ATM mutant cellular phenotype in B-cell chronic lymphocytic leukaemia: clinical consequences and therapeutic implications

Skowrońska, Anna Maria (2013). ATM mutant cellular phenotype in B-cell chronic lymphocytic leukaemia: clinical consequences and therapeutic implications. University of Birmingham. Ph.D.

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ATM germ-line mutations have been identified in a proportion of patients with chronic lymphocytic leukaemia (CLL) but their role in the development of this tumour remains unknown. In the course of this study it was established that ATM pathogenic mutations were increased among patients with chromosome 11q deletion/loss of one ATM allele when compared to healthy control individuals but not in those who did not acquire this deletion in their leukemic clone. The results indicate that ATM germ-line heterozygosity does not play a role in CLL but may influence disease progression through complete ATM loss and clonal expansion.

The analysis of the clinical outcome among CLL patients from phase III LRF UK CLL4 trial identified a distinctive subgroup with a particularly poor prognosis. Those patients had bi-allelic inactivation of ATM gene and showed significantly reduced progression-free survival (PFS) compared to those with ATM wild-type or mono-allelic ATM defects. Furthermore, they had equally poor PFS as those with mono- and bi-allelic TP53 abnormalities. The clinical implication of this finding might include re-consideration of the treatment strategies for this particular subgroup of patients.

The improved understanding of the biological background of progressive and resistant CLL tumours, such as those with TP53 or ATM defects, results in a development of further targeted treatment strategies. The assessment of their efficacy and toxicity could be facilitated by CLL xenograft models. The optimization strategies overcoming the limitations of existing xenograft model were investigated during the course of this study. The results showed that partial depletion of patient CD3+, CD4+ or CD25+ cells prior to injection into NOG mice can prolong the engraftment of CLL cells within xenogenic microenvironment hence, providing expanded period of time for testing new therapeutic agents.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer Studies
Funders: None/not applicable
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)


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