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Patterns of oncogene co-expression at single-cell resolution influence clinical outcome in Diffuse Large B-Cell Lymphoma.

ABSTRACT: Intratumor heterogeneity (ITH) in oncogene expression is common in cancer, but it is not known if oncogenes exert combinatorial effects at the single cell level to influence clinical outcome. We address this question using quantitative spectral imaging to simultaneously measure the cellular co-expression of the oncogenes MYC, BCL2 and BCL6 in clinically annotated cohorts of Diffuse Large B-Cell Lymphoma (DLBCL). Unlike in non-malignant lymphoid tissue, where the co-expression of these oncogenes is spatially constrained, DLBCL samples show multiple permutations of oncogenic co-expression at the single cell level. Oncogene co-expression follows clustered and non-random spatial distribution, and is typically stable across different regions of a tumour. Interestingly, we noted that the extent of cells with the unique oncogene combination MYC+BCL2+BCL6- (M+2+6-) associates consistently with patient survival across three independent DLBCL cohorts. We then show that the fraction of M+2+6- co-expressing cells can be inferred from quantitative single oncogene data, as the overall frequencies of co-expression of these oncogenes are stochastic. Predicted values of M+2+6- cellular co-expression frequency from immunohistochemistry of MYC/BCL2/BCL6 (n=316) and multiple independent gene expression datasets (n=2522; 8 cohorts) consistently correlate with survival after R-CHOP chemotherapy, offering a novel strategy for identification of high-risk DLBCL. Finally, we use comparative RNAseq analysis of patient-derived M+2+6+ and M+2+6- B-cells to identify cyclin D2 as a potential BCL6-repressed mediator of the aggressive behavior of M+2+6- population. Overall, our work demonstrates that patterns of oncogene co-expression analyzed at single-cell resolution are clinically relevant, with implications for both diagnostics and target discovery in other cancer types.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203446 | GEO | 2022/05/23

REPOSITORIES: GEO

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Project description:MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification. 32 diffuse large B-cell lymphoma samples were hybridized to HG-U133A Affymetrix GeneChips. In addition, this study contains 30 already published samples, which contribute to GSE4475 (Hummel et al. 2006 (PMID 16760442)), as well as 18 already published samples from GSE22470 (Salaverria et al. 2011 (PMID 21487109)). No re-normalisation of the published samples was performed. The complete dataset representing: (1) the 32 diffuse large B-cell lymphoma Samples, (2) the 30 Samples from GSE4475 and (3) the 18 Samples from GSE22470, is linked below as a supplementary file

Project description:Aggressive double and triple hit (DH/TH) DLBCL feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls post-transcriptional dynamics of key mRNA species including those encoding BCL6, MYC and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E (eukaryotic translation initiation factor 4E). EIF4E drives nuclear export and translation of BCL6, MYC and BCL2 mRNA. eIF4E RIP-sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes BCR signaling, cellular metabolism and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counter-regulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative anti-lymphoma activity in DH/TH DLBCL in vitro and in vivo. We found that eIF4E activity regulates the nuclear export of BCL6, MYC, and BCL2 in DH/TH DLBCLs. To determine the extent of nuclear eIF4E activity in DH/TH DLBCLs and how these programs can support the oncogenic activity of BCL6, MYC and/or BCL2 transcripts, we conducted eIF4E-RIP of nuclear RNA followed by RNA-sequencing in OCI-Ly1 cells in triplicates. To understand the changes in gene expression after ribavarin in a clinically relevant sample, we generated a patient-derived xenograft (PDX) in NSG mice from a de-identified specimen isolated from a patient prior to treatment harboring a triple-hit ABC-type DLBCL. PDX cells from passage four (PDX-4) were implanted into NSG mice. When tumors were palpable, mice were randomized to receive vehicle or 80 mg/kg/b.i.d. ribavarin intraperitoneally for 10 days. We isolated RNA from tumors treated with vehicle (n=2) or ribavarin (n=2) and performed mRNA-seq.

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Patterns of oncogene co-expression at single-cell resolution influence clinical outcome in Diffuse Large B-Cell Lymphoma.

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