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Publications (4)35.73 Total impact

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    ABSTRACT: Secreted-frizzled related proteins (SFRPs) are modulators of the Wnt signaling pathway that is closely involved in normal and malignant hematopoiesis. Epigenetic deregulation of Wnt modulators leading to aberrant signaling has been reported in adult patients with acute myeloid leukemia (AML), but its occurrence in childhood patients with AML and the role of individual modulators are unclear. In this study, we examined SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in 83 patients with AML (59 children and 24 adults) and found preferential SFRP1 methylation and mRNA down-regulation in the prognostically favorable subgroup of AML with t(8;21) translocation. Among the 4 genes, SFRP1 methylation independently predicted prolonged event-free and relapse-free survivals in childhood patients with nonacute promyelocytic leukemia with nonadverse cytogenetics. Mechanistically, we further demonstrated that RUNX1-ETO, the t(8;21) fusion product, specifically bound the SFRP1 promoter and repressed its transcription via a consensus RUNX binding site. In t(8;21)-leukemia cells, SFRP1 selectively inhibited canonical Wnt signaling and cellular proliferation that were associated with concomitant down-regulation of Wnt/β-catenin target genes, including CCND1 and MYC. Taken together, we identified SFRP1 as a transcriptional repression target of the t(8;21) fusion protein and demonstrated a novel mechanism of Wnt activation in a specific subtype of AML.
    Blood 12/2011; 118(25):6638-48. DOI:10.1182/blood-2011-05-354712 · 9.78 Impact Factor
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    ABSTRACT: RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by 2 promoters P1 and P2, RUNX3 is frequently inactivated by P2 methylation in solid tumors. Growing evidence has suggested a role of this transcription factor in hematopoiesis. However, genetic alterations have not been reported in blood cancers. In this study on 73 acute myeloid leukemia (AML) patients (44 children and 29 adults), we first showed that high RUNX3 expression among childhood AML was associated with a shortened event-free survival, and RUNX3 was significantly underexpressed in the prognostically favorable subgroup of AML with the t(8;21) and inv(16) translocations. We further demonstrated that this RUNX3 repression was mediated not by P2 methylation, but RUNX1-ETO and CBFbeta-MYH11, the fusion products of t(8;21) and inv(16), via a novel transcriptional mechanism that acts directly or indirectly in collaboration with RUNX1, on 2 conserved RUNX binding sites in the P1 promoter. In in vitro studies, ectopically expressed RUNX1-ETO and CBFbeta-MYH11 also inhibited endogenous RUNX3 expression. Taken together, RUNX3 was the first transcriptional target found to be commonly repressed by the t(8;21) and inv(16) fusion proteins and might have an important role in core-binding factor AML.
    Blood 08/2008; 112(8):3391-402. DOI:10.1182/blood-2008-02-137083 · 9.78 Impact Factor
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    ABSTRACT: Severe acute respiratory syndrome (SARS) is a public health concern worldwide. By studying the human leukocyte antigen (HLA) types A, B, DR, and DQ alleles in 90 Chinese patients with serologically confirmed SARS infections, we identified a strong association between HLA-B*0703 (OR, 4.08; 95% CI, 2.03-8.18; P=.00072 [Bonferroni-corrected P value, P(c) <.0022]) and -DRB1*0301 (OR, 0.06; 95%, 0.01-0.47; P=.00008 [after Bonferroni correction, P<.0042]) and the development of SARS. Moreover, the frequency of B*0703 and B60 coinheritance (9.6%; 95% CI, 4.6%-19.0%) in our SARS group was significantly higher (P=3x10(-9)) than that expected in the general population (0.4%). These genetic data will critically affect both the study of the pathogenesis of SARS and the design of vaccination programs.
    The Journal of Infectious Diseases 09/2004; 190(3):515-8. DOI:10.1086/421523 · 5.78 Impact Factor
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    ABSTRACT: Cholangiocarcinoma comprises 5-20% of all primary malignant tumors of the liver. However, the lack of information about the genetic basis of cholangiocarcinoma has impeded characterization and understanding of its biological behavior. In this study, genome-wide aberrations in 13 cases of cholangiocarcinoma were examined by the molecular cytogenetic technique, comparative genomic hybridization. Frequent gains of 1q, 3q, 8q, 15q and 17q, and common losses on 3p, 4q, 6q, 9p, 17p and 18q were found. The finding of common chromosome 3p loss (approximately 40%) with a minimal deleted region of 3p13-p21 has prompted our further investigation on the tumor suppressor gene RASSF1A, located at 3p21.3. Using bisulphite modification followed by methyl-specific PCR, a high incidence of methylated RASSF1A promoter region was detected in our current series (9/13 cases; 69%). Further expression analysis on the nine cases with promoter hypermethylation indicated much reduced RASSF1A expression compared to normal livers. Our current molecular cytogenetic investigation on primary cholangiocarcinoma provided overall karyotypic information and represents the first report on the methylation status of RASSF1A in cholangiocarcinoma. The high incidence of 3p loss and RASSF1A promoter hypermethylation detected may have implications for this tumor suppressor gene in the malignant progression of cholangiocarcinoma.
    Journal of Hepatology 12/2002; 37(5):633-9. DOI:10.1016/S0168-8278(02)00269-6 · 10.40 Impact Factor