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

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 BRAFV600E mutation. Ten percent of cHCL patients are BRAFWT 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.

Hairy Cell Leukemia: Where Are We in 2023?

“…The BRAF V600E mutation, which is also seen in solid tumors such as melanoma and lung cancer, has since been shown to be present in the vast majority of cases of HCL and constitutes an activating mutation which translates into increased proliferation and survival of malignant cells. Patients with a classical immunophenotype but who lack BRAF V600E may harbor alternative BRAF mutations [ 20 , 21 •]. Additional driver mutations in the MAP2K1 pathway may be present, and one case series demonstrated MAP2K1 mutations in one-third of those who were unmutated for BRAF [ 1 ••, 21 •, 22 ].…”

Hairy Cell Leukemia

“…The replacement produces an amino acid change from valine (V) to glutamate (E) at position 600 (V600E) of the protein sequence, ultimately leading to aberrant activation of BRAF kinase and the downstream MEK-ERK signaling. Indeed, the BRAF V600E mutation has been found to be more or less ubiquitous in studies involving hundreds of classic HCL patients (4,15,16). The BRAF V600E mutation itself is clonal and heterozygous, although a minority of patients lose the wild-type allele as a result of a concomitant 7q deletion (13,17).…”

“…A characteristic molecular feature of the disease, present in ≥95% of cases, is the BRAF V600E somatic mutation. It is important to distinguish between classic HCL and HCL-like diseases, including splenic B-cell lymphoma/leukemia, unclassifiable, as well as the variant form of HCL (HCL-v) and the splenic diffuse red pulp lymphoma (SDRPL) (3,4). Monocytopenia is characteristic of classic HCL (1,2).…”

Novel targeted treatments in hairy cell leukemia and other hairy cell-like disorders

“…Current information on the different somatic mutations observed in the different entities is based on limited data, namely whole exome sequencing (WES) ( 3 , 7 – 9 ) or targeted sequencing analysis ( 10 , 11 ) ( Figures 1 , 2 ). The activation of RAS-Mitogen-Activated Protein Kinases (MAPK) signaling is the key therapeutic target in HCL.…”

“…Other SVs were identified such as CHD7 , SLC2A8 and CLE6A with allele frequencies comparable to BRAF and could be potential drivers. In a large cohort of 98 patients, inactivating Kruppel like factor ( KLF2 ) (19p13.1) mutations were the second most altered genes after BRAF and observed in 21% of cases ( 11 ). KLF2 is a transcription factor controlling the differentiation of multiple B-cell subpopulations, including marginal zone B-cells.…”