MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype

Ellen Leich, Alberto Zamo, Heike Horn, Eugenia Haralambieva, Bernhard Puppe, Randy D. Gascoyne, Wing Chung Chan, Rita M. Braziel, Lisa M Rimsza, Dennis D. Weisenburger, Jan Delabie, Elaine S. Jaffe, Jude Fitzgibbon, Louis M. Staudt, Hans Konrad Mueller-Hermelink, Mariarita Calaminici, Elias Campo, German Ott, Luis Hernández, Andreas Rosenwald

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Abstract

A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32FLgrades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype.

Original languageEnglish (US)
Pages (from-to)5550-5558
Number of pages9
JournalBlood
Volume118
Issue number20
DOIs
StatePublished - Nov 17 2011

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Follicular Lymphoma
Germinal Center
MicroRNAs
B-Lymphocytes
Cells
Phenotype
Messenger RNA
Ports and harbors
Statistical methods
Genes
Apoptosis
Cell Cycle Checkpoints
Cell Differentiation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Leich, E., Zamo, A., Horn, H., Haralambieva, E., Puppe, B., Gascoyne, R. D., ... Rosenwald, A. (2011). MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype. Blood, 118(20), 5550-5558. https://doi.org/10.1182/blood-2011-06-361972

MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype. / Leich, Ellen; Zamo, Alberto; Horn, Heike; Haralambieva, Eugenia; Puppe, Bernhard; Gascoyne, Randy D.; Chan, Wing Chung; Braziel, Rita M.; Rimsza, Lisa M; Weisenburger, Dennis D.; Delabie, Jan; Jaffe, Elaine S.; Fitzgibbon, Jude; Staudt, Louis M.; Mueller-Hermelink, Hans Konrad; Calaminici, Mariarita; Campo, Elias; Ott, German; Hernández, Luis; Rosenwald, Andreas.

In: Blood, Vol. 118, No. 20, 17.11.2011, p. 5550-5558.

Research output: Contribution to journalArticle

Leich, E, Zamo, A, Horn, H, Haralambieva, E, Puppe, B, Gascoyne, RD, Chan, WC, Braziel, RM, Rimsza, LM, Weisenburger, DD, Delabie, J, Jaffe, ES, Fitzgibbon, J, Staudt, LM, Mueller-Hermelink, HK, Calaminici, M, Campo, E, Ott, G, Hernández, L & Rosenwald, A 2011, 'MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype', Blood, vol. 118, no. 20, pp. 5550-5558. https://doi.org/10.1182/blood-2011-06-361972
Leich E, Zamo A, Horn H, Haralambieva E, Puppe B, Gascoyne RD et al. MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype. Blood. 2011 Nov 17;118(20):5550-5558. https://doi.org/10.1182/blood-2011-06-361972
Leich, Ellen ; Zamo, Alberto ; Horn, Heike ; Haralambieva, Eugenia ; Puppe, Bernhard ; Gascoyne, Randy D. ; Chan, Wing Chung ; Braziel, Rita M. ; Rimsza, Lisa M ; Weisenburger, Dennis D. ; Delabie, Jan ; Jaffe, Elaine S. ; Fitzgibbon, Jude ; Staudt, Louis M. ; Mueller-Hermelink, Hans Konrad ; Calaminici, Mariarita ; Campo, Elias ; Ott, German ; Hernández, Luis ; Rosenwald, Andreas. / MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype. In: Blood. 2011 ; Vol. 118, No. 20. pp. 5550-5558.
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T1 - MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype

AU - Leich, Ellen

AU - Zamo, Alberto

AU - Horn, Heike

AU - Haralambieva, Eugenia

AU - Puppe, Bernhard

AU - Gascoyne, Randy D.

AU - Chan, Wing Chung

AU - Braziel, Rita M.

AU - Rimsza, Lisa M

AU - Weisenburger, Dennis D.

AU - Delabie, Jan

AU - Jaffe, Elaine S.

AU - Fitzgibbon, Jude

AU - Staudt, Louis M.

AU - Mueller-Hermelink, Hans Konrad

AU - Calaminici, Mariarita

AU - Campo, Elias

AU - Ott, German

AU - Hernández, Luis

AU - Rosenwald, Andreas

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N2 - A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32FLgrades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype.

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