BRAF V600E mutation in hairy cell leukemia: from bench to bedside

Abstract

Hairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently. In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from “hairy” to “smooth,” and eventually apoptosis. The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). The median relapse free-survival was about 19 months in patients who had achieved CR and 6 months in those who had obtained a partial response. Future therapeutic perspectives include: (1) combining BRAF inhibitors with MEK inhibitors or immunotherapy (anti-CD20 monoclonal antibody) to increase the percentage of CRs and (2) better understanding of the molecular mechanisms underlying resistance of HCL cells to BRAF inhibitors.

Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai–Dorfman disease

“…Phosphorylated and activated ERK translocates to the nucleus where it regulates the activity of several transcription factors, which in turn induce expression of genes required for survival and proliferation (26, 27). It is now well-established that mutations that constitutively activate members of this pathway occur in several non-hematologic malignancies, including melanoma, gliomas and carcinomas of the thyroid gland, lung, colon, ovary and hepatobiliary system (28–30), as well as hematologic diseases, namely hairy cell leukemia, chronic myelomonocytic leukemia, Langerhans cell histiocytosis and Erdheim-Chester disease (15, 31–34). In the last decade, the discovery of BRAF V600E mutation in Langerhans cell histiocytosis and Erdheim-Chester disease, followed by MAP2K1 mutations in BRAF -wild type Langerhans cell histiocytosis, significantly unraveled the underlying biology of these disorders.…”

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

“…These CN changes were evident in peripheral blood MNCs at disease initiation and relapse but not during remission, consistent with their somatic nature in HCL cells ( Figure 1C). Although recurrent 7q deletions have previously been reported in cHCL, [2][3][4]14 additional genes in the minimally deleted region of 7q beyond BRAF included SMO (7q32) and BRAF (7q34) itself. As a result, 7q deletion resulted in loss of heterozygosity of the BRAFV600E allele ( Figure 1D,F), as evidenced by the higher BRAFV600E variant allele frequency of 7q-deleted versus 7q-diploid cHCL (79% vs 22%, respectively; Wilcoxon matched-pairs signed rank test P 5 .0039).…”

“…Furthermore, cHCL and vHCL differ in therapeutic response and prognosis, with vHCL responding poorly to purine analogs (PAs), with a median survival less than half that of cHCL. [1][2][3][4][5] In addition, the mutations present in each HCL subtype are distinct, with BRAFV600E mutations in ;100% of cHCLs, 6,7 whereas ;30% of vHCLs harbor activating mutations in MAP2K1, 8,9 encoding the MEK1 kinase just downstream of BRAF. These data have furthered our understanding of and therapeutic approaches for HCL; however, studies of diverse cancers marked by the BRAFV600E mutation suggest that additional alterations are frequently required for tumor initiation and/ or progression in BRAFV600E-mutant cells.…”

<b><i>BRAF</i></b> V600 Mutational Status in Melanoma Correlates with Cytologic Features in Fine-Needle Aspirate Specimens

“…HCL is characterized by an eccentrically located nucleus with fine chromatin and an abundant amount of gray-blue cytoplasm with "shaggy" margins. Virtually, all HCL harbor the BRAF V600 mutation and demonstrate an overall rate of response to BRAF inhibitors approaching 100% [20]. BRAF V600E alone did not represent a marker for poor outcomes in PTC; however, when associated with alterations in other genes a subset of PTC was identified with an increased risk of recurrence and decreased survival [21,22].…”