BRAF mutations in non-Hodgkin's lymphoma

Lee, Jung Woo; Yoo, Nam Jin; Soung, Young Hwa; Kim, H S; Park, W S; Kim, S Y; Park, J Y; Cho, Y G; Kim, C J; Ko, Young Hyeh; Nam, Soon Woo; Lee, S H

doi:10.1038/sj.bjc.6601371

Cited by 65 publications

(48 citation statements)

References 9 publications

(9 reference statements)

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“…However, mutations that activate the MAPK-ERK signaling pathway are rare in hematologic malignancies despite the apparent requirement for precise control over MAPK-ERK pathway activity to prevent immune cell transformation. [49][50][51] On the other hand, there is evidence that loss-of-function mutations in genes that encode negative regulators of MAPK-ERK pathway signaling promote lymphomas. For example, children with neurofibromatosis type 1, which is most often caused by inactivation of the NF1-negative regulator of RAS, have a 10-fold increased risk of developing a lymphoid malignancy compared with unaffected children.…”

Section: Discussionmentioning

confidence: 99%

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Frank¹,

Dawson²,

Bensinger

et al. 2009

Blood

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B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B-and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg Bcell tumors to discover tumor-associated IntroductionHyperactivation of the RAS-RAF-MEK-ERK signaling pathway (MAPK-ERK pathway) promotes a variety of cancers, including hematologic malignancies, by enhancing cell proliferation and cell survival and by affecting differentiation. 1,2 The MAPK-ERK pathway can be constitutively activated by tumor type-specific gain-of-function mutations in (or overexpression of) upstream pathway members, such as growth factor receptors, RAS, and RAF, and by loss-of-function mutations in (or repression of) negative pathway regulators, such as NF1, SPROUTY, or SPRED proteins. 3 Ectopic expression of T-cell leukemia 1 (TCL1), a gene that encodes a 14-kDa protein that augments AKT pathway signaling in lymphocytes, is common in mature B-cell leukemias and lymphomas. [4][5][6] A causative role for ectopic TCL1 expression in lymphocyte transformation is supported by the observation that a spectrum of Tand B-cell tumors form in TCL1 transgenic (TCL1-tg) mice, in which the human TCL1 gene is ectopically expressed under the control of an E-B29 promoter in mature lymphocytes. 7 The mechanism(s) by which ectopic TCL1 expression promotes T and B lymphocyte transformation is not fully understood. In T cells, TCL1 augments AKT and MAPK-ERK signaling with each pathway independently contributing to increase T-cell proliferation in TCL1-tg mice. 8 There is also evidence that the tumorigenic activity of TCL1 involves more than augmentation of AKT signaling because it has been shown that increasing AKT activity in B cells to levels higher than are detected in TCL1-tg B cells by deleting Pten, a negative regulator of AKT, fails to cause lymphocyte transformation. 9 Moreover, it is not known what effect TCL1 has on MAPK-ERK signaling in B cells. The observation that in humans and TCL1-tg mice there is a long latency before B-and T-cell tumors form after ectopic expression of TCL1 is consistent with the conclusion that additional changes beyond TCL1-mediated augmentation of AKT signaling are needed to transform lymphocytes.Because TCL1 expression is more frequently dysregulated in B-cell compared with T-cell tumors, we have focused on its role in B-cell malignancies. B-cell lymphomas from TCL1-tg mice display aneuploidy and chromosomal translocations. In many of these lymphomas, trisomy 15 and its associated c-MYC overexpression results in a lesion that histologically and molecularly resembles human Burkitt lymphoma (BL). 10,11 In addition to genetic alterations, TCL1-tg B-cell tumors also display reproducible genomewide p...

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Section: Discussionmentioning

confidence: 99%

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Frank¹,

Dawson²,

Bensinger

et al. 2009

Blood

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“…Active mutations have been shown to play a role in a wide variety of human cancer development through increased activation of downstream kinases. 33,34 PIM1 is a serine/threonine kinase involved in several biological functions including cell survival, proliferation and differentiation. 35 PIM1 has been shown to be involved in several hematopoietic cancers, and has recently been identified as a target of aberrant somatic hypermutation in diffuse large B-cell lymphomas.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

Wallentine

Kim

Seiler

et al. 2007

Laboratory Investigation

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Mass spectrometry-based proteomics in conjunction with liquid chromatography and bioinformatics analysis provides a highly sensitive and high-throughput approach for the identification of proteins. Hodgkin lymphoma is a form of malignant lymphoma characterized by the proliferation of Reed-Sternberg cells and background reactive lymphocytes. Comprehensive analysis of proteins expressed and released by Reed-Sternberg cells would assist in the discovery of potential biomarkers and improve our understanding of its pathogenesis. The subcellular proteome of the three cellular compartments from L428 and KMH2 Hodgkin lymphoma-derived cell lines were fractionated, and analyzed by reversephase liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Additionally, proteins released by Hodgkin lymphoma-derived L428 cells were extracted from serum-free culture media and analyzed. Peptide spectra were analyzed using TurboSEQUEST s against the UniProt protein database (5.26.05; 188 712 entries). A subset of the identified proteins was validated by Western blot analysis, immunofluorescence microscopy and immunohistochemistry. A total of 1945 proteins were identified with 785 from the cytosolic fraction, 305 from the membrane fraction, 441 from the nuclear fraction and 414 released proteins using a minimum of two peptide identifications per protein and an error rate of o5.0%. Identification of proteins from diverse functional groups reflected the functional complexity of the Reed-Sternberg proteome. Proteins with previously reported oncogenic function in other cancers and from signaling pathways implicated in Hodgkin lymphoma were identified. Selected proteins without previously demonstrated expression in Hodgkin lymphoma were validated by Western blot analysis (B-RAF, Erb-B3), immunofluorescence microscopy (Axin1, Tenascin-X, Mucin-2) and immunohistochemistry using a tissue microarray (BRAF, PIM1). This study represents the first comprehensive inventory of proteins expressed by Reed-Sternberg cells of Hodgkin lymphoma and demonstrates the utility of combining cellular subfractionation, protein precipitation, tandem mass spectrometry and bioinformatics analysis for comprehensive identification of proteins that may represent potential biomarkers of the disease.

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“…A klasszikus hajas sejtes leukémia és a BRAF V600E-mutáció kimutatására irányuló vizsgálatok az eredeti közlemény (Tiacci, 2011) sem ismeretlen a BRAF különböző misszenz mutációi-nak igen ritkán előforduló jelenléte, például myeloma multiplexben, krónikus lymphoid leukaemiában, diffúz nagy B-sejtes lymphomában vagy akut lymphoid leukaemiában [12,13,14,15].…”

Section: Táblázatunclassified

Recurrent somatic mutation in hairy cell leukemia

2013

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A hajas sejtes leukémia olyan érett B-sejtes non-Hodgkin-lymphoma, amelyet egyedi klinikai, morfológiai és immunfenotípusbeli sajátosságok jellemeznek. A betegséget splenomegalia, progresszív pancytopenia és relatív indolens lefolyás kíséri. A diagnózis megszületése után a klinikai stádiumtól függ, hogy a "watchful waiting" stratégiát választ-juk, avagy azonnali kezelés szükséges. Az első vonalban javasolt purin-nukleozid analógokkal (cladribin, pentostatin) akár több évtizedig tartó komplett remisszió is elérhető. A hajas sejtes leukémia néha igen komoly differenciáldiag-nosztikai kérdéseket felvető betegség. A pontos diagnózis igen nagy horderejű, hiszen a rokon kórképek prognózisa és kezelése nagymértékben különbözik a hajas sejtes leukémiáétól. Ezért volt kiemelkedő fontosságú az a felismerés, hogy létezik olyan genetikai elváltozás, amely e betegségek elkülönítő diagnózisában döntő értékű. A BRAF gén V600E szomatikus mutációja hajas sejtes leukémiában szenvedő betegek csontvelői mintáiból izolált DNS-ben minden esetben jelen van, míg a rokon kórképekre ezen mutáció hiánya a jellemző. A szerzők a mutáció felismerésének és a mutációvizsgálat alkalmazásának jelentőségét foglalják össze. Orv. Hetil., 2013, 154, 123-127. Kulcsszavak: hajas sejtes leukémia, BRAF Recurrent somatic mutation in hairy cell leukemiaHairy cell leukemia is a mature B-cell non-Hogkin lymphoma characterized by unique clinical, morphological and immunhistochemical features. Patients with hairy cell leukemia usually present with splenomegaly, progressive pancytopenia and a relative indolent clinical course. The diagnosis does not always indicate immediate treatment, as treatment depends on the clinical stage of the leukemia. Asymptomatic disease without progression requires a watchful waiting policy, while other categories usually need treatment. The treatment of choice is purin nucleosid analogues (pentostatin, cladribine) which can achieve complete remission even for decades. Interferon and monoclonal CD20 antibodies can also signifi cantly prolong tevent free survival. Unfortunately, only the latter two therapies are easily available in Hungary. Splenectomy, which was suggested as fi rst line treatment before the era of purin nucleosid analogues, is only recommended as ultimum refugium. Although hairy cell leukemia is a well-defi ned lymphoproliferative disease, sometimes it is diffi cult to differentiate it from other similar entities such as hairy cell leukema variant, splenic marginal zone lymphoma, small lymphocytic lymphoma etc. Making the correct diagnosis is of utmost importance because of the great difference in treatment modalities. Recently, a somatic mutation was found in all analysed hairy cell leukemia samples, but not in other splenic B-cell lymphomas. This article reviews the signifi cance of this observation and presents the different types of methods for the detection of this mutation. Orv. Hetil., 2013, 154, 123-127. Keywords: hairy cell leukemia, BRAF (Beérkezett: 2012. november 27.; elfogadva: 2012. december 19.) ...

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BRAF mutations in non-Hodgkin's lymphoma

Cited by 65 publications

References 9 publications

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

Recurrent somatic mutation in hairy cell leukemia

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