Poster Presentation 6th Australian Health and Medical Research Congress 2012

Investigating Undetected ATM Dysfunction in Chronic Lymphocytic Leukaemia (#452)

Krisanda Mole 1 , Sinoula Apostolou , Karen Lower , Bryone J Kuss
  1. Flinders University, Bedford Park, SA, Australia

The ATM/p53- mediated DNA damage response pathway plays a major role in the development of many cancers. In Chronic Lymphocytic Leukaemia (CLL), patients lacking a functional Ataxia Telangiectasia Mutated (ATM) gene display a more aggressive clinical phenotype, poorer overall survival and often do not respond well to conventional chemotherapy (Austen et al. 2005). Consequently, these patients may benefit from alternative therapies that are independent of the ATM/p53 pathway. Therefore, the ability to define patients with a non-functional ATM gene would guide selection of therapy. Interstitial deletions at 11q23 (the region containing the ATM gene) is a common cause of loss of ATM function in CLL and can be easily tested in routine diagnostic laboratories using Fluorescence In Situ Hybridisation (FISH) techniques. However, loss of ATM function can also occur through other mechanisms that include (but are not limited to) mutation of the ATM gene (Austen et al. 2005).
The aim of this work therefore, has been to develop techniques for defining subgroups of CLL patients based on a functional assay of ATM activity using the phosphorylation of downstream targets of ATM detected by western blotting and correlated with the DNA sequence of ATM for each patient, which remains the gold standard for detection of ATM abnormalities. The ATM functional assay facilitates stratifying patients based on DNA damage repair which is clearly reduced in high risk CLL independent of standard prognostic markers.

The major findings from this work are as follows:
• Direct sequencing of the ATM gene detects otherwise unidentified functionally significant ATM mutations.
• Western blot analysis of downstream targets of the ATM protein can be used to detect functional differences in the ATM mediated DNA repair pathways additional to direct sequencing.
• In a limited study, this appears to have prognostic value for CLL patients, which is to be confirmed in a larger patient cohort.