Abstract
Simple SummaryHairy 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.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.
Highlights
The 2017 WHO classification of haematological malignancies recognises classical hairy cell leukaemia (HCLc) as a discrete entity and its variant form (HCLv) and splenic diffuse red pulp lymphoma (SDRPL) as provisional entities [1]
To ascertain the contribution of mutant BRAF to the HCLc phenotype, hairy cells from 26 patients were exposed in vitro to the specific BRAF inhibitors, vemurafenib or dabrafenib, or the MEK inhibitor trametinib. This resulted in the silencing of a gene expression signature which is specific to HCLc among B-cell tumours, with downregulation of genes including CCND1, CD25, and feedback inhibitors of ERK signalling such as members of the dual-specificity phosphatase (DSP) gene family
A major focus of this review was the key role that the discovery of the almost ubiquitous clonal BRAFV600E mutation has played in understanding the biology of HCLc and its importance both in differential diagnosis and as a therapeutic target
Summary
The 2017 WHO classification of haematological malignancies recognises classical hairy cell leukaemia (HCLc) as a discrete entity and its variant form (HCLv) and splenic diffuse red pulp lymphoma (SDRPL) as provisional entities [1]. HCLv has an incidence of 0.04/100,000, a median age at presentation of 70 years, and a male-to-female ratio of 1.5–2 It was first described in 1980 in two patients with bulky splenomegaly, a marked leucocytosis with villous lymphocytes, and splenic histology showing red pulp involvement similar to that seen in HCLc, together with a number of distinctive features not found in HCLc. It was first described in 1980 in two patients with bulky splenomegaly, a marked leucocytosis with villous lymphocytes, and splenic histology showing red pulp involvement similar to that seen in HCLc, together with a number of distinctive features not found in HCLc These include the absence of monocytopenia, larger tumour cells with prominent nucleoli, and bone marrow that is easy to aspirate due to absence or minimal marrow reticulin. The whole-exome sequencing of a single case of HCLc led to the discovery of a single somatic, point mutation in the DNA sequence of v-Raf murine sarcoma viral oncogene homolog B (BRAF), a kinase-encoding proto-oncogene. Tnohrismvaalirtiiaebsisliutychmaasythreeflinecatcttihveataicoqnuoisfitcieolnl coyfcaledidnihtiiobnitaolrgs,eannodmtihceabdnifoferrmenaltiitaiteisonsuscthagaes, ttrhaenisncaricptitvoamtiiocnanodf ceeplligceynceletiicnfheiabtiutroerss,oafnthdethceelldtiyffpeereinntwiathiiocnh stthaegBe,RtAraFnmscuritpattioomniacraisneds [e2p2i,g2e3n].etic features of the cell type in which the BRAF mutation arises [22,23]
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