scholarly journals Neoantigen Landscape Supports Feasibility of Personalized Cancer Vaccine for Follicular Lymphoma

2022 ◽  
Author(s):  
Cody A Ramirez ◽  
Felix Frenkel ◽  
Michelle Becker ◽  
Erica K Barnell ◽  
Ethan D McClain ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Cancer Vaccine ◽  
Cell Receptor ◽  
Missense Mutations ◽  
Rna Seq ◽  
Vaccine Strategy ◽  
High Quality ◽  
Treatment Paradigm ◽  
Personalized Cancer

Personalized cancer vaccines designed to target neoantigens represent a promising new treatment paradigm in oncology. In contrast to classical idiotype vaccines, we hypothesized that polyvalent vaccines could be engineered for the personalized treatment of follicular lymphoma (FL) using neoantigen discovery by combined whole exome sequencing (WES) and RNA sequencing (RNA-Seq). Fifty-eight tumor samples from 57 patients with FL underwent WES and RNA-Seq. Somatic and B-cell clonotype neoantigens were predicted and filtered to identify high-quality neoantigens. B-cell clonality was determined by alignment of B-cell receptor (BCR) CDR3 regions from RNA-Seq data, grouping at the protein level, and comparison to the BCR repertoire of RNA-Seq data from healthy individuals. An average of 52 somatic mutations per patient (range: 2-172) were identified, and two or more (median: 15) high-quality neoantigens were predicted for 56 of 58 samples. The predicted neoantigen peptides were composed of missense mutations (76%), indels (9%), gene fusions (3%), and BCR sequences (11%). Building off of these preclinical analyses, we initiated a pilot clinical trial using personalized neoantigen vaccination combined with PD-1 blockade in patients with relapsed or refractory FL (#NCT03121677). Synthetic long peptide (SLP) vaccines were successfully synthesized for and administered to all four patients enrolled to date. Initial results demonstrate feasibility, safety, and potential immunologic and clinical responses. Our study suggests that a genomics-driven personalized cancer vaccine strategy is feasible for patients with FL, and this may overcome prior challenges in the field.

Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8054-8054
Author(s):  
Cody Ramirez ◽  
Felix Frenkel ◽  
Olga Plotnikova ◽  
Vladislav Belousov ◽  
Alexander Bagaev ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Pilot Trial ◽  
In Silico Analysis ◽  
Clinical Results ◽  
Immune Checkpoint Blockade ◽  
Missense Mutations ◽  
Rna Seq ◽  
High Quality ◽  
Vaccine Candidates

8054 Background: Follicular lymphoma (FL) is incurable with conventional therapies and poorly responsive to immune checkpoint blockade. There is a need for new therapies without long-term complications of chemotherapy and with curative potential. We hypothesize that FL contains tumor-specific mutant antigens (TSMAs) that can be targeted by the immune system by vaccination. Recent reports have highlighted the potential for unique immunoglobulin peptides to elicit immune response in lymphomas. We utilized whole exome sequencing (WES) and RNA sequencing (RNA-Seq) of FL patient samples to infer HLA genotype, and predict TSMAs with the goal of designing a personalized cancer vaccine, supported by recent reports of this approach in solid cancers. Methods: DNA and RNA from 58 patients’ FL biopsies underwent WES and RNA-Seq. pVACtools and MiXCR predicted potential somatic and B-cell clonotype neoantigens, which were filtered to identify high quality TSMAs. B-cell oligoclonality was determined by comparison to B-cell receptor (BCR) repertoire profiling of healthy individual lymph nodes. RNA-seq data allowed us to identify expressed TSMAs. Complementary in silico analysis based on mRNA-based peptide reconstruction and custom HLA affinity binding predictions were performed. Results: An average of 52 somatic mutations per patient (range: 2-172) were identified. At least one high quality TSMA was predicted for 57 of 58 patients. Five or more TSMA candidates were identified for 52 (90%) patients with a mean of 17 predicted peptides per patient (range: 0-45). 81% (813/1,004) of the total predicted TSMA peptides arose from missense mutations, 9% (94/1,004) from indels, and 10% (97/1,004) from BCR. 78% (45/58) of patients have both somatic and BCR vaccine candidates, while 21% (12/58) of patients had only somatic vaccine candidates. Predicted TSMAs were identified in multiple genes recurrently mutated in lymphoma (e.g., BCL2). There was a high prediction concordance with the orthogonal BostonGene Vaccine Module V1 pipeline. These pre-clinical results led to a first-in-human pilot trial of personalized TSMA vaccine combined with anti-PD-1 mAb for rel/ref FL patients (NCT03121677), with one response observed within 4 patients evaluable for response to date. Conclusions: TSMA peptides suitable for cancer vaccines were identified for most FL patients via next-generation sequencing, MiXCR and pVACtools. This pre-clinical study suggests that FL patients will be candidates for TSMA vaccine clinical trials and pilot clinical results provide proof of concept for this approach.

scholarly journals RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease

2017 ◽  
Vol 64 (4) ◽  
pp. 476-481 ◽  
Author(s):  
Jerome Bouquet ◽  
Jennifer L. Gardy ◽  
Scott Brown ◽  
Jacob Pfeil ◽  
Ruth R. Miller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Disease ◽  
T Cell ◽  
B Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Rna Seq ◽  
Viral Pathogen ◽  
Complex Chronic Disease

scholarly journals BraCeR: B-cell-receptor reconstruction and clonality inference from single-cell RNA-seq

2018 ◽  
Vol 15 (8) ◽  
pp. 563-565 ◽  
Author(s):  
Ida Lindeman ◽  
Guy Emerton ◽  
Lira Mamanova ◽  
Omri Snir ◽  
Krzysztof Polanski ◽  
...  
Keyword(s):  
B Cell ◽  
Single Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Rna Seq

Massive Parallel Sequencing of Full-Length B-Cell Receptor Sequences Reveals HLA-Dependent Shaping of the B-Cell Immune Repertoire

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4143-4143
Author(s):  
Marvyn T. Koning ◽  
Sander A.J. van der Zeeuw ◽  
Marcelo Navarrete ◽  
Cornelis A.M. van Bergen ◽  
Valeri Nteleah ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Full Length ◽  
Lymphoma Cells ◽  
Hla Alleles ◽  
Hla Binding

Abstract Peptides of the B-cell receptor (BCR) may be presented in HLA molecules and therefore be recognized as epitopes by T cells. Bioinformatic evidence indicates that follicular lymphoma cells are selected against expression of a clonal BCR with a high cumulative predicted binding of BCR-derived peptides to the respective patient's HLA complex (Strothmeyer, Blood 2010). This observation suggests T-cell-mediated immunosurveillance against outgrowth of follicular lymphoma cells according to BCR HLA binding strength. Here, we investigate whether this phenomenon pertains to peripheral B cells in 6 healthy donors: 2 donors homozygous for HLA A01*01 / B08*01, 2 homozygous for HLA A02*01 / B7*02, and 2 donors heterozygous for these alleles. Unbiased representation of full-length V(D)J sequences was considered essential for correct data interpretation. PCR primers annealing to conserved motifs of BCR variable regions (e.g. BIOMED-2 protocol) fail to amplify a fraction of BCR, particularly those modified by somatic hypermutation. Therefore, we developed an improved anchored PCR strategy: cDNA was synthesized from poly(A)-RNA from peripheral blood with primers that anneal to specific Ig constant regions. In the same reaction, the 3' cDNA end is extended by switching to an oligonucleotide template containing an anchor sequence (SMART technology; Clontech). Anchor-tagged cDNA was amplified with a primer annealing to the anchor in combination with a nested constant region-specific reverse primer. Dumbbell adapters were added to the termini of 250 ng of purified PCR products. Circular consensus sequencing of single molecules was performed on the PacBio platform (Pacific Biosciences). Using one SMRT PacBio cell per amplicon, separate sequence libraries were created for μ, γ, κ, and λ BCR transcripts. Sequences covered by at least five reads were selected with SMRT Portal software to obtain >95% of sequences without sequence errors as demonstrated on multiple B-cell lines. Selected sequences were analysed by HighV-QUEST software (Alamyar, Immunome Research 2012). After exclusion of non-BCR sequences and duplicate BCR transcripts, a median of 5318 (range: 670-8752) individual BCR sequences was obtained per library. Binding affinity of nonamers in in-silico-translated BCR were calculated for the 4 HLA alleles by the NetMHC 3.4 algorithm. The fractions of BCR lacking any weak HLA binding peptide (NetMHC IC50 <500nM) within a library were compared between donors positive or negative for any HLA molecule. μ VDJ transcripts without HLA binding peptides were significantly more frequent for all HLA alleles in donors that actually express that particular allele (Table). With the exception of HLA A01*01, similar results were observed for γ transcripts. While the fraction of κ VJ transcripts without an HLA binder was overall higher in HLA A01*01 and B08*01, HLA-positive individuals had higher proportions of non-HLA binding sequences. λ transcripts were less likely to contain HLA binders with respect to HLA B07*02 and B08*01 but not to the HLA A alleles. Analogous analyses were performed for CDR3 regions as annotated by HighV-QUEST plus six amino acids on either flank. In 10 of 16 analyses, CDR3 sequences were less likely to contain an HLA binder in HLA-positive individuals; in three analyses an opposite effect was seen (Table). These results indicate that the peripheral BCR repertoire is shaped by HLA alleles in healthy individuals, most likely by T-cell mediated recognition of BCR peptides. Ongoing studies expand this fundamental finding with respect to the IC50 threshold, the number of nonamers, and additional HLA alleles. Our results warrant investigation of the potential role of HLA-dependent shaping of the BCR repertoire for the immune defense and the development of autoimmune disease and B-cell lymphoma. Table 1V(D)J without HLA binding peptideCDR3 without HLA binding peptideHLADonorμγκλμγΚλ A01*01Positive21%41%61%37%87%90%98%70%Negative16%42%59%38%92%92%96%65%P<0.001n.s.<0.01n.s.<0.001n.s.<0.01<0.001 A02*01Positive6%4%3%32%77%77%77%70%Negative4%1%2%32%75%69%78%78%P<0.001<0.001<0.01n.s.<0.01<0.001n.s.<0.001 B07*02Positive31%13%3%13%79%73%91%96%Negative27%8%2%6%79%69%90%98%P<0.001<0.01<0.01<0.001n.s.<0.05<0.05<0.001 B08*01Positive30%35%64%64%89%87%92%96%Negative14%28%62%61%88%82%90%93%P<0.001<0.001<0.01<0.001<0.01<0.001<0.01<0.001 Disclosures No relevant conflicts of interest to declare.

scholarly journals Human Follicular Lymphoma Cells Contain Oligomannose Glycans in the Antigen-binding Site of the B-cell Receptor

2006 ◽  
Vol 282 (10) ◽  
pp. 7405-7415 ◽  
Author(s):  
Catherine M. Radcliffe ◽  
James N. Arnold ◽  
David M. Suter ◽  
Mark R. Wormald ◽  
David J. Harvey ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Binding Site ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antigen Binding ◽  
Antigen Binding Site ◽  
Lymphoma Cells

scholarly journals Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma

2020 ◽  
Author(s):  
Anna M. Nia ◽  
Kamil Khanipov ◽  
Brooke L. Barnette ◽  
Robert L. Ullrich ◽  
George Golovko ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
B Cell ◽  
Acute Phase Response ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Time Dependent ◽  
Rna Seq ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

Abstract Background: One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z>13), which can lead to induction of hepatocellular carcinoma (HCC). However, little is known on the molecular mechanisms of HZE irradiation induced HCC.Results: We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n 56 Fe (0.2 Gy), 1 GeV/n 16 O (0.2 Gy), and 350 MeV/n 28 Si (0.2 Gy) ions in a mouse model for irradiation-induced HCC. C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the biological effects of these HZE ions, particularly immunological, such as Acute Phase Response Signaling, B Cell Receptor Signaling, IL-8 Signaling, and ROS Production in Macrophages. Also seen in this study were novel unannotated transcripts that were significantly affected by HZE. To investigate the biological functions of these novel transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues. A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes (e.g., Acute Phase Response Signaling, B Cell Receptor Signaling, IL-3 Signaling), and RNA Transcription/Expression.Conclusions: A large number of transcripts were found differentially expressed post-HZE irradiation. These results provide valuable information for uncovering the differences in molecular mechanisms underlying HZE specific induced HCC carcinogenesis. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation, and may also have important implications for discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.

scholarly journals Ibrutinib-Resistant Mantle Cell Lymphoma Undergoes Metabolic Reprogramming Towards Oxphos

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 41-41
Author(s):  
Krystle Nomie ◽  
Liang Zhang ◽  
Yixin Yao ◽  
Yang Liu ◽  
Shaojun Zhang ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Gene Set Enrichment Analysis ◽  
Rna Seq ◽  
Advisory Committees ◽  
Oncogenic Pathways

Abstract Introduction Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma subtype and constitutive activation of the B-cell receptor pathway is a hallmark of B-cell lymphomas. Bruton's tyrosine kinase (BTK) is a critical component of the B-cell receptor pathway, and ibrutinib, a first-in-class, once-daily, and oral covalent inhibitor of BTK, was developed to reduce/silence B-cell receptor pathway activity, leading to clinically remarkable anti-tumor activity. In our prior multiple-center Phase II clinical trial, the overall response rate in relapsed/refractory MCL patients was 68% (Wang et al., NEJM, 2013), surpassing the effectiveness of other therapies. Although ibrutinib is extremely efficacious in patients with relapsed/refractory MCL, the one-year overall survival rate of ibrutinib-exposed patients who relapse is only 22%. Methods Patient primary cells were isolated from MCL patients treated with ibrutinib either prior to treatment or at treatment discontinuation. Whole exome sequencing (WES) was performed to determine the mutational landscape of ibrutinib resistance. RNA-seq was employed to compare the gene expression profiles between ibrutinib-sensitive and -resistant patient samples. Gene set enrichment analysis was utilized to identify dysregulated molecular pathways associated with the resistant phenotype. The RNA-seq data were then validated with reverse phase protein array (RPPA) analysis of ibrutinib-sensitive and -resistant MCL cell lines. Metabolic assays including the measurement of mitochondria respiration rates with the Seahorse analyzer and reactive oxygen species (ROS) levels, targeted metabolomics, and ATP analysis. Functional studies targeting this molecular pathway were conducted, including in vitro cell viability and apoptosis assays, as well as in vivo efficacy studies in an ibrutinib-resistant MCL patient-derived xenograft mouse model. Results WES data analysis identified frequent inactivating somatic alterations in ATM, KMT2D, and TP53 in both the ibrutinib-sensitive and -resistant tumors. CDKN2A (5/7, 71%) was frequently deleted, and the deletion was only observed in the ibrutinib-resistant tumors (p = 0.010). The RNA-seq analysis identified a total of 63 protein-coding genes as the most differentially expressed genes (DEGs) between the ibrutinib-resistant and -sensitive groups, with a fold change of ≥ 2 or ≤ -2 and the false discovery rate (FDR q-value) ≤ 0.01. Among the DEGs, 26 genes were upregulated in ibrutinib-resistant tumors. In addition, gene set enrichment analysis (GSEA) revealed the marked upregulation of oncogenic pathways including c-MYC, mTOR (mTORC1), Wnt, and NF-ĸb signaling, followed by cell cycle, apoptosis, BCR signaling and DNA repair in the ibrutinib-resistant tumors. Notably, in addition to these oncogenic pathways, the metabolic pathways, including oxidative phosphorylation (OXPHOS), were significantly enriched in the ibrutinib-resistant tumors (normalized enrichment score > 3 and FDR q-value < 1e-5). In further support of this finding, metabolomics analysis and the measurement of ATP production and mitochondrial respiration indicated that the OXPHOS pathway is the predominant metabolic pathway employed by ibrutinib-resistant MCL cells. To determine the effects of targeting these pathways, OXPHOS was inhibited with a novel electron transport complex I inhibitor (IACS-010759, developed by MD Anderson Cancer Center) in both MCL cell lines and ibrutinib-resistant MCL patient-derived xenograft (PDX) models. Single agent IACS-010759 treatment at 10 mg/kg oral gavage for 5 consecutive days/week completely prevented tumor growth compared with the vehicle control as shown by measuring tumor volume (n = 5, p < 0.0001) and human β2M levels (n = 5; p < 0.0001) throughout treatment. No apparent toxicities were observed in the IACS-010759-treated MCL PDX mice. Conclusion This current study warrants the exploitation of active cancer metabolic pathways, especially OXPHOS, to improve the clinical outcomes of MCL and additional lymphoma, which is actively being investigated in a Phase I lymphoma clinical trial (NCT03291938). Disclosures Wang: AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria.

Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior

Blood ◽  
2021 ◽  
Author(s):  
Giorgia Chiodin ◽  
Joel D. Allen ◽  
Dean Bryant ◽  
Philip Rock ◽  
Enrica Antonia Martino ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Variable Region ◽  
Cell Receptor ◽  
Antigen Binding ◽  
Post Translational Modification ◽  
Antigen Binding Site ◽  
Lymphoma Cells ◽  
X Ray Crystallography ◽  
Significant Gene

Glycosylation of the surface immunoglobulin variable region is a remarkable follicular lymphoma-associated feature rarely seen in normal B cells. Here, we define a subset of diffuse large B-cell lymphomas (DLBCL) which acquire N-glycosylation sites selectively in the immunoglobulin (Ig) complementary-determining-regions (CDR) of the antigen-binding sites. Mass-spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures due to burial in the CDR loops. Acquisition of sites occurs in ~50% of germinal center B-cell-like DLBCL, mainly of the genetic EZB subtype, irrespective of IGHV-D-J use. This markedly contrasts with the activated B-cell-like DLBCL Ig, which rarely has sites in the CDR, and appears not to acquire oligomannose-type structures. Acquisition of CDR-located acceptor sites associates with mutations of epigenetic regulators and BCL2 translocations, indicating an origin shared with follicular lymphoma. Within the EZB subtype, these sites associate with more rapid disease progression and with significant gene-set enrichment of the B-cell receptor, PI3K/AKT/MTORC1, glucose metabolism, and MYC signaling pathways, particularly in the fraction devoid of MYC translocations. The oligomannose-type glycans on the lymphoma cells interact with the candidate lectin DC-SIGN, mediating low-level signals, and lectin-expressing cells form clusters with lymphoma cells. Both clustering and signaling are inhibited by antibodies specifically targeting the DC-SIGN carbohydrate-recognition-domain. Oligomannosylation of the tumor immunoglobulin is a post-translational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN-expressing M2-polarized macrophages.

Immunogenetic Profiling of Follicular Lymphoma Reveals Universal N-Glycosylation Sites Introduced into the B Cell Receptor by Somatic Mutation and Suggests Relevance to Lymphoma Pathogenesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 606-606
Author(s):  
Christian H. Ottensmeier ◽  
Katy J. McCann ◽  
Peter Johnson ◽  
Freda K. Stevenoson
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Somatic Mutation ◽  
Essential Feature ◽  
Variable Region ◽  
Cell Receptor ◽  
Single Amino Acid ◽  
Cell Repertoire ◽  
Antigen Binding Site ◽  
Glycosylation Sites

Abstract Immunogenetic analysis of B-cell malignancies can provide important information that relates to the cellular origin and clonal history of these lymphomas and give clues as to possible pathogenic mechanisms. In follicular lymphoma (FL), immunoglobulin variable region (V) genes are commonly somatically mutated and display intraclonal heterogeneity consistent with location in the germinal centre (GC). In this analysis of 44 cases of FL we find that, with minor exceptions, both the VH and VL gene usage reflects that of the normal B cell repertoire, indicative of a common antigenic drive and in support of a final transforming event in the GC. We have previously reported a high incidence of potential N-glycosylation sites in the VH genes of FL, which have been introduced by the process of somatic mutation. Here we have assessed both the VH and VL genes and find that sites are universally present and further demonstrate that they are available for functional glycosylation. The majority of sites are found in VH (81%) and are located predominantly within CDR2 and CDR3, with few sites present in the FRs. Sites are also evident in VL (45%) where they are focused mainly in CDR3 and CDR1. A minor subset (10%) has sites in VL only. In total, 26 different N-glycosylation motifs were observed, with NIS being the most commonly used. The natural motif in the V4–34 germline gene appears unimportant, and can be lost. Scrutiny of the somatic mutations giving rise to these motifs reveals that the acquisition of sites was predominantly (73%) achieved by a single amino acid (aa) replacement to Asn at position 1 of the motif, either with or without an additional, non-essential aa replacement at another position. Common ‘hotspots’ were observed within the CDR2 for the VH gene segments V3–23, V3–48, V3–07 and V3–15. It appears likely that the acquisition of N-glycosylation sites in the antigen-binding site during somatic mutation in the GC and the subsequent addition of oligosaccharides is important to the lifestyle of FL and may provide a critical second tumorigenic event. In turn, it may be possible to exploit this seemingly essential feature to develop novel therapeutic approaches.

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