scholarly journals BRAF mutation in hairy cell leukemia

2014 ◽  
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.

scholarly journals The Biology of Classic Hairy Cell Leukemia

2021 ◽  
Vol 22 (15) ◽  
pp. 7780
Author(s):  
Jan-Paul Bohn ◽  
Stefan Salcher ◽  
Andreas Pircher ◽  
Gerold Untergasser ◽  
Dominik Wolf
Keyword(s):  
Hairy Cell Leukemia ◽  
Infectious Complications ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogues ◽  
B Cell Malignancy ◽  
Activating Mutation ◽  
Open Issue ◽  
Almost All

Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the bone marrow and spleen. Despite tremendous therapeutic advances achieved with the implementation of purine analogues such as cladribine into clinical practice, the culprit biologic alterations driving this fascinating hematologic disease have long stayed concealed. Nearly 10 years ago, BRAF V600E was finally identified as a key activating mutation detectable in almost all HCL patients and throughout the entire course of the disease. However, additional oncogenic biologic features seem mandatory to enable HCL transformation, an open issue still under active investigation. This review summarizes the current understanding of key pathogenic mechanisms implicated in HCL and discusses major hurdles to overcome in the context of other BRAF-mutated malignancies.

scholarly journals Genomics of Hairy Cell Leukemia

2017 ◽  
Vol 35 (9) ◽  
pp. 1002-1010 ◽  
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).

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

Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3330-3332 ◽  
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.

Increased Expression of Myc in Hairy Cell Leukemia, and Cell-Sensitivity to JQ1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5112-5112
Author(s):  
Evgeny Arons ◽  
Hong Zhou ◽  
Yonghong Wang ◽  
Daniel Edelman ◽  
Robert J. Kreitman ◽  
...  
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Poor Prognosis ◽  
Braf V600e ◽  
Leukemic Cells ◽  
Annexin A1 ◽  
Expression Data ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Wild Type

Abstract Classic hairy cell leukemia (HCL), comprising 2% of leukemias, is an indolent B-cell malignancy with malignant lymphocytes expressing B-cell antigens CD20 and CD22, CD103, CD11c, CD25, Annexin A1, BRAF V600E mutation, and monoclonal immunoglobulin (Ig) rearrangement. HCL variant (HCLv), which is ~10% as common as HCL, has much poorer response to therapy and more aggressive course, lacks CD25 and Annexin A1, and is wild-type for BRAF. HCLv is considered separate from HCL by the World Health Organization in the unclassifiable splenic B-cell leukemia/lymphomas. Another poor-prognosis group overlaps HCL and HCLv in which unmutated IGHV4-34 Ig rearrangement is expressed. IGHV4-34+ leukemic cells can resemble classic HCL with CD25 and Annexin A1 expression, but are BRAF wild-type. No uniform mutation has been identified for HCLv and IGHV4-34+ HCL, although MAP2K1 (MEK1) mutations have recently been identified in half of cases. Thus HCLv and IGHV4-34+ HCL are less indolent leukemias with few therapy options and no known molecular target. To study HCLv and IGHV4-34+ HCL, leukemic samples were purified by negative B-cell isolation followed by positive CD11c sorting. Following extraction (Qiagene, AllPrep DNA/RNA Kit), RNA samples from patients were analyzed in microarray studies (Human HT-12 v4 BeadChips, Illumina, Inc.). Expression data were compared by unpaired nonparametric analysis using Mann-Whitney. MYC expression using one probe (log2 values, mean +/- standard deviation) was 7.30 +/- 1.51 for 37 HCL vs 9.77 +/- 1.15 for 32 HCLv or IGHV4-34+ HCL (2-sided p<0.0001). For the other probe, expression was 7.07 +/- 1.51 vs 9.44 +/- 1.17 (p<0.0001). Expression data for MYC had previously been submitted for 31 chronic lymphocytic leukemia (CLL) and 16 HCL samples (Dataset GSE2350, Basso et al, Nat Genet, 37:382, 2005). By 1 probe for MYC, expression was 8.07 +/- 0.55 for CLL vs 9.31 +/- 1.19 for HCL (p=0.0023). By another MYC probe, expression was 9.28 +/- 0.47 for CLL vs 10.22 +/- 0.98 for HCL (p=0.0032). To investigate potential therapeutic relevance of aberrant MYC expression in HCL, HCLv and IGHV4-34+ HCL, the bromodomain and extra terminal (BET) protein inhibitor JQ1, which has been associated with down-regulation of c-Myc via Brd4, was incubated with primary leukemic cells and ATP incorporation was measured. JQ1 inhibited 12 samples of HCL (IC50s 214 +/- 217 nM) more potently than 14 samples of CLL (IC50s 1.77uM +/-2.62 uM, p=0.020), and also inhibited 14 samples of HCLv or IGHV4-34+ HCL (IC50s 221 +/- 234 nM) more potently than the 14 CLL samples (p=0.0079). However, JQ1 inhibition was similar comparing HCL and HCLv or IGHV4-34+ HCL (p=0.89). To exclude non-specific inhibition of the cells, the inactive control molecule JQ1R was tested and was only 6.0% +/- 4.0% as active as JQ1 toward HCL or HCLv or IGHV4-34+ HCL samples. Normal peripheral blood mononuclear cells were resistant (IC50 > 20 uM). In conclusion, our results show that MYC expression is higher in HCLv and IGHV4-34+ HCL than in classic HCL and higher in classic HCL than CLL. Moreover, JQ1 inhibits HCL or its variants more potently than CLL, although the inhibition assay used does not detect a difference between the variants and classic HCL. Further experiments with other inhibitors will be needed to determine if the increased expression of MYC in HCL and its poor-prognosis variants can be exploited for treatment. Disclosures No relevant conflicts of interest to declare.

Molecular Evidence of Ongoing Antigen Driven Somatic Hypermutation in the Natural History of Classic and Variant Hairy Cell Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2648-2648
Author(s):  
Evgeny Arons ◽  
Sarah Davies ◽  
Katherine Still ◽  
Nathan Chai ◽  
Katherine Potocka ◽  
...  
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Conflicts Of Interest ◽  
Somatic Hypermutation ◽  
Braf V600e ◽  
Molecular Evidence ◽  
Malignant Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Normal Peripheral Blood

Abstract Classic hairy cell leukemia (HCL) is a clonal chronic B-cell malignancy representing 2% of all leukemias, with neoplastic B lymphocytes in the blood, bone marrow and organs of the classic reticuloendothelial system. HCL variant (HCLv) is less common, typically has inferior prognosis, and usually lacks several HCL-related features including BRAF V600E, CD25, and Annexin A1. The malignant cells in HCL and HCLv patients have one or in unusual cases two different functional immunoglobulin heavy chain rearrangements. Significant variability can be observed in the 3rd complementarity determining region (CDR3), comprising the variable heavy (IGHV), diversity (IGHD), and joining (IGHJ) domains. A role for continued antigen selection in the pathogenesis and evolution of HCL and HCLv has been suggested but limited evidence has been found. We examined HCL and HCLv-derived IGHV genes by massive parallel deep sequencing in 15 HCL and 7 HCLv cases. In all studied samples, a productive monoclonal tumor-derived IGH sequence was detected. Analysis of all reads sharing clonal CDR3 motifs revealed the existence of dominant subclone expansion and multiple subclonal variants. Analysis of phylogenetic trees indicated multiple branching and therefore exposure to multiple rounds of somatic hypermutation (SHM) in the evolution of clonally-related malignant cells. To investigate a possible cause of the high SHM activity and the large number of subclones in HCL and HCLv, we studied the expression of activation induced cytidine deaminase (AID), an enzyme essential for somatic hypermutations, expressed by germinal center (GC) B-cells where SHM occurs. In 5 HCL and 3 HCLv cases we detected a high expression level of AID mRNA, including wild-type and 2 splice variants; in 10 HCL, 4 HCLv, and 3 normal peripheral blood samples, AID expression was not detected using standard end-point PCR conditions. However, more sensitive real-time quantitative PCR detected AID transcripts in virtually all tested HCL and HCLv cases, although the range of transcript levels was large between different cases and varied with individual cases over time. The data obtained for both HCL and HCLv fit a model of tumorigenesis in which the BRAF V600E mutation (or another event in HCLv) initiates neoplastic transformation in a GC B-cell committed to terminal differentiation, but still thereafter still targeted by ongoing SHM Disclosures No relevant conflicts of interest to declare.

BRAF V600E is also seen in unclassifiable splenic B-cell lymphoma/leukemia, a potential mimic of hairy cell leukemia

Blood ◽  
2013 ◽  
Vol 122 (17) ◽  
pp. 3084-3085 ◽  
Author(s):  
Philipp W. Raess ◽  
David Mintzer ◽  
Michael Husson ◽  
Megan O. Nakashima ◽  
Jennifer J. D. Morrissette ◽  
...  
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia

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

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 188-191 ◽  
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.

scholarly journals Successful treatment of synchronous hairy cell leukaemia and diffuse large B cell lymphoma in a patient with severe hypercalcemia and extensive osteolytic lesions

2021 ◽  
pp. 73-73
Author(s):  
O. Markovic ◽  
M. Gotic ◽  
V. Cemerikic ◽  
A. Divac ◽  
D. Marisavljevic
Keyword(s):  
B Cell ◽  
Hairy Cell Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Braf V600e ◽  
Cell Leukaemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction: Although secondary malignancies usually occur at different times after HCL treatment, (simultaneous) occurrence of HCL and other malignancies at the same time is very rare. Synchronous hairy cell leukemia (HCL) and diffuse large B cell lymphoma (DLBCL) has not been described so far. Case report: We report a 62-years old female patient who presented with intense constitutional symptoms, hypercalcaemia, pancytopenia and osteolytic destruction of the left shoulder joint. Immunohistochemical analysis of the bone marrow revealed presence of two populations: a population of HCL cells and a population of DLBCL cells with the expression of c-myc and bcl-2 ("double expressor" DLBCL) and high proliferative activity (Ki-67+cells>90%). FISH analysis showed amplification of the bcl-2 gene. In addition, BRAF V600E mutation was detected. After intensive treatment with immunochemotherapy, radiotherapy and bisphosphonates patient achieved complete remission, lasting for more than two years. Conclusion: As the association of hairy cell leukemia and lymphoma is a very rare, diagnosis of synchronous occurrence of two lymphoproliferative diseases is diagnostic and therapeutic challenge. It remains unclear whether DLBC and HCL are derived from two different malignant clones or DLBCL developed by transformation of HCL as the result of clonal evolution of B-cell clone.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2657-2657
Author(s):  
Enrico Tiacci ◽  
Gianluca Schiavoni ◽  
Maria Paola Martelli ◽  
Emanuela Boveri ◽  
Roberta Pacini ◽  
...  
Keyword(s):  
B Cell ◽  
Therapeutic Target ◽  
Hairy Cell Leukemia ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Erk Pathway ◽  
Clinical Use ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Braf Mutations

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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