Abstract for presentation at 11th International Congress of Human Genetics

Genetic Heterogeneity in Familial AML: A Role for Genes Other Than RUNX1 and CEBPA?

  • Ella Wilkins, Walter & Eliza Hall Institute of Medical Research, Australia
  • Ms Catherine Carmichael, Walter & Eliza Hall Institute of Medical Research, Australia
  • Dr Robert Escher, Walter & Eliza Hall Institute of Medical Research, Australia
  • Dr Joelle Michaud, Walter & Eliza Hall Institute of Medical Research, Australia
  • Mrs Ping Cannon, Walter & Eliza Hall Institute of Medical Research, Australia
  • Dr Graeme Suthers, The University of Adelaide, Australia
  • Ms Meryl Altree, Child Health Research Institute, Australia
  • Ms Carolyn Butcher, Child Health Research Institute, Australia
  • Prof Richard D'Andrea, Child Health Research Institute, South Australia, Australia
  • Dr Mark Currie, Lewis Gale Clinic, United States
  • A/Prof Jonathon Drachman, University of Washington, United States
  • A/Prof Graham Young, University of Sydney, Australia
  • Dr Peter Bardy, Queen Elizabeth Hospital, South Australia, Australia
  • Dr Uday Popat, Baylor College of Medicine, United States
  • 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

    • Families exhibiting genetic predisposition to specific haematological cancers enable investigation of initial and downstream events leading to malignancy. To date, only two familial haematological malignancy loci have been identified: mutations in the runt-related transcription factor, RUNX1 (twelve pedigrees), and the CCAAT-enhancer binding protein, CEBPA (two pedigrees) predispose to acute myeloid leukaemia (AML). Germline RUNX1 mutations predispose to AML with constitutive thrombocytopenia resulting from a platelet defect. Germline CEBPA mutations predispose to AML with associated eosinophilia.
    Direct sequencing of samples from eight pedigrees with a predisposition to AML has identified a previously described CEBPA mutation in one pedigree and novel RUNX1 mutations in two pedigrees. One patient with a germline RUNX1 mutation also has a secondary mutation affecting this gene. Additionally, MLPA analysis of leukemic cells from this patient identified amplification of RUNX1 and karyotyping confirmed acquired trisomy 21. Whether these three genetic events affect the same allele is currently under investigation. To date, we have been unable to identify a mutation in RUNX1 or CEBPA in the five remaining pedigrees, strongly suggesting a role for other genes in familial AML. This genetic heterogeneity is further supported by phenotypic heterogeneity observed between pedigrees.
    RUNX1 and CEBPA are co-factors, supporting a hypothesis that perturbation of particular genetic networks leads to AML development and that other critical genes will lie within these interconnected pathways. We propose that identification of additional genes predisposing to leukaemia will shed light on pathways involved in disease development, particularly initial steps in malignant transformation, and may permit improved therapeutic strategies.

    Conference Organiser - ICMS Pty Ltd