Abstract for presentation at 11th International Congress of Human Genetics

An Integrative Genomics approach in dominant familial Acute Myeloid Leukaemia (AML)

  • Ms Catherine Carmichael, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Robert Escher, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Ken Simpson, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Joelle Michaud, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Ms Ella Wilkins, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Tim Beissbarth, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Ms Suzanne Thomas, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Dr Gordon Smyth, The Walter and Eliza Hall Institute of Medical Research, Australia
  • Prof Olufunmilayo Olopade, University of Chicago, United States
  • A/Prof Marshall Horwitz, University of Washington, United States
  • Dr Hamish Scott, Walter & Eliza Hall Institute, Victoria, Australia

    • Haematological malignancies arise from a multistep pathway of genetic alterations. Initial steps in these pathways may be defined by studying families inheriting a predisposition to malignancies such as AML. These studies are often hindered by the morbidity, sporadic incidence, and unknown penetrance of disease. Thus, additional genomic methods are required to complement linkage analyses.
    In 3 families, with autosomal dominant transmission of AML, we are integrating the power of 6 approaches 1.linkage analysis, 2.gene expression profiling 3.bioinformatic analysis 4.candidate gene analysis 5.functional studies and 6.pathology samples. 1.‘Candidate region’ linkage analysis, due to DNA, sample and family size limitations, identified a putative susceptibility locus on chr:16q22. Ten genes from this region have been ruled out. 2.Affymetrix gene expression profiling of familial lymphoblast cell lines, combined with our linkage data, is being used to identify/prioritise candidate genes. 3.Bioinformatic analyses include in silico promoter analyses, to identify overrepresented DNA-binding motifs in differentially expressed genes, gene ontology analyses, to identify affected pathways/networks, and geneset testing, to identify significant links to other datasets. Geneset testing has suggested involvement of a RUNX1 network. 4.Several candidate genes involved in AML, including RUNX1 and CEBPA, have been ruled out by sequencing and MLPA analysis. 5.Functional analyses will help cluster additional family members, or additional families, with mutations in the same gene/genetic network. 6.Use of pathology samples to increase linkage power is being investigated.
    Integrating genomic techniques and linkage analysis will increase the success of familial haematological disease gene identification. The study of leukaemia-predisposing genes, and the networks perturbed, will increase understanding of early steps in leukaemogenesis and direct future research into therapies and treatments.

    Conference Organiser - ICMS Pty Ltd