Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma

Javeed Iqbal, Yulei Shen, Xin Huang, Yanyan Liu, Laura Wake, Cuiling Liu, Karen Deffenbacher, Cynthia M. Lachel, Chao Wang, Joseph Rohr, Shuangping Guo, Lynette M. Smith, George Wright, Sharathkumar Bhagavathi, Karen Dybkaer, Kai Fu, Timothy C. Greiner, Julie M. Vose, Elaine Jaffe, Lisa RimszaAndreas Rosenwald, German Ott, Jan Delabie, Elias Campo, Rita M. Braziel, James R. Cook, Raymond R. Tubbs, James O. Armitage, Dennis D. Weisenburger, Louis M. Staudt, Randy D. Gascoyne, Timothy W. McKeithan, Wing C. Chan

Research output: Contribution to journalArticle

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Abstract

We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P =.002). We identified a 27-miRNA signature that included v-myc avianmyelomatosis viral oncogene homolog(MYC) targets and enabled the differentiation ofBLfromDLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, includingGCB-DLBCL,activatedB-cell (ABC)-DLBCL, andPMBL. Interestingly, most of the unclassifiable-DLBCL byGEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue,making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.

Original languageEnglish (US)
Pages (from-to)1137-1145
Number of pages9
JournalBlood
Volume125
Issue number7
DOIs
StatePublished - Feb 12 2015
Externally publishedYes

Fingerprint

B-Cell Lymphoma
MicroRNAs
Cells
B-Lymphocytes
B-Lymphocyte Subsets
Oncogenes
Transcriptome
Gene expression
Germinal Center
Thymoma
Burkitt Lymphoma
Lymphoma, Large B-Cell, Diffuse
Vincristine
Prednisone
Treatment Failure
Paraffin
Biomarkers
Doxorubicin
Cyclophosphamide
Formaldehyde

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Medicine(all)
  • Hematology
  • Cell Biology

Cite this

Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma. / Iqbal, Javeed; Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M.; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M.; Wright, George; Bhagavathi, Sharathkumar; Dybkaer, Karen; Fu, Kai; Greiner, Timothy C.; Vose, Julie M.; Jaffe, Elaine; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Armitage, James O.; Weisenburger, Dennis D.; Staudt, Louis M.; Gascoyne, Randy D.; McKeithan, Timothy W.; Chan, Wing C.

In: Blood, Vol. 125, No. 7, 12.02.2015, p. 1137-1145.

Research output: Contribution to journalArticle

Iqbal, J, Shen, Y, Huang, X, Liu, Y, Wake, L, Liu, C, Deffenbacher, K, Lachel, CM, Wang, C, Rohr, J, Guo, S, Smith, LM, Wright, G, Bhagavathi, S, Dybkaer, K, Fu, K, Greiner, TC, Vose, JM, Jaffe, E, Rimsza, L, Rosenwald, A, Ott, G, Delabie, J, Campo, E, Braziel, RM, Cook, JR, Tubbs, RR, Armitage, JO, Weisenburger, DD, Staudt, LM, Gascoyne, RD, McKeithan, TW & Chan, WC 2015, 'Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma', Blood, vol. 125, no. 7, pp. 1137-1145. https://doi.org/10.1182/blood-2014-04-566778
Iqbal, Javeed ; Shen, Yulei ; Huang, Xin ; Liu, Yanyan ; Wake, Laura ; Liu, Cuiling ; Deffenbacher, Karen ; Lachel, Cynthia M. ; Wang, Chao ; Rohr, Joseph ; Guo, Shuangping ; Smith, Lynette M. ; Wright, George ; Bhagavathi, Sharathkumar ; Dybkaer, Karen ; Fu, Kai ; Greiner, Timothy C. ; Vose, Julie M. ; Jaffe, Elaine ; Rimsza, Lisa ; Rosenwald, Andreas ; Ott, German ; Delabie, Jan ; Campo, Elias ; Braziel, Rita M. ; Cook, James R. ; Tubbs, Raymond R. ; Armitage, James O. ; Weisenburger, Dennis D. ; Staudt, Louis M. ; Gascoyne, Randy D. ; McKeithan, Timothy W. ; Chan, Wing C. / Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma. In: Blood. 2015 ; Vol. 125, No. 7. pp. 1137-1145.
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abstract = "We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of na{\"i}ve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P =.002). We identified a 27-miRNA signature that included v-myc avianmyelomatosis viral oncogene homolog(MYC) targets and enabled the differentiation ofBLfromDLBCL, a distinction comparable with the {"}gold standard{"} GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, includingGCB-DLBCL,activatedB-cell (ABC)-DLBCL, andPMBL. Interestingly, most of the unclassifiable-DLBCL byGEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue,making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.",
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AU - Iqbal, Javeed

AU - Shen, Yulei

AU - Huang, Xin

AU - Liu, Yanyan

AU - Wake, Laura

AU - Liu, Cuiling

AU - Deffenbacher, Karen

AU - Lachel, Cynthia M.

AU - Wang, Chao

AU - Rohr, Joseph

AU - Guo, Shuangping

AU - Smith, Lynette M.

AU - Wright, George

AU - Bhagavathi, Sharathkumar

AU - Dybkaer, Karen

AU - Fu, Kai

AU - Greiner, Timothy C.

AU - Vose, Julie M.

AU - Jaffe, Elaine

AU - Rimsza, Lisa

AU - Rosenwald, Andreas

AU - Ott, German

AU - Delabie, Jan

AU - Campo, Elias

AU - Braziel, Rita M.

AU - Cook, James R.

AU - Tubbs, Raymond R.

AU - Armitage, James O.

AU - Weisenburger, Dennis D.

AU - Staudt, Louis M.

AU - Gascoyne, Randy D.

AU - McKeithan, Timothy W.

AU - Chan, Wing C.

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AB - We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P =.002). We identified a 27-miRNA signature that included v-myc avianmyelomatosis viral oncogene homolog(MYC) targets and enabled the differentiation ofBLfromDLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, includingGCB-DLBCL,activatedB-cell (ABC)-DLBCL, andPMBL. Interestingly, most of the unclassifiable-DLBCL byGEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue,making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.

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