Unique mutation and gene expression in High Hyperdiploid Acute Lymphoblastic Leukaemia with whole chromosome uniparental isodisomy

Whole genome copy number alterations, targeted gene-panel and RNA sequencing were used to investigate differences in high hyperdiploid (HH) B-cell acute lymphoblastic leukemia (ALL), with and without whole chromosome uniparental isodisomy (wUPD). Patients with wUPD demonstrated a higher modal number of chromosomes with gains of chromosome 5. Mutations in genes within epigenetic pathways with upregulation of genes involved in cellular response to stress and stimuli were seen in wUPD, in contrast to mutations in RAS/RTK pathways and upregulation of genes in RNA Polymerase III pathway in noUPD. AP-1 transcription factors and NUDT18, potentially implicated in thiopurine drug resistance, were upregulated in wUPD. wUPD was associated with female gender, higher presenting white cell count and lower end of induction minimal residual disease levels, though survival rates were similar in the two groups. Genome-wide differences in HH ALL with and without UPD suggest plausible biological explanations for the heterogeneity in therapeutic response.