Background: The c-myb oncogene is a transcription factor that regulates proliferation, differentiation and apoptosis of haematopoietic cells and activated T cells by binding to promoter sequences of such genes as c-myc or bcl-2 that are expressed in cutaneous T-cell lymphoma (CTCL). Objective: Our study was performed in order to evaluate c-myb expression as a quantitative parameter for differential diagnosis in leukaemic and non-leukaemic variants of CTCL. Methods: c-myb expression was analysed in lesional skin and in the peripheral blood of 21 patients with mycosis fungoides (MF), 15 patients with Sézary syndrome (SS) and 15 patients with inflammatory skin diseases using immunohistochemistry and semiquantitative as well as quantitative RT-PCR. Results: Immunohistochemistry confirmed expression of c-myb in the lesional skin of the majority of CTCL patients with a tendency towards higher expression in SS (1.86 ± 0.5) versus MF (1.2 ± 0.7) while c-myb was absent from the lesional skin of patients with inflammatory skin diseases. c-myb was overexpressed in the peripheral blood in all SS patients (100% SS vs. 35.7% MF) at a high expression level (51,335.31 ± 31,960.32 AU in SS vs. 1,226.35 ± 1,258.29 AU in MF using semiquantitative RT-PCR, and 5.72 × 10–2 ± 2.27 × 10–2 in SS vs. 0.91 × 10–2 ± 1.18 × 10–2 in MF vs. 0.24 × 10–2 ± 0.11 × 10–2 in inflammatory skin disease using quantitative RT-PCR). CD4+ cells from the peripheral blood of SS patients and cell lines in vitro showed the highest c-myb expression levels upon quantitative RT-PCR (23.27 × 10–2 and 10.78 × 10–2 ± 7.24 × 10–2). Conclusion: Overexpression of c-myb in skin lesions of both non-leukaemic and leukaemic CTCL independent of the stage of the disease indicates that it acts early in disease development. Nevertheless, if positive, c-myb expression in lesional skin is a clear-cut diagnostic marker for CTCL as compared to inflammatory skin diseases. High-level expression of c-myb in the peripheral blood as assessed by quantitative RT-PCR constitutes an additional diagnostic parameter for SS and may be especially useful in cases in which morphological determination of Sézary cells or FACS analysis of CD7 and CD26 remain inconclusive.

1.
Diamandidou E, Colome-Grimmer M, Fayad L, Duvic M, Kurzrock R: Transformation of mycosis fungoides/Sézary syndrome: Clinical characteristics and prognosis. Blood 1998;92:1150–1159.
2.
Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, Diaz-Peréz JL, Geerts ML, Goos M, Knobler R, Ralfkiaer E, Santucci M, Smith N, Wechsler J, van Vloten WA, Meijer CJLM: EORTC classification for primary cutaneous lymphomas: A proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 1997;90:354–371.
3.
Herne KL, Talpur R, Breuer-McHam J, Champlin R, Duvic M: Cytomegalovirus seropositivity is significantly associated with mycosis fungoides and Sézary syndrome. Blood 2003;101:2132–2136.
4.
Zucker-Franklin D, Hooper WC, Evatt BL: Human lymphotropic retroviruses associated with mycosis fungoides: Evidence that human T-cell lymphotropic virus type II (HTLV-II) as well as HTLV-I may play a role in the disease. Blood 1992;80:1537–1545.
5.
Jackow CM, Cather JC, Hearne V, Asano AT, Musser JM, Duvic M: Association of erythrodermic cutaneous T-cell-lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor Vβ gene expansion. Blood 1997;89:32–40.
6.
Mao X, Lillington D, Scarisbrick JJ, Mitchell T, Czepulkowski B, Russell-Jones R, Young B, Whittaker SJ: Molecular cytogenetic analysis of cutaneous T-cell lymphomas: Identification of common genetic alterations in Sézary syndrome and mycosis fungoides. Br J Dermatol 2002;147:464–475.
7.
Dalloul A, Laroche L, Bagot M, Mossalayi M, Fourcade C, Thacker DJ, Hogge DE, Merle-Béral, Debré P, Schmitt C: Interleukin-7 is a growth factor for Sézary lymphoma cells. J Clin Invest 1992;99:90–94.
8.
Papadavid E, Economidou J, Psarra A, Kapsimali V, Mantzana V, Antoniou C, Limas K, Stratigos A, Stavrianeas N, Avgerinou G, Katsambas A: The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sézary syndrome Br J Dermatol 2003;148:709–718.
9.
Döbbeling U, Dummer R, Laine E, Potoczna N, Qin JZ, Burg G: Interleukin-15 is an autocrine/paracrine viability factor for cutaneous T-cell lymphoma cells. Blood 1998;92:252–258.
10.
Peris K, Cerroni L, Kerl H, Radaskiewicz T, Chimenti S, Höfler H: Expression of c-myc in cutaneous lymphomas and pseudolymphomas. Dermatology 1991;183:1–6.
11.
Dummer R, Michie SA, Kell D, Gould JW, Haeffner AC, Smoller BR, Warnke RA, Wood GS: Expression of bcl-2 protein and Ki-67 nuclear proliferation antigen in benign and malignant cutaneous T-cell infiltrates. J Cutan Pathol 1995:11–17.
12.
Qin JZ, Dummer R, Burg G, Döbbeling U: Constitutive and interleukin-7/interleukin-15 stimulated DNA binding of Myc, Jun, and novel Myc-like proteins in cutaneous T-cell lymphoma cells. Blood 1999;93:260–267.
13.
Mao X, Orchard G, Lillington DM, Russel-Jones R, Young BD, Whittaker SJ: Amplification and overexpression of JunB is associated with primary cutaneous T-cell lymphomas. Blood 2003;101:1513–1519.
14.
Simon J, Dippel E, Kodelja V, Orfanos CE: C-myb expression in leukemic and non-leukemic variants of cutaneous T-cell lymphomas. Arch Dermatol Res 2000;292:91.
15.
Qin JZ, Zhang CL, Kamarashev J, Dummer R, Burg G, Döbbeling U: Interleukin-7 and interleukin-15 regulate the expression of the bcl-2 and c-myb genes in cutaneous T-cell lymphoma cells. Blood 2001;98:2778–2783.
16.
Shen-Ong GL: The myb oncogene. Biochim Biophys Acta 1990;1032:39–52.
17.
Roussel M, Saule S, Lagrou C: Three new types of viral oncogene of cellular origin specific for haematopoietic cell transformation. Nature 1986;281:452–455.
18.
Mucenski ML, McLain K, Kier AB, Swerdlow SH, Schreiner CM, Miller TA, Pietryga DW, Scott WJ, Potter SS: A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 1991;65:677–689.
19.
Nakagoshi H, Kanei-Ishii C, Sawazaki T, Mizuguchi G, Ishii S: Transcriptional activation of c-myc gene by the c-myb and b-myb gene products. Oncogene 1992;7:1233–1240.
20.
Lüscher B, Christenson E, Litchfield DW, Krebs EG, Eisenman RN: Myb DNA binding inhibited by phosphorylation at a site deleted during oncogenic activation. Nature 1990;344:517–521.
21.
Zobel A, Kalkbrenner F, Guehmann S, Nawrath M, Vorbrueggen G, Moelling K: Interaction of v- and v-Myb proteins with regulatory sequences of the c-myc gene. Oncogene 1991;6:1397–1407.
22.
Frampton J, Ramqvist T, Graf T: V-Myb of E26 leukemia virus up-regulates bcl-2 and suppressed apoptosis in myeloid cells. Genes Dev 1996;10:2720–2731.
23.
Salomoni P, Perrotti D, Martinez R, Franceschi C, Calabretta B: Resistance to apoptosis in CTLL-2 cells constitutively expressing c-Myb is associated with induction of BCL-2 expression and Myb-dependent regulation of bcl-2 promoter activity. Proc Natl Acad Sci USA 1997;94:3296–3301.
24.
Badiani PA, Kioussis D, Swirsky DM, Lampert IA, Weston K: T-cell-lymphomas in v-Myb transgenic mice. Oncogene 1996;13:2205–2212.
25.
Barletta C, Pelicci PG, Kenyon LC, Smith SD, Dalla-Favera R: Relationship between the c-myb locus and the 6q-chromosomal aberration in leukemias and lymphomas. Science 1987;235:1064–1067.
26.
Kauraniemi P, Hedenfalk I, Persson K, Duggan DJ, Tanner M, Johannsson O, Olsson H, Trent JM, Isola J, Borg A: Myb oncogene amplification in hereditary BRCA1 breast cancer. Cancer Res 2000;60:5323–5328.
27.
Griffin CA, Baylin SB: Expression of the c-myb oncogene in human small cell lung carcinoma. Cancer Res 1985;45:272–275.
28.
Birococcio A, Benassi B, D’Agnano I, D’Angelo C, Buglioni S, Mottolese M, Ricciotti A, Citro G, Cosimelli M, Ramsay RG, Calabretta B, Zupi G: C-Myb and Bcl-x overexpression predicts poor prognosis in colorectal cancer. Am J Pathol 2001;158:1289–1299.
29.
Brignole C, Pagnan G, Marimpietri D, Cosimo E, Allen TM, Pastorino F: Targeted delivery system for antisense oligonucleotides: A novel experimental strategy for neuroblastoma treatment. Cancer Lett 2003;197:231–235.
30.
MF Cooperative Group Steering Committee: Mycosis fungoides cooperative study. Arch Dermatol 1975;111:457–459.
31.
Dippel E, Goerdt S, Assaf C, Stein H, Orfanos CE: Cutaneous T-cell lymphoma severity index and T-cell gene rearrangement. Lancet 1997;350:1776–1777.
32.
Djemadji-Oudjiel N, Goerdt S, Kodelja V, Schmuth M, Orfanos CE: Immunohistochemical identification of type II alternatively activated dendritic macrophages (RM 3/1+++, MS-1±, 25F9–) in psoriatic dermis. Arch Dermatol Res 1996;288:757–764.
33.
Poenitz N, Dippel E, Klemke CD, Qadoumi M, Goerdt S: Jessner’s lymphocytic infiltration of the skin: A CD8+ polyclonal reactive skin condition. Dermatology 2003;207:276–284.
34.
Thompson CB, Challoner PB, Neiman PE, Groudine M: Expression of the c-myb proto-oncogene during cellular proliferation. Nature 1986;319:374–380.
35.
Ferrao P, Macmillan EM, Ashman LK, Gonda: Enforced expression of full length c-Myb leads to density-dependent transformation of murine haemopoietic cells. Oncogene 1995;11:1631–1638.
36.
Tesch H, Michels M, Jucker M, Pahl I, Klein S, Bading H, Moelling V: Heterogeneous expression of c-myb protein in human leukemia detected by simultaneous two color flow cytometric analysis. Leuk Res 1992;16:265–274.
37.
Slamon DJ, de Kernion JB, Verma IM, Cline MJ: Expression of cellular oncogenes in human malignancies. Science 1984;224:256–262.
38.
Ramsay RG, Friend A, Vizantios Y, Freeman R, Sicurella C, et al: Cyclooxygenase-2, a colorectal cancer nonsteroidal anti-inflammatory drug target, is regulated by c-MYB. Cancer Res 2000;60:1805–1809.
39.
Korsmeyer SJ: BCL-2 gene family and the regulation of programmed cell death. Cancer Res 1999;59:1693–1700.
40.
Dippel E, Klemke D, Hummel M, Stein H, Goerdt S: T-cell clonality of undetermined significance. Blood 2001;98:247–248.
41.
Jones D, Dang NH, Duvic M, Washington LBT, Huh YO: Absence of CD26 expression is a useful marker for diagnosis of T-cell lymphoma in peripheral blood. Am J Clin Pathol 2001;115:885–892.
42.
Ramsay RG, Barton AL, Gonda TJ: Targeting c-Myb expression in human disease. Expert Opin Ther Targets 2003;7:235–248.
43.
Agarwal N, Gewirtz AM: Oligonucleotide therapeutics for hematologic disorders. Biochim Biophys Acta 1999;1489:85–96.
44.
Funato T, Satou J, Kozawa K, Fujimaki S, Miura T, Kaku M: Use of c-myb antisense oligonucleotides to increase the sensitivity of human colon cancer cells to cisplatin. Oncol Rep 2001;8:807–810.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.