PIM as a Rational Target for B-Cell Lymphomas.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3946-3946
Author(s):  
Cristina Gomez-Abad ◽  
Helena Pisonero ◽  
Juan F Leal ◽  
Giovanna Roncador ◽  
Jose A. Martinez-Climent ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Specific Inhibitor ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Micromolar Range ◽  
Large B Cell ◽  
Stat Pathway

Abstract Abstract 3946 Poster Board III-882 INTRODUCTION The Pim kinases are a family of serine/threonine kinases composed by three members: Pim1, Pim2 and Pim3, involved in the phosphorylation and regulation of several proteins that are essential for cell cycle progression, metabolism or apoptosis (BAD, p21, p27KIP, AKT, Mdm2 and cMyc, among them). Overexpression, translocation or amplification of Pim family have been described in many human cancers, including B-cell Non Hodgkin's Lymphoma, Multiple Myeloma, Prostate cancer and Pancreatic cancer. In addition, 50% of patients diagnosed with diffuse large B-cell Lymphoma (DLBCL) present somatic mutations in Pim1. Despite of its important role in cancer progression, very few chemical inhibitors have been described in the literature, being effective all of them in the high micromolar range. PURPOSE Validating PIM as a rational therapeutic target in B-cell lymphoma, developing tools for patient stratification and pharmacodynamic studies on PIM inhibition. MATERIAL AND METHODS Gene expression profiling and Copy Number data were obtained from a series of 94 B-cell Non-Hodgkin Lymphoma patients (DLBCL, FL, MALT, MCL and NMZL). The effect of Pim inhibition was checked on cell lines by using a novel specific inhibitor for the Pim family (ETP-39010). Newly produced antibodies and RT-PCR primers and protocols were standarized. RESULTS Gene expression data revealed high Pim isoforms expression in a subset of patients with Mantle cell lymphoma (MCL), and Diffuse Large B-cell lymphoma (DLBLC)-ABC type. CGH analysis focused on chromosomal regions containing Pim family and its main regulatory upstream pathway (JAK/STAT) was performed. Heterozygous gains of Pim1 (6p21.2) and Pim3 (22q13.33) were identified in 13.6% of DLBCL patients and in 4.2% of MCL. Alterations in JAK/STAT pathway were also detected in 59.1% of DLBCL patients, and 37.5% of MCL patients presented any alteration in JAK/STAT pathway, being frequent losses of JAK2 chromosomal region. Analysis of additional pathways involved in the up-stream regulation of Pim family disclosed heterozygous gains of PIK3C3 in 40.9% of DLBCL patients, and gains of PIK3CA in 45.9% of MCL patients. Lymphoma cell lines (15) derived from both MCL (9) and ABC-DLBLC (6) subtype, have been analyzed by qRT-PCR and Western-blot, showing variable expression levels of Pim1, Pim2 and Pim3. IC50 obtained for the ETP-39010 compound is in the low micromolar range for the MCL (0.7-8.7 micromolar) and DLBCL-ABC (0.8-10.3 micromolar) cell lines. Since Pim kinase family phosphorilate multiple sites of Bad and AKT, we have checked the inhibition of its phosphorilation as molecular biomarkers for the ETP-39010 effect. Our data show an inhibition of at least 20% of pBad (S112) and almost a complete inhibition of pAKT (S473) 4h after treatment. In addition, cell cycle arrest at G1 and induction of apoptosis were observed 24h after the treatment. CONCLUSION Pim family genes are a rational therapeutic target in MCL and DLBCL-ABC lymphoma subtypes. Stratification and pharmacodynamic markers have been developed for PIM inhibition using a novel specific inhibitor compound -ETP-39010-. Disclosures: No relevant conflicts of interest to declare.

MicroRNA Expression Profiling of Diffuse Large B-Cell Lymphoma Reveals Differences between Germinal Center-Like and Activated B Cell-Like Subtypes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3002-3002
Author(s):  
Charles H. Lawrie ◽  
Shamit Soneji ◽  
Christopher D. Cooper ◽  
Chris Hatton
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lines ◽  
Expression Profile ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Clinical Cases

Abstract MicroRNAs (miRNA) are a recently discovered class of short non-coding RNA molecules that negatively regulate gene expression. They have been shown to play a critical role in many biological functions. In humans about 320 miRNAs have been identified, some of which are expressed in a cell-specific and developmental stage-specific manner. Recently it has been shown that the expression profile of miRNAs can be used to subtype clinical cases (and cell lines) according to diagnosis with a greater degree of accuracy than traditional gene expression analysis. The identity of miRNAs associated with different lymphoma types however remains poorly defined. Previous expression studies have revealed the presence of at least two subtypes of diffuse large B-cell lymphoma (DLBCL) representing the postulated cell of origin; those that are germinal center B cell derived (GCB-type) and those that are activated B-cell derived (ABC-type). The latter subtype has been linked with poor prognostic outcome. It is not known whether these subtypes are also defined at the miRNA level. Therefore we examined the miRNA expression profile of DLBCL cell lines of defined subtypes as well as sub-populations of B-lymphocytes by microarray analysis. Consistent with recent publications, we found that mir-19a, 19b and 17-5p (part of mir-17-92 cluster) were up-regulated in cell lines but not in normal lymphocyte populations. Furthermore, cluster analysis showed that GCB-type cell lines (SUD-HL4, SUD-HL6 & SUD-HL10) have a distinct miRNA profile from ABC-type cell lines (OCI-Ly3 & OCI-Ly10). Most notably, high levels of expression of mir-155, mir-181b and mir-325 were found in ABC-type cell lines whilst high levels of mir-181a were found in GCB-type cell lines. We looked at expression of mir-155, 181a, 143, 145, 378 and 16 in these cell lines as well as clinical cases of DLBCL by RNase-protection assay. Consistent with the microarray data, we found that mir-155 was expressed in ABC-type cell lines but not GCB-type cell lines whilst the converse was true for mir-181a. Clinical cases showed similar patterns of expression but have still to be sub-typed according to immunohistochemical markers. Although still preliminary, our data suggests that miRNA profiling may be a useful tool in predicting the subtype of DLBCL cases and hence clinical outcome.

scholarly journals Recurrent IL4R Somatic Mutations in Diffuse Large B-Cell Lymphoma Lead to an Altered Gene Expression Profile and Changes in Tumor Microenvironment Composition

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 669-669 ◽  
Author(s):  
Elena Viganò ◽  
Gerben Duns ◽  
Daisuke Ennishi ◽  
Randy D. Gascoyne ◽  
Ryan D. Morin ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Patient Outcomes ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Time To Progression ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Stat Pathway

Abstract The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is an important and conserved pathway in lymphocytes which is activated by extracellular stimuli such as cytokines and growth factors. Aberrant activation of the JAK-STAT pathway is a hallmark of a variety of lymphomas which leads to increased proliferation/survival as well as immune evasion. Regarding the latter, it has been previously described that activation of the JAK-STAT signaling pathway can alter the secretome of lymphoma cells and the composition of the tumor microenvironment (TME). Specifically, our group reported PTPN1 loss-of-function as well as IL4R gain-of-function (p.I242N) mutations up-regulate the expression of the immune regulatory chemokine CCL17 through a STATs-dependent mechanism in primary mediastinal B cell lymphoma (PMBCL). Here, we assembled a cohort of 340 diffuse large B cell lymphoma (DLBCL) patients uniformly treated with R-CHOP to investigate JAK-STAT signaling mutations (targeted gene sequencing), copy number alteration (SNP arrays), gene expression (RNAseq) and TME composition (Cibersort, IHC). We confirmed the presence of mutations in SOCS1, STAT6 and 9p24 amplification with a frequency of 13.8%, 2.5%, 11.4%, respectively. Interestingly, we also identified the presence of somatic IL4R mutations in DLBCL, including the hotspot p.I242N mutation previously reported in PMBCL. Similarly to what was reported for other alterations in the JAK-STAT pathway, IL4R mutations were significantly enriched in GCB-DLBCL as compared to the ABC subtype, unclassified or double hit lymphomas with DLBCL morphology (p=0.045). Within the GCB group, patients carrying mutations in IL4R showed inferior disease-specific survival (p=0.029) and time to progression (p=0.023) after R-CHOP therapy. Mutational analysis revealed IL4R mutation being significantly concurrent together with mutations in ACTB, KLML6, MYC, STAT6, NLRC5, TNFAIP3 and mutually exclusive with EZH2 mutations (p<0.05). However, among those gene mutations, only mutations in IL4R risk-stratified patients with GCB DLBCL and showed inferior patient outcomes. Moreover, mutations in the extracellular and transmembrane domains of IL4R resulted in gain-of-function leading to constitutive activation of the JAK-STAT pathway in vitro. Gene expression analysis of primary patient samples carrying IL4R mutations displayed increased CCL17 expression (p=0.027), which positively correlated with the level of the T-regulatory marker FOXP3 by IHC (p=0.005). In addition, in silico TME composition analysis revealed a role of IL4R mutations in inducing changes in macrophage polarization. Specifically, we observed an enrichment of an M2-like macrophage phenotype in primary patient specimens carrying IL4R mutations (p=0.01) and a high M2/M1 ratio was significantly associated with inferior patient outcomes (time to progression, log rank p=0.027). In summary, our data suggest a common mechanism between PMBCL and DLBCL where aberrant JAK-STAT activation mediated by mutations in IL4R plays a significant role in altering chemokine expression profiles and TME changes. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding. Steidl:Roche: Consultancy; Seattle Genetics: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Tioma: Research Funding; Juno Therapeutics: Consultancy.

scholarly journals Upregulation of Cereblon Expression By the DNA Methyltransferase Inhibitor Azacytidine Strongly Enhances Lenalidomide Cytotoxicity in Germinal Center B-Cell-like (GCB) and Activated B-Cell-like (ABC) Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2253-2253 ◽  
Author(s):  
Silvia L Locatelli ◽  
Roberto Papait ◽  
Giuseppa Careddu ◽  
Ada Koschorke ◽  
Giuliano G Stirparo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
B Cell ◽  
Cell Lines ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Germinal Center B Cell ◽  
Large B Cell

Abstract INTRODUCTION: Lenalidomide monotherapy exerts clinical activity in relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) with better response rate and progression-free survival being recorded in activated B-cell-like (ABC) rather than germinal center B-cell-like (GCB)-DLBCL. Reasons for such a difference are likely due to different expression of key molecules involved in mediating activity of Lenalidomide, such as Interferon regulatory factor 4(IRF4) and cereblon (CRBN). Evidences supporting the key role of DNA methylation and histone modifications in regulating genome stability and gene expression in DLBCL prompted us to investigate the capacity of Azacytidine in modulating Lenalidomide activity, thereby sensitizing GCB-DLBCL to Lenalidomide and enhancing Lenalidomide efficacy in ABC-DLBCL. METHODS: DLBCL cell lines with ABC (U-2932, RIVA) or GCB (SU-DHL4, SU-DHL6) genotype were used to investigate the effects of Lenalidomide and Azacytidine on cell growth and cell death. Western blotting (WB) and immunofluorescence analysis were used to assess modulating effects of the two-drug combination on molecular determinants of Lenalidomide activity. Additionally, we studied CRBN, IRF4 and CRBN binding proteins expression, such as Ikaros and Aiolos (IKZF1 and IKZF3) by real time polymerase chain reaction (RT-PCR) in response to drug treatment. RESULTS: Graded concentrations of Lenalidomide (0.1-100 µM) inhibited cell proliferation by 20% to 40% and increased cell death up to 30% to 40% in ABC-DLBCL cell lines, whereas had minimal effects on GCB-DLBCL cell lines. Untreated ABC-DLBCL but not GCB-DLBCL consistently showed a high expression of CRBN and IRF4. Upon Lenalidomide treatment (3 days) CRBN was significantly upregulated and IRF4 downregulated in ABC-DLBCL, but not GCB-DLBCL cells. Since DNA methylation regulates gene expression in DLBCL cell lines, we next examined whether Azacytdine could modulate CRBN and IRF4 expression and in turn enhance responsiveness to Lenalidomide. Exposure of both ABC- and GCB-DLBCL cell lines to Azacytidine (up to 72 hours) induced a marked increase of CRBN and IRF4 transcripts; addition of Lenalidomide strongly increased Azacytidine-induced increase of CRBN and significantly downregulated IRF4 expression; the combined treatment induced a marked downregulation of Ikaros and Aiolos protein levels. At the cellular level, the concomitant Azacytidine (10 μM)/Lenalidomide (10 μM) treatment inhibited in a synergistic manner the mean (±SEM) cell growth of both ABC-DLBCL (Lena: -16 ± 4%; AZA: -22 ± 2%; AZA/Lena: -70 ± 1%, P<0.001) and GCB-DLBCL (Lena: -17 ± 3%; AZA: -40 ± 4%; AZA/Lena: -82 ± 2%, P<0.001). Additionally, the two drug exposure was associated with a 3-fold decrease of S phase cells(Lena: 28 ± 2%; AZA: 22 ± 0.8%; AZA/Lena: 9 ± 1%, P<0.001); a marked p21 overexpression, and a 3- to 4-fold cell death increase (P<0.001) in both ABC- and GCB-DLBCL. CONCLUSIONS: Our results indicate that Azacytidine sensitizes GCB-DLBCL to the cytotoxic effects of Lenalidomide and enhances Lenalidomide efficacy against ABC-DLBCL resulting in synergistic anti-proliferative and pro-apoptotic effects in both ABC- and GCB-DLBCL cell lines. Cytotoxicity of the two drug combination is mediated by signaling events involving CRBN upregulation and IRF4 downregulation leading to CRBN-binding proteins downregulation. Azacytidine-dependent activation of CRBN and IRF4 expression allow to hypothesize a methylation-driven regulation of these genes. These results might provide a rationale for clinical studies using Azacytidine and Lenalidomide combination in ABC- and GCB-DLBCL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transformation of Follicular Lymphoma into Primary Mediastinal B-Cell Lymphoma-like Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4479-4479
Author(s):  
Tristan Loveday ◽  
Gerben Duns ◽  
Lisa M. Rimsza ◽  
Karen Rech ◽  
James R. Cook ◽  
...  
Keyword(s):  
Gene Expression ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Sequence Variants ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Stat Pathway

Abstract Objectives: We identified a case of follicular lymphoma (FL) that transformed into a morphologic diffuse large B-cell lymphoma (DLBCL), which by gene expression profiling showed a primary mediastinal (PMBL)-like gene expression profile (GEP) (Lymph3Cx; Blood 2018;132:2401-5). A search identified 4 additional transformed FL (tFL) cases with a PMBL-like GEP, which we further studied to determine how similar these tFLs were to classic cases of PMBL. Methods: The morphology and previously reported immunophenotype were reviewed, and CD30, CD23, MAL, CD273/PDL2, and CD200 immunohistochemical stains (IHC) were performed. Whole exome sequencing (WES) and copy number analysis (CNA) to evaluate genes typically altered in FL and PMBL were performed. Results: None of the tFLs arose in the mediastinum or had a previous history of mediastinal disease. All cases showed typical centroblastic DLBCL cytology, with fine sclerosis typical of PMBL. 3/3 were GCB by the Hans IHC algorithm, 1/3 were MYC+, 3/3 BCL2+, 1/5 CD30+, 3/5 CD23+, 4/5 MAL+, 0/5 CD273/PDL2+, 1/5 CD200+, and 0/2 EBER+. Rearrangements of MYC, BCL2, or BCL6 were identified by FISH in 0/3, 1/3, and 2/3 cases, respectively. WES demonstrated sequence variants in genes associated with both FL (CREBBP [60%], KMT2D [40%], and TNFRSF14 [40%]) and PMBL (JAK-STAT pathway genes [80%], B2M [20%], and CD58 [20%]). 2 of the mutations identified in the tFLs have previously been shown to result in JAK-STAT activation (STAT6 p.E372K [PNAS 2016;113:13015-20] and SOCS1 p.F101L [Oncogene 2002;21:4351-62] identified in 1/5 cases each). CNA showed gains/amplification of REL in 3/5 cases, gains/amplification of STAT6 in 2/5, gains of large sections of chromosome 16, including IL4R, in 2/5, and both deletions and gains of 11q in 1/5. See Figure demonstrating the 5 cases on the Y-axis and the chromosomes on the X-axis. Conclusions: The tFLs in this small series seem to represent PMBL-like DLBCLs, rather than classic PMBLs, and have a blended pattern of immunophenotypic and genomic features between FL/DLBCL and PMBL. Although the cases express some PMBL-associated markers (CD23 and MAL), there is less frequent staining for others (CD30, CD273/PDL2, and CD200). The cases harbor both FL-associated and PMBL-associated sequence variants, including 40% with mutations known to activate the JAK-STAT pathway. This frequency of mutations in JAK-STAT pathway genes is higher than that seen in typical FL/DLBCL, but perhaps lower than in classic PMBL (Blood 2019;134:802-13). PMBL also frequently has gains/amplifications of 9p24.1, which was not seen in our cohort. However, gains/amplification of REL/2p, which is seen in approximately 50% of PMBL, was identified in 60% of the tFLs. The 11q aberration identified in 1 case would be unusual for PMBL, and is instead more commonly associated with a subset of aggressive lymphomas with Burkitt-like features (Haematologica 2019;104:1822-9). Recently, lymphomas with similar blended features between DLBCL and PMBL, which were not arising in the setting of tFL, have been reported (Duns G, et al. Blood 2021). Our study extends the types of biological transformations, in addition to more classic DLBCL, that can be seen in FL. These tFLs with blended PMBL-DLBCL biology may have implications for therapeutic decision making including targeted therapies used in PMBL. Figure 1 Figure 1. Disclosures Rimsza: NanoString Technologies: Other: Fee-for-service contract. Steidl: Curis Inc.: Consultancy; Trillium Therapeutics: Research Funding; Bayer: Consultancy; Epizyme: Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Research Funding.

Distinct Genetic Aberrations in Molecular Subtypes of Diffuse Large B Cell Lymphoma Detected by Array CGH.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2631-2631
Author(s):  
Georg Lenz ◽  
George W. Wright ◽  
Sandeep Dave ◽  
Wenming Xiao ◽  
John Powell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
B Cell ◽  
Cell Lines ◽  
Copy Number ◽  
Molecular Subtypes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category with at least three different molecular subtypes distinguishable by gene expression profiling, termed germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL). We performed array comparative genomic hybridization (aCGH) in patient samples and cell lines representing different DLBCL subtypes to determine if they utilize distinct pathogenetic mechanisms. Using an array consisting of 386, 165 oligonucleotides (NimbleGen), we performed aCGH on 203 untreated de novo DLBCL samples and 30 DLBCL cell lines, and the same samples were profiled for gene expression using Affymetrix U133 plus arrays. Patient samples included 72 GCB DLBCLs, 74 ABC DLBCLs, 31 PMBLs, and 26 unclassified DLBCLs. Following segmentation of the aCGH data into intervals with a uniform copy number, segments were combined into minimal common regions (MCRs) that were recurrently altered in more than one sample. Statistical differences in MCR frequency between DLBCL subtypes were corrected for multiple hypothesis testing using a false discovery rate (FDR) calculation. The DLBCL subtypes differed in the frequency of MCRs residing at many chromosomal loci, and we used gene expression data to define potential target genes in these MCRs. The INK4a/ARF tumor suppressor locus on 9p21 was selectively lost in ABC DLBCL: homozygous deletions of INK4a/ARF was observed in 20% of ABC DLBCLs but in only 3% of GCB DLBCLs and never in PMBLs (FDR=4.5 E-3). Among ABC DLBCLs, loss of INK4a/ARF was associated with increased proliferation rate, as measured by a proliferation gene expression signature, and adverse survival (p=0.007, log rank test). 16% of ABC DLBCL cases had gain/amplification and overexpression of SPIB, a gene on 19q13 encoding an ETS family transcription factor that is characteristically expressed in ABC DLBCL. This copy number alteration was observed much less frequently in GCB DLBCL (3%) and never in PMBL (FDR=2.6 E-2). GCB DLBCLs had recurrent amplification and overexpression of C13orf25, which encodes the mir-17-92 polycistronic cluster of microRNAs that is transcriptionally activated by c-myc and cooperates with c-myc to accelerate tumor development. C13orf25 amplification was detected in 16% of GCB DLBCLs but in only 3% of PMBLs and never in ABC DLBCL (FDR=3.8 E-3). Recurrent amplification and overexpression of JAK2 on 9p24 was observed in 35% of PMBL cases, but only in 5% of GCB DLBCLs and 4% of ABC DLBCLs respectively (FDR=6.2 E-4). In summary, aCGH revealed copy number abnormalities in DLBCL that had strikingly different frequencies in the three DLBCL subtypes, supporting the hypothesis that these subtypes represent distinct diseases that utilize different oncogenic mechanisms. Our analysis specifically implicated the INK4a/ARF locus as a tumor suppressor and SPIB as an oncogene in ABC DLBCL, the mir-17-92 microRNA cluster as an oncogene in GCB DLBCL, and JAK2 as an oncogene in PMBL.

scholarly journals Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Selin Merdan ◽  
Kritika Subramanian ◽  
Turgay Ayer ◽  
Johan Van Weyenbergh ◽  
Andres Chang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
B Cell ◽  
Risk Prediction ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Signatures ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractThe clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.

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