In this issue of Blood, Xi and colleagues report on v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in hairy cell leukemia (HCL) subsets, demonstrating that BRAF V600E mutations are absent in variant HCL forms and in a subset of classic HCL (HCLc).1
Specifically, the authors found nonmutated wild-type BRAF in all cases of variant HCL, in all HCL cases expressing IGHV4-34, and surprisingly also in 21% of HCLc, disturbing the uniform picture of BRAF mutations in HCL.2 In this series, BRAF mutations, which previously were described to be present in all cases of HCLc,2 were detected in only 79% of HCLc. Xi et al propose that this genetic diversity supports the classification of variant and IGHV4-34+ HCL cases as distinct disease subgroups with a pathogenesis different from HCLc, in terms of clinical presentation, immunophenotypic differences, and inferior responses to standard therapy.
BRAF is a member of the serine–threonine kinase RAF family, and participates in the mitogen-activated protein kinase (MAPK) signaling cascade downstream of RAS signaling proteins, transmitting survival and proliferation signals from cell surface receptors to the nucleus. BRAF mutations initially were discovered as oncogenic events in solid tumors, most notably in melanoma.3 The mutated BRAF protein containing an amino acid switch at position 600 (V600E) results in the activation of BRAF kinase activity, causing constitutive downstream signaling and cell growth.
The recent initial report about BRAF mutations in HCL, based on whole-exome sequencing of HCL cells, caused great interest and excitement,2 given that such a long-sought recurrent genetic lesion in HCL had not previously been identified. The high frequency of V600E BRAF mutations in HCLc and lack of such mutations in other B-cell malignancies indicates that this mutation represents a disease-defining mutation in HCL. The initial report about BRAF mutations in HCL based on 48 HCL samples has been extended and corroborated in larger cohorts of patients from different institutions, using allele-specific PCR assays.4-6
The findings by Xi et al overall confirm the importance and high prevalence of BRAF mutations in HCLc.1 It is tempting to speculate that lack of BRAF mutations in a significant proportion of immunophenotype-defined HCLc cases (n = 11) could be related to the higher prevalence of HCLc patients who were on treatment or unresponsive to standard therapy in this series,1 but as discussed by Xi et al, such HCLc cases with wild-type BRAF clinically do not appear to behave differently compared with BRAF-mutated cases.
Other potential developments of BRAF mutations in HCL are novel diagnostic possibilities and options for therapeutic targeting of BRAF, using BRAF inhibitors. Based on the data by Xi et al, BRAF mutational analysis can help distinguishing HCLc from HCL variant and IGHV4-34+ cases on the molecular level, and therefore such analyses are likely to become part of the diagnostic armamentarium in HCL. The therapeutic potential of targeting BRAF mutations in HCL is more difficult to predict. In vitro responsiveness of BRAF-mutated HCL to the BRAF inhibitor PLX-47202 supports further development of BRAF inhibitors in HCL patients.
Despite the current excitement about BRAF in HCL, we need to keep in mind that the importance of BRAF mutations for HCL pathogenesis and disease progression remains ill-defined. The mere presence of V600E BRAF mutations does not indicate that this genetic lesion is critical for the disease process or that BRAF inhibitors will follow the successful path of BCR-ABL kinase inhibitors. The phase 3 experience with the BRAF inhibitor vemurafenib (PLX4032) in previously untreated melanoma demonstrates that this kinase inhibitor improves overall and progression-free survival in patients with BRAF V600E mutation compared with dacarbazine.7 However, such BRAF inhibitor–induced remissions are typically short-lived because of development of resistance. This resistance to BRAF inhibitors is because of the ability of melanoma cells to flexibly switch their signaling programs among different RAF isoforms,8 underscoring the complexity and oftentimes redundancy of cell signaling, and the ability of cancer cells to adapt and bypass certain signaling modules that are pharmacologically blocked. In-depth analyses into the function of BRAF in HCL, and clinical trials with BRAF inhibitors such as vemurafenib in HCL will help to better define the role of V600E BRAF mutations in HCL and will strengthen our understanding of the molecular pathogenesis of HCL.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■