The Genomics of Hairy Cell Leukaemia and Splenic Diffuse Red Pulp Lymphoma

SIMPLE SUMMARY: Hairy cell leukaemia is a rare chronic lymphoid malignancy with distinctive clinical and laboratory features which include an enlarged spleen, low blood counts, and infiltration of the spleen and bone marrow, with lymphocytes that have a villous or hairy cytoplasmic border. Historically it has been responsive to a range of treatment modalities including splenectomy, alpha interferon, and more recently chemotherapy, but none are curative. This review describes the chromosome abnormalities, genomic mutations, DNA methylation patterns, and immunoglobulin gene usage in this disease. We then discuss how the discovery of a specific mutation in a single gene (BRAF), present in almost all cases but not in hairy cell variant or splenic lymphoma with villous lymphocytes, two other splenic lymphomas with similar features, has provided new insights into its biology, a new diagnostic test, and a new therapeutic target. ABSTRACT: Classical hairy cell leukaemia (HCLc), its variant form (HCLv), and splenic diffuse red pulp lymphoma (SDRPL) constitute a subset of relatively indolent B cell tumours, with low incidence rates of high-grade transformations, which primarily involve the spleen and bone marrow and are usually associated with circulating tumour cells characterised by villous or irregular cytoplasmic borders. The primary aim of this review is to summarise their cytogenetic, genomic, immunogenetic, and epigenetic features, with a particular focus on the clonal BRAFV600E mutation, present in most cases currently diagnosed with HCLc. We then reflect on their cell of origin and pathogenesis as well as present the clinical implications of improved biological understanding, extending from diagnosis to prognosis assessment and therapy response.