Molecular Genetic Characterization of Acute Lymphoblastic Leukemia with a Poor Prognosis

University dissertation from Division of Clinical Genetics, Lund University

Abstract: Acute lymphoblastic leukemia (ALL) affects individuals at all ages, with peak incidences in children <4 years and adults >50 years. ALL is broadly categorized into B-cell precursor (BCP) and T-cell ALL with specific clinical features associated with outcome. In contrast to pediatric ALL, which has a favorable prognosis, adult ALL is associated with a much poorer outcome with less than 40% overall survival rates, decreasing with higher age. The presence of specific acquired genetic abnormalities is important for diagnosis, prognostication, and treatment stratification. ALL can be further categorized into subgroups defined by structural or ploidy abnormalities. One such subgroup, hypodiploid ALL (<46 chromosomes) is seen in 5-8% of all cases, and associated with a very dismal prognosis. It can be further subdivided into two distinct genetic and clinical subgroups, namely near-haploidy (24-31 chromosomes) and low hypodiploidy (32-39 chromosomes), and, comprising cases with a more heterogenous background, high hypodiploidy (40-43 chromosomes) and cases with 44 and 45 chromosomes. Near-haploid and low hypodiploid ALL are very rare, comprising less than 1% of BCP ALL, with overall survival rates of <30%.
The general aim of my PhD project has been to characterize ALL patients with a poor prognosis, including adult ALL (article I) and hypodiploid ALL (article II-IV). To investigate the genetic landscape of adult ALL, we performed SNP array analysis on 126 ALL cases. Characteristic deletions seen in pediatric ALL were detected, furthermore, comparison of diagnostic and relapse clonal relationship showed evolution from an ancestral clone in the majority of cases, highlighting similarities in childhood and adult disease. In addition, the analysis revealed several recurrent cryptic genetic events not previously implicated with adult ALL, including the BCAT1, BTLA,
NR3C1, PIK3AP1 and SERP2 genes. In articles II-IV the genetic and epigenetic background of hypodiploid ALL was further investigated using SNP array analysis, exome and RNA sequencing, methylation array analysis and FISH analysis. Characteristic chromosomal patterns were confirmed and subtype specific alterations targeting IKZF3, NF1, FLT3 and TP53 were identified near-haploid and low hypodiploid respectively. Furthermore, due to the specific pattern of CDKN2A deletions in one case, we could conclude that chromosomal loss was the primary event with further microdeletions occurring after the near-haploidization. Combining SNP array and FISH analysis, a sublconal pattern was detected in three cases harboring >79 chromosomes, showing a possible hypodiploid origin due to the extensive loss of heterozygosity identified in such cases. That all three cases harbored TP53 mutations emphasized similarities to low hypodiploid ALL. In conclusion, screening for specific genetic abnormalities routinely in the clinic may improve prognostication and treatment stratification in cases with a poor prognosis.

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