BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

Abstract

Key Points• The V600E kinase-activating mutation of BRAF profoundly shapes the distinct identity of HCL among B-cell neoplasms.• Clinically available BRAF and MEK inhibitors exert potent antileukemic activity in patients' HCL cells in vitro and in vivo.Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia

“…The BRAF V600E mutation was also shown to play a key role in shaping the specific molecular signature, morphology, and antiapoptotic behavior of HCL. 8 Molecular and genomic studies identify prognostic factors in HCL that are associated with different responses to therapy. [9][10][11][12][13] The consistent application of these respective prognostic parameters may have an impact on the optimal management of patients.…”

Are Cladribine and Rituximab Enough for the Treatment of Relapsed Hairy Cell Leukemia?

“…Vemurafenib (2 × 240 mg daily) used in induction, followed by a maintenance treatment with 240 mg once a day (after complete hematological remission) could also be useful to manage the relapsed HCL [2]. BRAF and MAK inhibitors were able to lead to the loss of HCL-specific gene expression signature [17]. Vemurafenib also normalized hematopoietic stem/progenitor cell frequencies, which have marked alterations in HCL [18].…”

“…moxetumomab pasudotox), BRAF inhibitors such as vemurafenib [16] or dabrafenib, MEK inhibitors such as trametinib [17], and B cell receptor signaling kinase inhibitors such as ibrutinib [16]. Vemurafenib (2 × 240 mg daily) used in induction, followed by a maintenance treatment with 240 mg once a day (after complete hematological remission) could also be useful to manage the relapsed HCL [2].…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…For mutant BRAF, the inhibitor vemurafenib is already in clinical trials in relapsed/refractory HCL, demonstrating high activity even among heavily pre-treated patients. 3,95 New types of promising inhibitors have also been developed for EZH2 (a histone methyl transferase), 96 SF3B1 (a splicing factor), 97 NOTCH1 98 and IDH2, 99 and in some cases have already entered early phase clinical trials. The high frequency of TET2 and/or DNMT3A mutations in AITL and other T FHderived PTCL may also support the rationale to use demethylating agents as an alternative way to treat patients, supported by the results of a recent single report.…”