Constant Activation of the RAF-MEK-ERK Pathway As a Diagnostic and Therapeutic Target in Hairy Cell Leukemia.

Abstract Abstract 2657 The BRAF-V600E mutation defines genetically hairy cell leukemia (HCL) among B-cell leukemias and lymhphomas. In solid tumors, BRAF-V600E is known to aberrantly activate the oncogenic MEK-ERK pathway, and targeted BRAF and/or MEK inhibitors have shown remarkable efficacy in clinical trials of melanoma patients. However, the MEK-ERK pathway status in HCL has not been thoroughly investigated so far. Therefore, as a read-out of MEK-ERK pathway activation, we assessed phospho-ERK expression in 37 HCL patients using immunohistochemistry on routine biopsies and/or Western blotting on purified leukemic cells. Beside confirming the constant presence of BRAF-V600E in all patients, we documented ubiquitous phospho-ERK expression in HCL. Conversely, all 44 HCL-like cases in parallel studied (40 splenic marginal zone lymphoma, 2 HCL-variant and 2 splenic lymphoma/leukemia unclassifiable) were devoid of BRAF-V600E and none expressed phospho-ERK. Lack of phospho-ERK expression was also documented in two exceptionally rare cases of non-HCL CD5-negative B-cell lymphoproliferative disorders not otherwise specifiable that were previously described to harbour the BRAF-V600E mutation on allele-specific PCR (Arcaini et al, Blood 2012;119:188–191), pointing to the presence of this mutation in only a small part of the leukemic clone in these cases. Our findings support the use of phospho-ERK immunohistochemistry in the differential diagnosis between HCL and HCL-like neoplasms and establish the MEK-ERK pathway as a rational therapeutic target in HCL. Disclosures: Tiacci: Not applicable: Dr. Tiacci filed a patent for the clinical use of BRAF mutations as biomarkers of HCL. Other. Inghirami:OncoEthix SA: Research Funding. Falini:Not applicable: Dr. Falini filed a patent for the clinical use of BRAF mutations as biomarkers of HCL. Other.

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Both variant and IGHV4-34–expressing hairy cell leukemia lack the BRAF V600E mutation

Blood ◽

10.1182/blood-2011-09-379339 ◽

2012 ◽

Vol 119 (14) ◽

pp. 3330-3332 ◽

Cited By ~ 138

Author(s):

Liqiang Xi ◽

Evgeny Arons ◽

Winnifred Navarro ◽

Katherine R. Calvo ◽

Maryalice Stetler-Stevenson ◽

...

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Poor Prognosis ◽

Braf V600e Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

Wild Type ◽

Ighv Gene ◽

Gene Usage

Abstract Recently, the BRAF V600E mutation was reported in all cases of hairy cell leukemia (HCL) but not in other peripheral B-cell neoplasms. We wished to confirm these results and assess BRAF status in well-characterized cases of HCL associated with poor prognosis, including the immunophenotypically defined HCL variant (HCLv) and HCL expressing the IGHV4-34 immunoglobulin rearrangement. Fifty-three classic HCL (HCLc) and 16 HCLv cases were analyzed for BRAF, including 5 HCLc and 8 HCLv expressing IGHV4-34. BRAF was mutated in 42 (79%) HCLc, but wild-type in 11 (21%) HCLc and 16 (100%) HCLv. All 13 IGHV4-34+ HCLs were wild-type. IGHV gene usage in the 11 HCLc BRAF wild-type cases included 5 IGHV4-34, 5 other, and 1 unknown. Our results suggest that HCLv and IGHV4-34+ HCLs have a different pathogenesis than HCLc and that a significant minority of other HCLc are also wild-type for BRAF V600.

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The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms

Blood ◽

10.1182/blood-2011-08-368209 ◽

2012 ◽

Vol 119 (1) ◽

pp. 188-191 ◽

Cited By ~ 112

Author(s):

Luca Arcaini ◽

Silvia Zibellini ◽

Emanuela Boveri ◽

Roberta Riboni ◽

Sara Rattotti ◽

...

Keyword(s):

Molecular Marker ◽

B Cell ◽

Hairy Cell Leukemia ◽

Lymphoproliferative Disorders ◽

Braf V600e Mutation ◽

Braf V600e ◽

Splenic Marginal Zone Lymphoma ◽

Hairy Cell ◽

Cell Leukemia ◽

Specific Pcr

Abstract The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL). We developed an allele-specific PCR for this mutation and studied 62 patients with HCL, 1 with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia, and 57 with B-cell chronic lymphoproliferative disorders. The BRAF V600E mutation was detected in all HCL cases and in only 2 of the remaining 178 patients. These 2 subjects had B-cell chronic lymphoproliferative disorders that did not fulfill the diagnostic criteria for HCL. Despite the positive PCR finding, the mutation could not be detected by Sanger sequencing in these 2 cases, suggesting that it was associated with a small subclone. We conclude that the BRAF V600E mutation is present in all patients with HCL and that, in combination with clinical and morphologic features, represents a reliable molecular marker for this condition.

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Faculty Opinions recommendation of The utility of BRAF V600E mutation-specific antibody VE1 for the diagnosis of hairy cell leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725292083.793544947 ◽

2018 ◽

Author(s):

Sascha Dietrich

Keyword(s):

Specific Antibody ◽

Hairy Cell Leukemia ◽

Braf V600e Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia

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BRAF mutation in hairy cell leukemia

Oncology Reviews ◽

10.4081/oncol.2014.253 ◽

2014 ◽

Cited By ~ 6

Author(s):

Ahmad Ahmadzadeh ◽

Saeid Shahrabi ◽

Kaveh Jaseb ◽

Fatemeh Norozi ◽

Mohammad Shahjahani ◽

...

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Common Mutation ◽

Hairy Cell ◽

Cell Leukemia ◽

Mitogen Activated Protein ◽

Almost All

BRAF is a serine/threonine kinase with a regulatory role in the mitogen-activated protein kinase (MAPK) signaling pathway. A mutation in the RAF gene, especially in BRAF protein, leads to an increased stimulation of this cascade, causing uncontrolled cell division and development of malignancy. Several mutations have been observed in the gene coding for this protein in a variety of human malignancies, including hairy cell leukemia (HCL). BRAF V600E is the most common mutation reported in exon15 of BRAF, which is observed in almost all cases of classic HCL, but it is negative in other B-cell malignancies, including the HCL variant. Therefore it can be used as a marker to differentiate between these B-cell disorders. We also discuss the interaction between miRNAs and signaling pathways, including MAPK, in HCL. When this mutation is present, the use of BRAF protein inhibitors may represent an effective treatment. In this review we have evaluated the role of the mutation of the BRAF gene in the pathogenesis and progression of HCL.

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Identification of the BRAF V600E mutation in Japanese patients with hairy cell leukemia and related diseases using a quenching probe method

International Journal of Hematology ◽

10.1007/s12185-018-2506-3 ◽

2018 ◽

Vol 108 (4) ◽

pp. 416-422

Author(s):

Hidekazu Itamura ◽

Masaru Ide ◽

Akemi Sato ◽

Naoko Sueoka-Aragane ◽

Eisaburo Sueoka ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Japanese Patients ◽

Braf V600e Mutation ◽

Probe Method ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

Quenching Probe

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Hairy cell leukemia with CCND1/IGH fusion gene and BRAF V600E mutation

Leukemia Research Reports ◽

10.1016/j.lrr.2020.100197 ◽

2020 ◽

Vol 13 ◽

pp. 100197 ◽

Cited By ~ 1

Author(s):

Zaid Abdel Rahman ◽

Firas Muwalla ◽

Liuyan Jiang ◽

James Foran

Keyword(s):

Hairy Cell Leukemia ◽

Fusion Gene ◽

Braf V600e Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia

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Genomics of Hairy Cell Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.1556 ◽

2017 ◽

Vol 35 (9) ◽

pp. 1002-1010 ◽

Cited By ~ 25

Author(s):

Enrico Tiacci ◽

Valentina Pettirossi ◽

Gianluca Schiavoni ◽

Brunangelo Falini

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Ex Vivo ◽

Braf Inhibitor ◽

Braf V600e ◽

Leukemic Cells ◽

Splenic Marginal Zone Lymphoma ◽

Hairy Cell ◽

Cell Leukemia ◽

Purine Analogs

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).

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