Identification of novel molecular prognostic markers for paediatric T-cell acute lymphoblastic leukaemia

Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
British Journal of Haematology (Impact Factor: 4.71). 06/2007; 137(4):319-28. DOI: 10.1111/j.1365-2141.2007.06576.x
Source: PubMed

ABSTRACT In the last four decades the survival of patients with newly diagnosed childhood T-cell acute lymphoblastic leukaemia (T-ALL) has improved dramatically. In sharp contrast, relapsed T-ALL continues to confer a dismal prognosis. We sought to determine if gene expression profiling could uncover a signature of outcome for children with T-ALL. Using 12 patient specimens obtained before therapy started, we examined the gene expression profile by oligonucleotide microarrays. We identified three genes, CFLAR, NOTCH2 and BTG3, whose expression at the time of diagnosis accurately distinguished the patients according to disease outcome. These genes are involved in the regulation of apoptosis and cellular proliferation. The prognostic value of the three predictive genes was assessed in an independent cohort of 25 paediatric T-ALL patients using quantitative real-time reverse transcription polymerase chain reaction. Patients assigned to the adverse outcome group had a significantly higher cumulative incidence of relapse compared with patients assigned to the favourable outcome group (46% vs. 8%, P = 0.029). Five-year overall survival was also significantly worse in the patients assigned to the adverse outcome group (P = 0.0039). The independent influence of the 3-gene predictor was confirmed by multivariate analysis. Our study provides proof of principle that genome-wide expression profiling can detect novel molecular prognostic markers in paediatric T-ALL.

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Available from: Katrin Hoffmann, Mar 31, 2015
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    • "The underexpression of VEGFA in the T-ALL datasets examined may also be indicative of favorable prognosis in the T-ALL patients. Gottardo et al. [73] also reported downregulation of Notch2 in their analysis of T-ALL and they associate this lowered expression to adverse outcome in the patients. "
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    ABSTRACT: Notch signaling plays a critical role in cell fate determination and maintenance of progenitors in many developmental systems. Notch receptors have been shown to be expressed on hematopoietic progenitor cells as well as to various degrees in peripheral blood T and B lymphocytes, monocytes, and neutrophils. Our aim was to understand the protein interaction network, using Notch1 protein name as query in STRING database and we generated a model to assess the significance of Notch1 associated proteins in Acute Lymphoblastic Leukemia (ALL). We further analyzed the expression levels of the genes encoding hub proteins, using Oncomine database, to determine their significance in leukemogenesis. Of the forty two hub genes, we observed that sixteen genes were underexpressed and eleven genes were overexpressed in T-cell Acute Lymphoblastic samples in comparison to their expression levels in normal cells. Of these, we found three novel genes which have not been reported earlier- KAT2B, PSEN1 (underexpressed) and CDH2 (overexpressed).These three identified genes may provide new insights into the abnormal hematopoietic process observed in Leukemia as these genes are involved in Notch signaling and cell adhesion processes. It is evident that experimental validation of the protein interactors in leukemic cells could help in the identification of new diagnostic markers for leukemia.
    Computational and Structural Biotechnology Journal 07/2012; 1(2):e201207005. DOI:10.5936/csbj.201207005
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    • "We have used two different approaches to identify gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Defined gene classifiers (such as the 5-GC) containing a smaller number of genes may be useful to augment existing risk stratification regimens for patients diagnosed with ALL as they can easily be adapted to qRT-PCR technology [18,22]. The complementary method we present here uses larger, biologically defined genesets that provide important clues to the underlying mechanisms of relapse. "
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    ABSTRACT: Continuous complete clinical remission in T-cell acute lymphoblastic leukemia (T-ALL) is now approaching 80% due to the implementation of aggressive chemotherapy protocols but patients that relapse continue to have a poor prognosis. Such patients could benefit from augmented therapy if their clinical outcome could be more accurately predicted at the time of diagnosis. Gene expression profiling offers the potential to identify additional prognostic markers but has had limited success in generating robust signatures that predict outcome across multiple patient cohorts. This study aimed to identify robust gene classifiers that could be used for the accurate prediction of relapse in independent cohorts and across different experimental platforms. Using HG-U133Plus2 microarrays we modeled a five-gene classifier (5-GC) that accurately predicted clinical outcome in a cohort of 50 T-ALL patients. The 5-GC was further tested against three independent cohorts of T-ALL patients, using either qRT-PCR or microarray gene expression, and could predict patients with significantly adverse clinical outcome in each. The 5-GC featured the interleukin-7 receptor (IL-7R), low-expression of which was independently predictive of relapse in T-ALL patients. In T-ALL cell lines, low IL-7R expression was correlated with diminished growth response to IL-7 and enhanced glucocorticoid resistance. Analysis of biological pathways identified the NF-kappaB and Wnt pathways, and the cell adhesion receptor family (particularly integrins) as being predictive of relapse. Outcome modeling using genes from these pathways identified patients with significantly worse relapse-free survival in each T-ALL cohort. We have used two different approaches to identify, for the first time, robust gene signatures that can successfully discriminate relapse and CCR patients at the time of diagnosis across multiple patient cohorts and platforms. Such genes and pathways represent markers for improved patient risk stratification and potential targets for novel T-ALL therapies.
    Molecular Cancer 05/2010; 9(1):105. DOI:10.1186/1476-4598-9-105 · 4.26 Impact Factor
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    • "Briefly, RNA was extracted from cell lines in exponential growth phase and hybridised to Affymetrix HG-U133A microarrays (Affymetrix, Santa Clara, CA, USA) in accordance with our previously published protocols (Beesley et al, 2005; Hoffmann et al, 2005; Gottardo et al, 2007). Microarray data were normalised using robust multiarray analysis (Irizarry et al, 2003) and all passed quality control criteria for noise, background, absent/ present calls and 3 0 /5 0 signal ratios for ACTB and GAPDH. "
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    ABSTRACT: Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.
    British Journal of Cancer 03/2010; 102(7):1200. DOI:10.1038/sj.bjc.6605632 · 4.84 Impact Factor
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