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Title: Characterisation of genetically unclassified subtypes of childhood B-cell precursor acute lymphoblastic leukaemia
Author: Stasevich, I.
ISNI:       0000 0004 7970 5889
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease at the cytogenetic and molecular genetic level. Recurrent acquired genetic abnormalities have been described in the leukaemic cells of patients with ALL, several of which are pathognomonic of the disease and can be used to monitor response to therapy. Improvements in the design and delivery of frontline treatment for childhood ALL have progressively increased survival rates over several decades. However, 15-20% of children with ALL continue to relapse. Most relapses in childhood B-cell precursor ALL (BCP-ALL) are not predicted using current prognostic features. Patients often do not exhibit any significant cytogenetic markers, belong to the "B-other" category of ALL and fall into an intermediate risk group; thereby raising the possibility of receiving inadequate treatment. Moreover, the mechanisms involved in the development of ALL in this subgroup remain primarily unclear. As a consequence, the molecular genetic characterisation of BCP-ALL without significant genetic abnormalities is essential for the identification of genetic alterations which could be implicated in the pathogenesis of this subtype of ALL and, therefore important for the prognosis and targeted treatment of this disease. This study investigated and genetically characterised a cohort of 68 patients without recurrent cytogenetic abnormalities associated with childhood BCP-ALL. Overall, the investigation identified a range of genetic aberrations including alterations of the transcription factors PAX5, IKZF1, ERG and ETV6. Alterations to the B-cell specific gene VPREB1, histone H genes and epigenetic modulators SETD2 and CHD2 were revealed. Deletions of tumour-suppressors CDKN2A/B and surrounding regions, rearrangements and mutations involving kinases and cytokine receptors PDGFRB, CRLF2, RAS, JAK2 and PTPN11 were also identified. The importance of the detection of EBF1-PDGFRB rearrangements, as also IKZF1 and ERG deletions, was demonstrated and should allow for better stratification of these patients into genetic risk groups. In addition, the identification of oncogenic mutations in signalling pathways and possible upregulation of the novel candidate gene TLE4 in PAX5+ ALL could serve as potential targets in therapy.
Supervisor: Kempski, H. ; Williams, O. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available