Deciphering Genetic Alterations of Hairy Cell Leukemia and Hairy Cell Leukemia-like Disorders in 98 Patients

SIMPLE SUMMARY: The diagnosis of hairy cell leukemia (cHCL) and HCL-like disorders, including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging, particularly in complex situations. The integration of all data, including molecular data, is essential for distinguishing the different entities. The BRAF(V600E) mutation is identified in most cHCL cases, whereas it is absent in vHCL and SDRPL. MAP2K1 mutations are observed in half of vHCL cases and in cHCL BRAF(WT) and they are associated with a worse prognosis. The interest in deep sequencing for the diagnosis and prognosis of hairy cell leukemia and HCL-like disorders is essential. Some KLF2 genetic alterations have been localized on the AID consensus motif, suggesting an AID-induced mutation mechanism. KLF2 is the second most altered gene in HCL, and mutations must be investigated to confirm whether AID could be responsible for the genetic alterations in this gene. Clonal evolution can be observed in half of the cases. ABSTRACT: Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia, monocytopenia and/or thrombocytopenia, identification of hairy cells that express CD103, CD123, CD25, CD11c and identification of the V600E mutation in the B-Raf proto-oncogene (BRAF) in 90% of cases. Monocytopenia is absent in vHCL and SDRPL patients and the abnormal cells do not express CD25 or CD123 and do not present the BRAF(V600E) mutation. Ten percent of cHCL patients are BRAF(WT) and the distinction between cHCL and HCL-like disorders including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging. We performed deep sequencing in a large cohort of 84 cHCL and 16 HCL-like disorders to improve insights into the pathogenesis of the diseases. BRAF mutations were detected in 76/82 patients of cHCL (93%) and additional mutations were identified in Krüppel-like Factor 2 (KLF2) in 19 patients (23%) or CDKN1B in 6 patients (7.5%). Some KLF2 genetic alterations were localized on the cytidine deaminase (AID) consensus motif, suggesting AID-induced mutations. When analyzing sequential samples, a clonal evolution was identified in half of the cHCL patients (6/12 pts). Among the 16 patients with HCL-like disorders, we observed an enrichment of MAP2K1 mutations in vHCL/SDRPL (3/5 pts) and genes involved in the epigenetic regulation (KDM6A, EZH2, CREBBP, ARID1A) (3/5 pts). Furthermore, MAP2K1 mutations were associated with a bad prognosis and a shorter time to next treatment (TTNT) and progression-free survival (PFS), independently of the HCL classification.