Genomics of Hairy Cell Leukemia

Abstract

Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis. Conversely, BRAF-V600E is absent in other B-cell neoplasms, including mimickers of HCL that require different treatments (eg, HCL-variant and splenic marginal zone lymphoma). Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. BRAF-V600E also represents a new therapeutic target. Patients’ leukemic cells exposed ex vivo to BRAF inhibitors are spoiled of their HCL identity and then undergo apoptosis. In clinical trials of patients with HCL who have experienced multiple relapses after purine analogs or who are refractory to purine analogs, a short course of the oral BRAF inhibitor vemurafenib produced an almost 100% response rate, including complete remission rates of 35% to 42%, without myelotoxicity. To further improve on these results, it will be important to clarify the mechanisms of incomplete leukemic cell eradication by vemurafenib and to explore chemotherapy-free combinations of a BRAF inhibitor with other targeted agents (eg, a MEK inhibitor and/or an anti-CD20 monoclonal antibody).

Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms

“…Inactivation of the tumor suppressor NF-1, a negative regulator of RAS, also results in constitutive MEK/ERK activation in myeloid malignancies (37,41). In these RAS-and RAF-driven malignancies, the activation of the MEK/ERK signaling pathway is well understood, and several approaches have been studied in preclinical and clinical contexts to therapeutically target activated MEK/ ERK signaling, particularly by RAF or MEK1/2 inhibition (42)(43)(44). RAF inhibitors mediate clinical benefits in hairy cell leukemia and melanoma with specific mutations in BRAF (45,46), and combined RAF and MEK1/2 inhibition can provide further improved efficacy in these cancers (47,48).…”

New treatment options in hairy cell leukemia with focus on BRAF inhibitors

“…Immunohistochemistry is based on the use of antibodies against BRAF‐V600E, CD20 (in patients who have not previously received rituximab), or CD79a (in patients previously treated with rituximab). In marrow aspirates, MRD can be detected with multicolor flow cytometry, conventional allele‐specific PCR for the BRAF‐V600E mutation or for the patient‐specific immunoglobulin rearrangement, and next‐generation sequencing or digital PCR for BRAF‐V600E, with a range of sensitivities down to 10 −6 . MRD analysis in the blood underestimates the disease burden, which is largely located in the bone marrow and the spleen.…”

“…Using a whole‐exome sequencing approach, we discovered in 2011 the BRAF‐V600E mutation as the causal genetic event of HCL (Figure ). This finding opened new perspectives on the biology, diagnosis, and therapy of HCL …”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…The discovery of BRAFV600E mutations provided a molecular basis to distinguish classic hairy cell leukemia (cHCL) from hairy cell leukemia (HCL) variant and HCL expressing IGHV4-34, 129,130 forms of HCL which are histologically similar but known to have a more aggressive clinical course and are less likely to respond to purine analog therapy compared with cHCL. Mutations in MAP2K1, encoding the kinase just downstream of BRAF, were identified in HCL variant, 131 and IGHV4-34 1 HCL.…”