventional cytogenetics, comparative genomic hybridization (CGH), and dual-color chromosomal painting. Philadelphia (Ph) chromosome was identified in every case studied. Only 5 among 20 CP patients had additional abnormalities while 13 of 18 patients with disease progression (BC + AP) showed extra numerical and/or structural chromosomal aberrations. Cytogenetically, the most common chromosome gains during BC and AP were double or triple Ph chromosomes (5 of 14 cases) and trisomy 8 (5 of 14 cases). Trisomies 7 and 17 (1 of 14 cases each) were also observed. CGH analysis detected genetic imbalances in eight cases. Gains of chromosome 20 (3 cases) and 17q (2 cases) were observed, respectively. The recurrent chromosome loss was the deletion of the short arm of chromosome 17, seen in one case with i(17)(q10) and one case with an unbalanced translocation (1;17). In one case, a very complex chromosomal rearrangement, del(3),del(6),der(6)t(17;3;6),der(17)t(6;17), was seen. A novel finding of this work is the involvement of chromosome 1(q12-21qter) in CML disease progression. Overrepresentation of 1(q12-21qter) region was detected by CGH in one case which had a derivative chromosome 17. This abnormal chromosome was later confirmed by fluorescence in situ hybridization (FISH) painting to be a fusion between chromosome 1 and 17 to form the der(17)t(1;17) (q12-21;p11). Two other cases showed the same region being involved in translocations, t(1;10)(q12-21;q26) and t(1;11)(q12-21;p15). It is possible that one or more genes residing on chromosome 1q12-21 may be important in the acute transformation of CML. In conclusion, we find that the combined use of CGH, chromosome painting, and classic cytogenetic analysis allows a better evaluation of the genomic aberration involved in CML blastic transformation, and offers new directions for its further molecular investigations.

Cancer Genetics and Cytogenetics, 2001

Blood, 2009

RNA-binding motif protein 15 (RBM15) is involved in the RBM15-megakaryoblastic leukemia 1 fusion ... more RNA-binding motif protein 15 (RBM15) is involved in the RBM15-megakaryoblastic leukemia 1 fusion in acute megakaryoblastic leukemia. Although Rbm15 has been reported to be required for B-cell differentiation and to inhibit myeloid and megakaryocytic expansion, it is not clear what the normal functions of Rbm15 are in the regulation of hematopoietic stem cell (HSC) and megakaryocyte development. In this study, we report that Rbm15 may function in part through regulation of expression of the proto-oncogene c-Myc. Similar to c-Myc knockout (c-Myc-KO) mice, long-term (LT) HSCs are significantly increased in Rbm15-KO mice due to an apparent LT-HSC to short-term HSC differentiation defect associated with abnormal HSC-niche interactions caused by increased N-cadherin and beta(1) integrin expression on mutant HSCs. Both serial transplantation and competitive reconstitution capabilities of Rbm15-KO LT-HSCs are greatly compromised. Rbm15-KO and c-Myc-KO mice also share related abnormalities in megakaryocyte development, with mutant progenitors producing increased, abnormally small low-ploidy megakaryocytes. Consistent with a possible functional interplay between Rbm15 and c-Myc, the megakaryocyte increase in Rbm15-KO mice could be partially reversed by ectopic c-Myc. Thus, Rbm15 appears to be required for normal HSC-niche interactions, for the ability of HSCs to contribute normally to adult hematopoiesis, and for normal megakaryocyte development; these effects of Rbm15 on hematopoiesis may be mediated at least in part by c-Myc.

Biochemical Systematics and Ecology, 2010

In the present phytochemical study on the leaves of Crataegus pinnatifida, a new monoterpene glyc... more In the present phytochemical study on the leaves of Crataegus pinnatifida, a new monoterpene glycoside, (3S,5R,6R,7E,9R)-3,6-epoxy-7-megastigmen-5,9-diol-9-O-β-Dglucopyranoside(6) and a new sesquilignan glycoside, acernikol-4’’-O-β-D-glucopyranoside (15), together with thirteen known compounds were isolated.