This review summarizes current knowledge regarding the role of BRAF in lymphoid and myeloid neoplasms, with a focus on hairy-cell leukemia, Langerhans cell histiocytosis, and Erdheim-Chester disease.
We compared the ability of Sanger sequencing, fluorescent single-strand conformational polymorphism (F-SSCP) and high resolution melting (HRM) analysis to detect BRAF mutations in 20 cases of HCL consisting of four archival Romanowsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample.
The detection of BRAFV600E by IHC is useful in the distinction of HCLs from other splenic-based lymphomas, although the identification of at least rare SMZLs containing this abnormality illustrates the continuing need for a multiparameter approach to diagnosis.
A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients.
Cell lines originating from HCL patients lack BRAF mutations but retain the typical piliferous morphology and the distinctive HCL immunophenotype, thus, constituting suitable tools for identifying alternative tumor genes and leukemic mechanisms in this malignancy.
Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox), BRAF inhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib.
This report presents a patient with HCL and malignant melanoma with the BRAFp.V600E mutation, and discusses the successful treatment of both cancers with the BRAF inhibitor dabrafenib.
Identification of the BRAFV600E mutation in nearly 100% of HCL patients has provided rationale for inclusion of BRAF inhibitors into the therapeutic armamentarium to treat HCL.
Unearthing of the BRAF mutation in self-renewing hematopoietic stem cells reveals an unexpected origin for hairy cell leukemia-a mature B cell malignancy-and a potential new therapeutic target (Chung et al., this issue).
Using this BRAFV600E mutation specific antibody, this immunohistochemical study has 100% sensitivity and 100% specificity for the diagnosis of HCL in our cohort.
We investigated BRAF mutations in 36 subjects with different forms of SM, but could not detect BRAF mutation in any of the cases, not even in the mast cell lineage of a patient with V600EBRAF-positive HCL.
Discovery of the BRAFV600E mutation as a disease-defining genetic event in hairy cell leukemia can be helpful in both differential diagnosis and treatment of this disease.
They include the V600EBRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia.
Advanced molecular techniques have identified distinct molecular aberrations in the Raf/MEK-ERK pathway and BRAF (V600E) mutations that drive the proliferation and survival of HCL B cells.
In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL.
Besides confirming the constant presence of BRAF-V600E in all patients with hairy cell leukemia, we observed ubiquitous phospho-ERK expression in this malignancy.
Several genetic alterations are intuitively "druggable" with existing agents, for example, kinase-activating lesions in high-risk B-cell ALL, NOTCH1 in both leukemia and lymphoma, and BRAF in hairy cell leukemia.
The thymidine kinase inhibitor vemurafenib, which inhibits the V600E mutant of BRAF, was reported to induce a CR in multiply relapsed and refractory HCL, with nearly complete clearing of MRD.
In contrast with the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy.
Diagnostically, the BRAF(V600E) mutation is a powerful molecular marker for papillary thyroid carcinoma and, quite possibly, hairy cell leukemia as well.