Chi Wai Eric So

King's College London, Londinium, England, United Kingdom

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Publications (46)567.9 Total impact

  • Maria Teresa Esposito, Chi Wai Eric So
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    ABSTRACT: DNA damage repair mechanisms are vital to maintain genomic integrity. Mutations in genes involved in the DNA damage response (DDR) can increase the risk of developing cancer. In recent years, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia (AML) or of disease relapse. Moreover, a growing body of literature has indicated that epigenetic silencing of DDR genes could contribute to the leukemogenic process. In addition, a variety of AML oncogenes have been shown to induce replication and oxidative stress leading to accumulation of DNA damage, which affects the balance between proliferation and differentiation. Conversely, upregulation of DDR genes can provide AML cells with escape mechanisms to the DDR anticancer barrier and induce chemotherapy resistance. The current review summarizes the DDR pathways in the context of AML and describes how aberrant DNA damage response can affect AML pathogenesis, disease progression, and resistance to standard chemotherapy, and how defects in DDR pathways may provide a new avenue for personalized therapeutic strategies in AML.
    Chromosoma 08/2014; · 3.34 Impact Factor
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    ABSTRACT: FMS-like tyrosine kinase 3 (FLT3) is expressed in human hematopoietic stem and progenitor cells (HSPC) but its role during embryogenesis is unclear. In acute myeloid leukemia (AML), internal tandem duplication (ITD) of FLT3 at the juxtamembrane (JMD) and tyrosine kinase (TKD) domains (FLT3-ITD+) occurs in 30% patients and is associated with inferior clinical prognosis. TKD mutations (FLT3-TKD+) occur in 5% cases. We made use of zebrafish to examine the role of flt3 in developmental hematopoiesis and model human FLT3-ITD+ and FLT3-TKD+ AML. Zebrafish flt3 JMD and TKD were remarkably similar to their mammalian orthologs. Morpholino knock-down significantly reduced the expression of l-plastin (pan-leukocyte), csf1r and mpeg1 (macrophage) as well as that of c-myb (definitive HSPC), lck and rag1 (T-lymphocyte). Expressing human FLT3-ITD in zebrafish embryos resulted in expansion and clustering of myeloid cells (pu.1+, mpo+, and cebpα+) which were ameliorated by AC220 and associated with stat5, erk1/2, and akt phosphorylation. Human FLT3-TKD (D835Y) induced significant, albeit modest, myeloid expansion resistant to AC220. This study provides novel insight to the role of flt3 during hematopoiesis and establishes a zebrafish model of FLT3-ITD+ and FLT3-TKD+ AML that may facilitate high throughput screening of novel and personalized agents.
    Blood 03/2014; · 9.78 Impact Factor
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    ABSTRACT: Although CEBPA mutations are among the most common genetic abnormalities in acute myeloid leukemia (AML), the transformation mechanism remains largely obscure. In this issue of Cancer Cell, Zhang and colleagues report that SOX4 is a direct target and crucial mediator of C/EBPα mutants in AML, revealing a potential therapeutic avenue.
    Cancer cell 11/2013; 24(5):557-559. · 25.29 Impact Factor
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    Tsz K Fung, Chi W So
    Oncotarget 08/2013; · 6.64 Impact Factor
  • Bernd B Zeisig, Chi Wai Eric So
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    ABSTRACT: Identification of tractable signaling molecules essential for leukemogenesis facilitates the development of effective targeted therapies. In this issue of Cancer Cell, Miller and colleagues report that Integrin Beta 3, which is largely dispensable for normal hematopoiesis, plays an important role and is a potential therapeutic target in mixed lineage leukemia.
    Cancer cell 07/2013; 24(1):5-7. · 25.29 Impact Factor
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    ABSTRACT: While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.
    Cancer cell 03/2013; 23(3):376-89. · 25.29 Impact Factor
  • Bon Ham Yip, Chi Wai Eric So
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    ABSTRACT: Transcription factors critical for normal hematopoietic stem cell functions are frequently mutated in acute leukemia leading to an aberrant re-programming of normal hematopoietic progenitor/stem cells into leukemic stem cells. Among them, re-arrangements of the mixed lineage leukemia gene (MLL), including chimeric fusion, partial tandem duplication (PTD), amplification and internal exonic deletion, represent one of the most common recurring oncogenic events and associate with very poor prognosis in human leukemias. Extensive research on wild type MLL and MLL-fusions has significant advanced our knowledge about their functions in normal and malignant hematopoiesis, which also provides a framework for the underlying pathogenic role of MLL re-arrangements in human leukemias. In contrast, research progress on MLL-PTD, MLL amplification and internal exonic deletion remains stagnant, in particular for the last two abnormalities where mouse model is not yet available. In this article, we will review the key features of both wild-type and re-arranged MLL proteins with particular focuses on MLL-PTD and MLL amplification for their roles in normal and malignant hematopoiesis.
    Experimental Biology and Medicine 03/2013; 238(3):315-323. · 2.80 Impact Factor
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    ABSTRACT: The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16INK4a as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16INK4a transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16INK4a. Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16INK4a. Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16INK4a. Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.
    The EMBO Journal 03/2013; · 9.82 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis and exemplifies a genetically heterogeneous disease. The patients with AML also show a heterogeneous response to therapy. Although all-trans retinoic acid (ATRA) has been successfully introduced to treat acute promyelocytic leukemia (APL), it is rather ineffective in non-APL AML. In our present study, 1200 off-patent marketed drugs and natural compounds that have been approved by the Food and Drug Administration (FDA) were screened for anti-leukemia activity using the retrovirus transduction/transformation assay (RTTA). Furazolidone (FZD) was shown to inhibit bone marrow transformation mediated by several leukemia fusion proteins, including AML1-ETO. Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than sixty years. We investigated the anti-leukemic activity of FZD in a series of AML cells. FZD displayed potent antiproliferative properties at submicromolar concentrations and induced apoptosis in AML cell lines. Importantly, FZD treatment of certain AML cells induced myeloid cell differentiation by morphology and flow cytometry for CD11b expression. Furthermore, FZD treatment resulted in increased stability of tumor suppressor p53 protein in AML cells. Our in vitro results suggest furazolidone as a novel therapeutic strategy in AML patients.
    PLoS ONE 01/2013; 8(8):e72335. · 3.73 Impact Factor
  • Cancer cell 11/2012; 22(5):698-698.e1. · 25.29 Impact Factor
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    ABSTRACT: Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs). Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of β-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development. On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease.
    Current opinion in hematology 04/2012; 19(4):280-6. · 5.19 Impact Factor
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    ABSTRACT: PcG and TrxG proteins mostly with opposite transcriptional activities play key roles in normal and malignant development. In this issue of Cancer Cell, Tan et al. report an unexpected collaboration between CBX8 and MLL-AF9 in leukemia, revealing a far more complicated functional crosstalk between these master epigenetic regulators in oncogenesis.
    Cancer cell 11/2011; 20(5):551-3. · 25.29 Impact Factor
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    ABSTRACT: The efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3-directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non-cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted.
    British Journal of Haematology 06/2011; 154(4):457-65. · 4.94 Impact Factor
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    ABSTRACT: Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1(-/-) cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1(-/-) cells. MLL-AF9 could not initiate leukemia in Bmi1(-/-)Hoxa9(-/-) mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for Bmi1, Hoxa9 regulates expression of p16(Ink4a)/p19(ARF) locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmi1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs.
    Cell stem cell 06/2011; 8(6):649-62. · 23.56 Impact Factor
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    Ngai Cheung, Chi Wai Eric So
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    ABSTRACT: Identification of transcription factors as prevalent targets affected by recurring chromosomal translocations has provided the first hint for the importance of transcriptional deregulation in haematological malignancies. However, the actual molecular functions of these leukaemia-associated transcription factors on gene expression remained largely unknown until the recent discovery of their association with specific enzymatic activities that modify epigenetic codes (at DNA and/or histone levels) of downstream transcriptional targets. Intriguingly, while only just about half of acute leukaemia associates with recurring translocations, emerging evidence indicates that cryptic mutations identified in the "normal-karyotype" leukaemia also frequently affect components of epigenetic machinery. We will review these recent findings and discuss their implications in understanding the biology of the disease and in development of effective cancer therapeutics.
    FEBS letters 04/2011; 585(13):2100-11. · 3.54 Impact Factor
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    ABSTRACT: Identification of molecular pathways essential for cancer stem cells is critical for understanding the underlying biology and designing effective cancer therapeutics. Here, we demonstrated that β-catenin was activated during development of MLL leukemic stem cells (LSCs). Suppression of β-catenin reversed LSCs to a pre-LSC-like stage and significantly reduced the growth of human MLL leukemic cells. Conditional deletion of β-catenin completely abolished the oncogenic potential of MLL-transformed cells. In addition, established MLL LSCs that have acquired resistance against GSK3 inhibitors could be resensitized by suppression of β-catenin expression. These results unveil previously unrecognized multifaceted functions of β-catenin in the establishment and drug-resistant properties of MLL stem cells, highlighting it as a potential therapeutic target for an important subset of AMLs.
    Cancer cell 12/2010; 18(6):606-18. · 25.29 Impact Factor
  • Colin Kwok, Bernd B Zeisig, Shuo Dong, Chi Wai Eric So
    Blood 04/2010; 115(15):3176-7. · 9.78 Impact Factor
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    ABSTRACT: Identifying transcriptional program(s) deregulated by oncoproteins is key to understanding the molecular basis of the disease. In this issue of Cancer Cell, two studies by Martens et al. and Wang et al. provide global blueprints for transcriptional targets and epigenetic modifications mediated by PML-RARalpha in acute promyelocytic leukemia.
    Cancer cell 02/2010; 17(2):112-4. · 25.29 Impact Factor
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    ABSTRACT: PRKAR1A (R1A)-retinoic acid receptor-alpha (R1A-RARalpha) is the sixth RARalpha-containing fusion protein in acute promyelocytic leukemia (APL). Using the murine bone-marrow retroviral transduction/transformation assay, we showed that R1A-RARalpha fusion protein could transform bone-marrow progenitor/stem cells. In gel-shift assays, R1A-RARalpha was able to bind to a panel of retinoic acid response elements both as a homodimer and as a heterodimer with RXRalpha, and demonstrated distinct DNA-binding characteristics compared with wild-type RARalpha/RXRalpha or other X-RARalpha chimeric proteins. The ratio of R1A-RARalpha to RXRalpha proteins affected the retinoic acid response element interaction pattern of R1A-RARalpha/RXRalpha complexes. Studies comparing R1A-RARalpha with R1A-RARalpha(DeltaRIIa) demonstrated that the RIIa protein interaction domain located within R1A was responsible for R1A-RARalpha homodimeric DNA binding and interaction with wild-type R1A protein. However, the RIIa domain was not required for R1A-RARalpha-mediated transformation because its deletion in R1A-RARalpha(DeltaRIIa) did not compromise its transformation capability. In contrast, introduction of point mutations within the RARalpha portion of either R1A-RARalpha or R1A-RARalpha(DeltaRIIa), previously demonstrated to eliminate RXRalpha interaction or treatment of transduced cells with RXRalpha shRNA or a RXRalpha agonist, reduced transformation capability. Thus, leukemic transformation by APL fusion protein PRKAR1A-RARalpha is critically dependent on RXRalpha, which suggests RXRalpha is a promising target for APL.
    Blood 11/2009; 115(3):643-52. · 9.78 Impact Factor
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    ABSTRACT: Although both heterodimeric subunits of core binding factors (AML1/RUNX1 and CBFbeta) essential for normal hematopoiesis are frequently mutated to form different chimeric fusion proteins in acute leukemia, the underlying molecular mechanisms and structural domains required for cellular transformation remain largely unknown. Despite the critical role of CBFbeta for wild-type AML1 function and its direct involvement in chromosomal translocation, we demonstrate that both the expression and interaction with CBFbeta are superfluous for AML1-ETO (AE)-mediated transformation of primary hematopoietic cells. Similarly, the hetero-oligomeric interaction with transcriptional repressor ETO family proteins and the highly conserved NHR1 domain in AE fusion are also dispensable for transforming activity. In contrast, AE-mediated transformation is critically dependent on the DNA binding and homo-oligomeric properties of the fusion. Abolishment of homo-oligomerization by a small-molecule inhibitor could specifically suppress AML1 fusion-mediated transformation of primary hematopoietic cells. Together, these results not only identify the essential molecular components but also potential avenues for therapeutic targeting of AE-mediated leukemogenesis.
    Proceedings of the National Academy of Sciences 03/2009; 106(8):2853-8. · 9.81 Impact Factor

Publication Stats

1k Citations
567.90 Total Impact Points

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Institutions

  • 2010–2013
    • King's College London
      • Division of Cancer Studies
      Londinium, England, United Kingdom
  • 2006–2009
    • Institute of Cancer Research
      Londinium, England, United Kingdom
    • Racing Laboratory of the Hong Kong Jockey Club
      Hong Kong, Hong Kong
  • 2002–2007
    • Stanford University
      • Department of Pathology
      Stanford, CA, United States
  • 1997–2000
    • The University of Hong Kong
      • Department of Pathology
      Hong Kong, Hong Kong