miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels

Blood - Tập 132 Số 22 - Trang 2389-2400 - 2018
Kateřina Musilová1,2, Ján Deván2, Kateřina Amruz Černá1,2, Václav Šeda1,2, Gabriela Mladonická Pavlasová1,2, Sonali Sharma2, Jan Oppelt2, Robert Pytlík3, Vít Procházka4, Zuzana Prouzová4, Martin Trbušek1, Lenka Zlámalíková5, Květoslava Lišková5, Lenka Krůzová4, Marie Jarošová4, Andrea Marečková1, Christoph Kornauth6, Ingrid Simonitsch‐Klupp6, Ana‐Iris Schiefer6, Olaf Merkel6, Heidi Móciková7, Pavel Burda8,9, Kateřina Machová Poláková8, Leoš Křen5, Jiřı́ Mayer1, Clive S. Zent10, Marek Trněný3, Andrew G. Evans10, Andrea Janíková1, Marek Mráz1,2
1Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
2Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
3First Department of Medicine – Department of Hematology, General University Hospital in Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic
4Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic
5Department of Pathology, University Hospital Brno, Brno, Czech Republic
6Department of Clinical Pathology, Medical University Vienna, Vienna, Austria
7Department of Internal Medicine and Hematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic
8Institute of Hematology and Blood Transfusion, Prague, Czech Republic
9Institute of Pathological Physiology, First Medical Faculty, Charles University, Prague, Czech Republic; and
10Departments of Pathology and Laboratory Medicine and Medicine, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY

Tóm tắt

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

Từ khóa


Tài liệu tham khảo

Montoto, 2011, Transformation of indolent B-cell lymphomas, J Clin Oncol, 29, 1827, 10.1200/JCO.2010.32.7577

Al-Tourah, 2008, Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma, J Clin Oncol, 26, 5165, 10.1200/JCO.2008.16.0283

Giné, 2006, The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma, Ann Oncol, 17, 1539, 10.1093/annonc/mdl162

Janikova, 2018, The incidence of biopsy-proven transformation in follicular lymphoma in the rituximab era. A retrospective analysis from the Czech Lymphoma Study Group (CLSG) database, Ann Hematol, 97, 669, 10.1007/s00277-017-3218-0

Montoto, 2007, Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma, J Clin Oncol, 25, 2426, 10.1200/JCO.2006.09.3260

Okosun, 2014, Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma, Nat Genet, 46, 176, 10.1038/ng.2856

Pasqualucci, 2014, Genetics of follicular lymphoma transformation, Cell Reports, 6, 130, 10.1016/j.celrep.2013.12.027

Lo Coco, 1993, p53 mutations are associated with histologic transformation of follicular lymphoma, Blood, 82, 2289, 10.1182/blood.V82.8.2289.2289

Yano, 1992, MYC rearrangements in histologically progressed follicular lymphomas, Blood, 80, 758, 10.1182/blood.V80.3.758.758

Lossos, 2002, Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes, Proc Natl Acad Sci USA, 99, 8886, 10.1073/pnas.132253599

Alhejaily, 2014, Inactivation of the CDKN2A tumor-suppressor gene by deletion or methylation is common at diagnosis in follicular lymphoma and associated with poor clinical outcome, Clin Cancer Res, 20, 1676, 10.1158/1078-0432.CCR-13-2175

Kridel, 2017, Can histologic transformation of follicular lymphoma be predicted and prevented?, Blood, 130, 258, 10.1182/blood-2017-03-691345

Fitzgibbon, 2007, Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma, Leukemia, 21, 1514, 10.1038/sj.leu.2404696

Elenitoba-Johnson, 1998, Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma, Blood, 91, 4677, 10.1182/blood.V91.12.4677

Bouska, 2014, Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma, Blood, 123, 1681, 10.1182/blood-2013-05-500595

Bouska, 2017, Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma, Leukemia, 31, 83, 10.1038/leu.2016.175

Davies, 2007, Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms, Br J Haematol, 136, 286, 10.1111/j.1365-2141.2006.06439.x

Farinha, 2010, The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation, Blood, 115, 289, 10.1182/blood-2009-07-235598

Farinha, 2010, Vascularization predicts overall survival and risk of transformation in follicular lymphoma, Haematologica, 95, 2157, 10.3324/haematol.2009.021766

Saifi, 2010, High ratio of interfollicular CD8/FOXP3-positive regulatory T cells is associated with a high FLIPI index and poor overall survival in follicular lymphoma, Exp Ther Med, 1, 933, 10.3892/etm.2010.146

Smeltzer, 2014, Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma, Clin Cancer Res, 20, 2862, 10.1158/1078-0432.CCR-13-2367

Mraz, 2014, miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1, Blood, 124, 84, 10.1182/blood-2013-09-527234

Mraz, 2012, MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia, Blood, 119, 2110, 10.1182/blood-2011-11-394874

Musilova, 2015, MicroRNAs in B-cell lymphomas: how a complex biology gets more complex, Leukemia, 29, 1004, 10.1038/leu.2014.351

Xiao, 2007, MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb [published correction appears in Cell. 2016;165(4):1027], Cell, 131, 146, 10.1016/j.cell.2007.07.021

He, 2005, A microRNA polycistron as a potential human oncogene, Nature, 435, 828, 10.1038/nature03552

Costinean, 2006, Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice, Proc Natl Acad Sci USA, 103, 7024, 10.1073/pnas.0602266103

Costinean, 2009, Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice, Blood, 114, 1374, 10.1182/blood-2009-05-220814

Gascoyne, 2017, The significance of FOXP1 in diffuse large B-cell lymphoma, Leuk Lymphoma, 58, 1037, 10.1080/10428194.2016.1228932

van Keimpema, 2014, FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells, Blood, 124, 3431, 10.1182/blood-2014-01-553412

van Keimpema, 2017, The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells, Haematologica, 102, 573, 10.3324/haematol.2016.156455

Flori, 2016, The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling, Blood, 127, 1438, 10.1182/blood-2015-08-662635

Dekker, 2016, Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1, Proc Natl Acad Sci USA, 113, E577, 10.1073/pnas.1524677113

Barrans, 2004, Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome, Blood, 104, 2933, 10.1182/blood-2004-03-1209

Banham, 2005, Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma, Clin Cancer Res, 11, 1065, 10.1158/1078-0432.1065.11.3

Brown, 2005, The FOXP1 transcription factor is expressed in the majority of follicular lymphomas but is rarely expressed in classical and lymphocyte predominant Hodgkin’s lymphoma, J Mol Histol, 36, 249, 10.1007/s10735-005-6521-3

Sagaert, 2006, Forkhead box protein P1 expression in mucosa-associated lymphoid tissue lymphomas predicts poor prognosis and transformation to diffuse large B-cell lymphoma, J Clin Oncol, 24, 2490, 10.1200/JCO.2006.05.6150

Choi, 2009, A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy, Clin Cancer Res, 15, 5494, 10.1158/1078-0432.CCR-09-0113

Meyer, 2011, Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab, J Clin Oncol, 29, 200, 10.1200/JCO.2010.30.0368

Visco, 2012, Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study [published correction appears in Leukemia. 2014;28(4):980, Leukemia, 26, 2103, 10.1038/leu.2012.83

He, 2014, Prognostic significance of miR-34a and its target proteins of FOXP1, p53, and BCL2 in gastric MALT lymphoma and DLBCL, Gastric Cancer, 17, 431, 10.1007/s10120-013-0313-3

Nyman, 2009, Bcl-2 but not FOXP1, is an adverse risk factor in immunochemotherapy-treated non-germinal center diffuse large B-cell lymphomas, Eur J Haematol, 82, 364, 10.1111/j.1600-0609.2009.01222.x

Wong, 2014, Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients [published correction appears in Leukemia. 2014;28(2):470], Leukemia, 28, 362, 10.1038/leu.2013.224

Mraz, 2009, MicroRNA isolation and stability in stored RNA samples, Biochem Biophys Res Commun, 390, 1, 10.1016/j.bbrc.2009.09.061

Jiang, 2012, Blockade of miR-150 maturation by MLL-fusion/MYC/LIN-28 is required for MLL-associated leukemia, Cancer Cell, 22, 524, 10.1016/j.ccr.2012.08.028

Zemanova, 2016, Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells, Oncotarget, 7, 62091, 10.18632/oncotarget.11388

Schauer, 1996, Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40 ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through modulation of I kappa B proteins, J Immunol, 157, 81, 10.4049/jimmunol.157.1.81

Sagardoy, 2013, Downregulation of FOXP1 is required during germinal center B-cell function, Blood, 121, 4311, 10.1182/blood-2012-10-462846

Casulo, 2015, Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study, J Clin Oncol, 33, 2516, 10.1200/JCO.2014.59.7534

Lawrie, 2007, MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma, Int J Cancer, 121, 1156, 10.1002/ijc.22800

Lawrie, 2009, Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma, J Cell Mol Med, 13, 1248, 10.1111/j.1582-4934.2008.00628.x

Zhong, 2012, Clinical and prognostic significance of miR-155 and miR-146a expression levels in formalin-fixed/paraffin-embedded tissue of patients with diffuse large B-cell lymphoma, Exp Ther Med, 3, 763, 10.3892/etm.2012.502

Cui, 2014, MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia, Blood, 124, 546, 10.1182/blood-2014-03-559690

Correia, 2015, BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma, Blood, 125, 658, 10.1182/blood-2014-04-571786

Thompson, 2016, miR-31 and miR-17-5p levels change during transformation of follicular lymphoma, Hum Pathol, 50, 118, 10.1016/j.humpath.2015.11.011

Di Lisio, 2010, Mantle cell lymphoma: transcriptional regulation by microRNAs, Leukemia, 24, 1335, 10.1038/leu.2010.91

Malumbres, 2009, Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas, Blood, 113, 3754, 10.1182/blood-2008-10-184077

Zhao, 2010, microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma, Blood, 115, 2630, 10.1182/blood-2009-09-243147

Chang, 2008, Widespread microRNA repression by Myc contributes to tumorigenesis, Nat Genet, 40, 43, 10.1038/ng.2007.30

O’Donnell, 2005, c-Myc-regulated microRNAs modulate E2F1 expression, Nature, 435, 839, 10.1038/nature03677

Kridel, 2015, Cell of origin of transformed follicular lymphoma, Blood, 126, 2118, 10.1182/blood-2015-06-649905

Hu, 2006, Foxp1 is an essential transcriptional regulator of B cell development, Nat Immunol, 7, 819, 10.1038/ni1358

Brown, 2016, FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas, Leukemia, 30, 605, 10.1038/leu.2015.299

van Keimpema, 2015, The forkhead transcription factor FOXP1 represses human plasma cell differentiation, Blood, 126, 2098, 10.1182/blood-2015-02-626176

Walker, 2015, FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma, Sci Signal, 8, ra12, 10.1126/scisignal.2005654

Craig, 2011, Myc-mediated repression of microRNA-34a promotes high-grade transformation of B-cell lymphoma by dysregulation of FoxP1, Blood, 117, 6227, 10.1182/blood-2010-10-312231

Mottok, 2018, FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy, Blood, 131, 226, 10.1182/blood-2017-08-799080

Rao, 2010, MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1, Immunity, 33, 48, 10.1016/j.immuni.2010.06.013

Alencar, 2011, MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP, Clin Cancer Res, 17, 4125, 10.1158/1078-0432.CCR-11-0224

Kwanhian, 2012, MicroRNA-142 is mutated in about 20% of diffuse large B-cell lymphoma, Cancer Med, 1, 141, 10.1002/cam4.29

Stamatopoulos, 2015, Opposite prognostic significance of cellular and serum circulating microRNA-150 in patients with chronic lymphocytic leukemia, Mol Med, 21, 123, 10.2119/molmed.2014.00214

Pritchard, 2012, Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies, Cancer Prev Res (Phila), 5, 492, 10.1158/1940-6207.CAPR-11-0370

Thông tin
Thông tin xuất bản

Blood

Tập 132 Số 22

2389-2400

Thông tin tác giả