New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes.

Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAFV600E mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type BRAF gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies ( BRAF , MAP2K1 , DUSP2 , MAPK15 , ARID1A , ARID1B , EZH2 , KDM6A , CREBBP , TP53 , CDKN1B , XPO1 , KLF2 , CXCR4 , NOTH1 , NOTCH2 , MYD88 , ANXA1 , U2AF1 , BCOR , and ABCA8 ). We analyzed 20 HCL-c and 4 HCL-v patients. The analysis of diagnostic samples mutations in BRAF ( n = 18), KLF2 ( n = 4), MAP2K1 ( n = 3), KDM6A ( n = 2), CDKN1B ( n = 2), ARID1A ( n = 2), CREBBP ( n = 2) NOTCH1 ( n = 1) and ARID1B ( n = 1). BRAFV600E was found in 90% (18/20) of HCL-c patients. In HCL-c patients with BRAFV600E , other mutations were found in 33% (6/18) of cases. All 4 HCL-v patients had mutations in epigenetic regulatory genes: KDM6A ( n = 2), CREBBP ( n = 1) or ARID1A ( n = 1). The analysis of sequential samples (at diagnosis and relapse) from 5 patients (2 HCL-c and 3 HCL-v), showed the presence of 2 new subclonal mutations ( BCORE1430X and XPO1E571K ) in one patient and variations of the mutated allele frequency in 2 other cases. In the HCL-v disease, we described new mutations targeting KDM6A that encode a lysine demethylase protein. This opens new perspectives for personalized medicine for this group of patients.