Pathophysiology of ALL Sample Clauses

Pathophysiology of ALL. Acute lymphoblastic leukaemia arises because of the abnormal proliferation and differentiation of a clonal population of lymphoid cells. Next generation sequencing and microarray analysis of large ALL cohorts have provided considerable understanding and insight into the genetic basis of this disease. Genome-wide associate studies (GWAS) to understand the genetic susceptibility of B-ALL have identified single-nucleotide polymorphisms (SNPs) at eight loci influencing ALL risk including, 7p12.2 (IKZF1), 9p21.3 (CDKN2A) and 10p12.2 (PIP4K2A)12. A meta-analysis of three independent GWAS data sets shed further light on the inherited predisposition to childhood ALL and described two additional risk loci at 2q22.3 and 8p24.2112. Furthermore, researchers found that certain SNPs display subtype-specific effects on high-hyperdiploid ALL and Ph-like ALL. Studies in the paediatric and young adult population have identified syndromes that predispose to ALL, such as Down syndrome, Fanconi anaemia and Bloom syndrome. Collectively however, these account for only a minority of cases13–15. Genetic aberrations are a hallmark of B-ALL and abnormalities frequently occur in genes encoding transcriptional regulators of lymphoid development. For example, in 60% of all B-ALL patients the genes PAX5, EBF1 and IKZF, which encode transcription factors associated with B-cell differentiation and development, are mutated16,17. Moreover, structural chromosomal alterations occur in most cases16,17. Such characteristic translocations include t(12;21) [ETV6-RUNX1] t(1;19) [TCF3-PBX1], t(9;22) [BCR-ABL1] and rearrangement of MLL18. Other commonly transformed pathways in ALL involve tumour suppression and cell-cycle regulation pathways; however, the precise genes involved varies among subtypes19. Classification of ALL began in 1987; the French American British (FAB) criteria divided ALL into 3 subtypes based on morphology (L1, L2 and L3)20. Later revised in 1997, the World Health Organisation (WHO) proposed a classification to account for morphology and cytogenetic profile of leukaemic blasts and identified three types of ALL: B-lymphoblastic, T-lymphoblastic and Burkitt-cell leukaemia21. In 2008, B- lymphoblastic leukaemia was divided into two subtypes: B-ALL with recurrent genetic abnormalities and B-ALL not otherwise specified. B-ALL with recurrent genetic abnormalities is further demarcated based on specific chromosomal rearrangements. Additionally, Burkitt- cell leukaemia was removed as a...
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