Dataset Information

Expression of the muscle-associated gene MYF6 in hairy cell leukemia.

ABSTRACT: Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A. BRAF V600E and the latter 4 markers are usually absent in the more aggressive and chemoresistant variant HCLv. To evaluate differences between HCL and HCLv, expression microarrays comparing HCL with HCLv were performed for 24694 genes using 47323 probes. Microarray data from 35 HCL and 27 HCLv purified samples showed the greatest HCL-HCLv difference in the muscle-associated gene MYF6, expressed by its 2 probes 18.5- and 10.8-fold higher in HCL than HCLv (p<0.0001). By real-time quantitative PCR (RQ-PCR), 100% of 152 classic HCL samples were MYF6-positive, vs 5 (6%) of 90 blood donors. MYF6-expression was also detected in 18 (35%) of 51 with HCLv, 11 (92%) of 12 with HCL expressing unmutated IGHV4-34, 35 (73%) of 48 with chronic lymphocytic leukemia (CLL), and 1 (8%) of 12 with mantle cell lymphoma. Hypomethylation status of MYF6 supported expression in HCL more than HCLv. Posttreatment blood samples becoming negative by flow cytometry remained MYF6+ by RQ-PCR in 42 (48%) of 87 HCL patients, and MYF6 RQ-PCR could detect 1 HCL in 105 normal cells. MYF6, universally expressed in HCL and in most CLL samples, may be a useful biomarker for these leukemias. Further studies are underway to determine the role of MYF6 in HCL.

SUBMITTER: Arons E

PROVIDER: S-EPMC7010284 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Expression of the muscle-associated gene MYF6 in hairy cell leukemia.

Arons Evgeny E Zhou Hong H Sokolsky Mark M Gorelik Daniel D Potocka Katherine K Davies Sarah S Fykes Erin E Still Katherine K Edelman Daniel C DC Wang Yonghong Y Meltzer Paul S PS Raffeld Mark M Wiestner Adrian A Xi Liqiang L Wang Hao-Wei HW Stetler-Stevenson Maryalice M Yuan Constance C Kreitman Robert J RJ

PloS one 20200210 2

Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A. BRAF V600E and the latter 4 markers are usually absent in the more aggressive and chemoresistant variant HCLv. To evaluate differences between HCL and HCLv, expression microarrays comparing HCL with HCLv were performed for 24694 genes using 47323 probes. Microarray data from 35 HCL and ...[more]

PMID: 32040482

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Project description: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).

Project description:In the category of mature B-cell neoplasms, splenic B-cell lymphoma and leukemia were clearly identified and include four distinct entities: hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL), splenic diffuse red pulp lymphoma (SDRPL) and the new entity named splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN). The BRAFV600E mutation is detected in nearly all HCL cases and offers a possibility of targeted therapy. BRAF inhibitors (BRAFi) represent effective and promising therapeutic approaches in patients with relapsed/refractory HCL. Vemurafenib and dabrafenib were assessed in clinical trials. The BRAFV600E mutation is missing in SDRPL and SBLPN: mitogen-activated protein kinase 1 (MAP2K1) mutations were found in 40% of SBLPN and VH4-34+ HCL patients, making possible to use MEK inhibitors (MEKi) such as trametinib, cobimetinib or binimetinib in monotherapy or associated with BRAFi. Other mutations may be associated and other signaling pathways involved, including the B-cell receptor signaling (BCR), cell cycle, epigenetic regulation and/or chromatin remodeling. In SDRPL, cyclin D3 (CCND3) mutations were found in 24% of patients, offering the possibility of using cell cycle inhibitors. Even if new emerging drugs, particularly those involved in the epigenetic regulation, have recently been added to the therapeutic armamentarium in HCL and HCL-like disorders, purine nucleoside analogs more and more associated with anti-CD20 monoclonal antibodies, are still used in the frontline setting. Thanks to the recent discoveries in genetics and signaling pathways in HCL and HCL-like disorders, new targeted therapies have been developed, have proven their efficacy and safety in several clinical trials and become essential in real life: BRAFi, MEKi, Bruton Tyrosine Kinase inhibitors (BTKi) and anti-CD22 immunotoxins. New other drugs emerged and have to be assessed in the future. In this article, we will discuss the main mutations identified in HCL and HCL-like disorders and the signaling pathways potentially involved in the pathogenesis of the different hairy cell disorders. We will discuss the results of the recent clinical trials, which will help us to propose an algorithm useful in clinical practice and we will highlight the different new drugs that may be used in the near future.

Dataset Information

Expression of the muscle-associated gene MYF6 in hairy cell leukemia.

Publications

Expression of the muscle-associated gene MYF6 in hairy cell leukemia.

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