Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease-specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole-genome analysis of BPDCN with a special focus on structural genomic alterations by using whole-genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide-level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss-of-IKZF1 expression pattern. Furthermore, up-regulation of cellular processes responsible for cell-cell and cell-ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients

Exploring the molecular pathogenetic basis of cutaneous lymphomas

Cutaneous lymphomas are hematological malignancies that present in the skin without evidence of extracutaneous disease at the time of diagnosis. This thesis explores the pathogenetic basis of common and rare cutaneous lymphoma entities (i.e. tumor-stage mycosis fungoides, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T‐cell lymphoma, blastic plasmacytoid dendritic cell neoplasm) by studying them using next-generation sequencing approaches. These studies had a special focus on structural genomic alterations (i.e. genomic rearrangements, copy number alterations), since a detailed examination of this type of genetic defects in cutaneous lymphomas using high-resolution techniques had been largely neglected in prior molecular studies. The body of work presented in this thesis expanded the understanding of the pathogenetic basis of four different cutaneous lymphoma entities. Firstly, it showed that structural genomic alterations play important roles in the pathobiology of cutaneous lymphomas. Secondly, it identified recurrently affected genes and cellular processes/pathways in each of the analyzed malignancies. Finally, it provided molecular insights that may be instrumental for the development of novel therapies in the future.Dutch Cancer SocietyLUMC / Geneeskund