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Transcription and Translation are Primary Targets of Pim Kinase Inhibitor SGI-1776 in Mantle Cell Lymphoma
Abstracts Michael B. Møller, Roberto N. Miranda, L. Jeffrey Medeiros, Ken H. Young
704
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX and The International
Transcription and Translation are Primary Targets of Pim Kinase Inhibitor SGI-1776 in Mantle Cell Lymphoma
DLBCL Rituximab-CHOP Consortium Program
Background: Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes according to gene expression signatures. ABC-DLBCL is characterized by its constitutive NF-kB activation and upregulation of a variety of target genes. However, it is not known which proteins contribute to the poor prognosis of ABC-DLBCL. Double-hit lymphoma with concurrent MYC and BCL2 rearrangements is a subset of aggressive lymphoma with a predominance of GCB immunophenotype. Design: A total of 466 cases of de novo DLBCL treated with R-CHOP chemotherapy were studied for MYC and BCL2 protein expression and its correlations with clinicopathologic features, cell-of-origin (COO) subtypes, molecular genetic changes, gene expression profiles (GEP), and clinical outcome. Results: Approximately 34% of DLBCL demonstrated MYC/BCL2 co-expression. Patients with MYC+BCL2+ DLBCL had markedly worse overall survival (p<0.0001) and progression-free survival (p<0.0001) compared with those without. Similar to double-hit DLBCL defined genetically, MYC/BCL2 co-expression was associated with multiple adverse prognostic factors included in the IPI risk stratification and poor treatment response. Nevertheless, neither MYC nor BCL2 protein expression was a standalone prognostic predictor in DLBCL or its COO subtypes. Different from genetically defined double-hit DLBCL, MYC+BCL2+ DLBCL showed a predominance of ABC subtype (ABC vs GCB: 46% vs 22% and 47% vs 17%, including and excluding those with MYC/BCL2 co-rearrangement respectively, p<0.0001). ABC and GCB-DLBCLs showed similar OS and PFS in the absence of MYC/BCL2 co-expression or considering cases with MYC/BCL2 co-expression only. GCB and ABC subtypes of MYC+BCL2+ DLBCL demonstrated gene signatures similar to those of GCB and ABC published previously. However, GCB and ABC-DLBCLs had similar GEP in the absence of MYC+BCL2+ DLBCL. Conclusion: 1. MYC/BCL2 DLBCL shows a predominance of GCB subtype whereas MYC+BCL2+ DLBCL demonstrates a predominance of ABC subtype. 2. MYC/BCL2 co-expression dictates the difference between the gene signatures of GCB and ABC-DLBCLs. 3. The combination of adverse prognostic impact and the high frequency of the MYC/BCL2 co-expression contributes to the inferior prognosis of ABC-DLBCL. 4. MYC/BCL2 co-expression assessed by immunohistochemistry significantly expands the spectrum of aggressive lymphoma defined genetically and provides a cost-effective approach to stratify DLBCL.
Qingshan Yang,1,2 Lisa S. Chen,1 Sattva S. Neelapu,3 Roberto N. Miranda,4 L. Jeffrey Medeiros,4 Varsha Gandhi1,5 1
Department of Experimental Therapeutics, The University of Texas
MD Anderson Cancer Center, Houston, TX; 2Graduate School of Biomedical Sciences, Houston, TX; and Department of; 3Lymphoma/ Myeloma; 4Hematopathology, and; 5Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Proviral integration site for Moloney murine leukemia virus (Pim) kinases are serine/threonine/tyrosine kinases and oncoproteins that promote tumor progression. Three isoforms of Pim kinases have been identified and are known to phosphorylate numerous substrates, with regulatory functions in transcription, translation, cell cycle, and survival pathways. These kinases are involved in production, proliferation, and survival of normal B cells and are overexpressed in B-cell malignancies such as mantle cell lymphoma (MCL). SGI-1776 is a small molecule and Pim kinase inhibitor with selectivity for Pim-1. We hypothesize that Pim kinase function can be inhibited by SGI1776 in MCL and that inhibition of phosphorylation of downstream substrates will disrupt transcriptional, translational, and cell cycle processes and promote cell death. SGI-1776 treatment in 4 MCL cell lines resulted in apoptosis induction. Phosphorylation of transcription (c-Myc) and translation targets (4E-BP1), tested in Jeko-1 and Mino, was declined. Consistent with these data, Mcl-1 and cyclin D1 protein levels were decreased. Importantly, similar to cell line data, MCL primary cells but not normal cells showed similar inhibition of substrate phosphorylation and cytotoxicity from SGI-1776 treatment. Genetic knockdown of Pim-1/ Pim-2 affected similar proteins in MCL cell lines. Collectively these data demonstrate Pim kinases as therapeutic targets in MCL.
Clinical Lymphoma, Myeloma & Leukemia September 2013
- S383
704
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX and The International
Transcription and Translation are Primary Targets of Pim Kinase Inhibitor SGI-1776 in Mantle Cell Lymphoma
DLBCL Rituximab-CHOP Consortium Program
Background: Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes according to gene expression signatures. ABC-DLBCL is characterized by its constitutive NF-kB activation and upregulation of a variety of target genes. However, it is not known which proteins contribute to the poor prognosis of ABC-DLBCL. Double-hit lymphoma with concurrent MYC and BCL2 rearrangements is a subset of aggressive lymphoma with a predominance of GCB immunophenotype. Design: A total of 466 cases of de novo DLBCL treated with R-CHOP chemotherapy were studied for MYC and BCL2 protein expression and its correlations with clinicopathologic features, cell-of-origin (COO) subtypes, molecular genetic changes, gene expression profiles (GEP), and clinical outcome. Results: Approximately 34% of DLBCL demonstrated MYC/BCL2 co-expression. Patients with MYC+BCL2+ DLBCL had markedly worse overall survival (p<0.0001) and progression-free survival (p<0.0001) compared with those without. Similar to double-hit DLBCL defined genetically, MYC/BCL2 co-expression was associated with multiple adverse prognostic factors included in the IPI risk stratification and poor treatment response. Nevertheless, neither MYC nor BCL2 protein expression was a standalone prognostic predictor in DLBCL or its COO subtypes. Different from genetically defined double-hit DLBCL, MYC+BCL2+ DLBCL showed a predominance of ABC subtype (ABC vs GCB: 46% vs 22% and 47% vs 17%, including and excluding those with MYC/BCL2 co-rearrangement respectively, p<0.0001). ABC and GCB-DLBCLs showed similar OS and PFS in the absence of MYC/BCL2 co-expression or considering cases with MYC/BCL2 co-expression only. GCB and ABC subtypes of MYC+BCL2+ DLBCL demonstrated gene signatures similar to those of GCB and ABC published previously. However, GCB and ABC-DLBCLs had similar GEP in the absence of MYC+BCL2+ DLBCL. Conclusion: 1. MYC/BCL2 DLBCL shows a predominance of GCB subtype whereas MYC+BCL2+ DLBCL demonstrates a predominance of ABC subtype. 2. MYC/BCL2 co-expression dictates the difference between the gene signatures of GCB and ABC-DLBCLs. 3. The combination of adverse prognostic impact and the high frequency of the MYC/BCL2 co-expression contributes to the inferior prognosis of ABC-DLBCL. 4. MYC/BCL2 co-expression assessed by immunohistochemistry significantly expands the spectrum of aggressive lymphoma defined genetically and provides a cost-effective approach to stratify DLBCL.
Qingshan Yang,1,2 Lisa S. Chen,1 Sattva S. Neelapu,3 Roberto N. Miranda,4 L. Jeffrey Medeiros,4 Varsha Gandhi1,5 1
Department of Experimental Therapeutics, The University of Texas
MD Anderson Cancer Center, Houston, TX; 2Graduate School of Biomedical Sciences, Houston, TX; and Department of; 3Lymphoma/ Myeloma; 4Hematopathology, and; 5Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Proviral integration site for Moloney murine leukemia virus (Pim) kinases are serine/threonine/tyrosine kinases and oncoproteins that promote tumor progression. Three isoforms of Pim kinases have been identified and are known to phosphorylate numerous substrates, with regulatory functions in transcription, translation, cell cycle, and survival pathways. These kinases are involved in production, proliferation, and survival of normal B cells and are overexpressed in B-cell malignancies such as mantle cell lymphoma (MCL). SGI-1776 is a small molecule and Pim kinase inhibitor with selectivity for Pim-1. We hypothesize that Pim kinase function can be inhibited by SGI1776 in MCL and that inhibition of phosphorylation of downstream substrates will disrupt transcriptional, translational, and cell cycle processes and promote cell death. SGI-1776 treatment in 4 MCL cell lines resulted in apoptosis induction. Phosphorylation of transcription (c-Myc) and translation targets (4E-BP1), tested in Jeko-1 and Mino, was declined. Consistent with these data, Mcl-1 and cyclin D1 protein levels were decreased. Importantly, similar to cell line data, MCL primary cells but not normal cells showed similar inhibition of substrate phosphorylation and cytotoxicity from SGI-1776 treatment. Genetic knockdown of Pim-1/ Pim-2 affected similar proteins in MCL cell lines. Collectively these data demonstrate Pim kinases as therapeutic targets in MCL.
Clinical Lymphoma, Myeloma & Leukemia September 2013
- S383