Double hit and double expressors in lymphoma: Definition and treatment

Riedell, Peter A.; Smith, Sonali M.

doi:10.1002/cncr.31646

Cited by 141 publications

(144 citation statements)

References 70 publications

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“…Most of our patients with DEL or DHL had a high stage (III, IV), intermediate to high IPI, and higher extra-node involvement (P <0.001). These results matched with many previous studies (Oliveira et al, 2017;Snuderl et al, 2010;Riedell et al, 2018;Friedberg, 2017, Reagan et al, 2017.…”

Section: Discussionsupporting

confidence: 93%

C-MYC and BCL2: Correlation between Protein Over-Expression and Gene Translocation and Impact on Outcome in Diffuse Large B Cell Lymphoma

Mohammed

Rashed

Abdelrahman

et al. 2019

Asian Pac J Cancer Prev

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Background:Due to lack of availability of gene expression profiling (GEP) for most developing countries and clinicians; the immunohistochemistry (IHC) is mostly used in the clinical application. The aim of our study is to check the possibility of using IHC to detect MYC and BCL2 in our patients with diffuse large B-cell lymphoma (DLBCL) instead of GEP to stratify them into high and low-risk groups. This will help in a proper treatment choice of subsequent improvement in the survival outcome.Method:During the study period, 90 DLBCL patients were eligible. MYC and BCL2 evaluated by IHC and gene rearrangement by real-time PCR (RT-PCR) and correlated with clinical-pathological features and survival.Results:Through IHC, the expression of MYC, BCL2, and double expression was detected in 35.6%, 46.7% and 30% of patients, respectively. While by RT-PCR, it was 4.53±0.74 for MYC compared with 2.18±0.78 for BCL-2. Most patients with BCL2+/MYC+; double-expressor and double-hit lymphomas (DEL and DHL) had high stage (III, IV), more extra-nodal involvement, (P value <0.001) and intermediate to high International Prognostic Index (IPI) risk profile (P-value <0.001). The median overall survival was 14 months and 6 months for DEL and DHL, respectively. While all patients with DHL died during the follow-up period, the median PFS were only 2 months for DEL. There was a statistically significant correlation between mRNA of MYC and BCL2 with their protein expression (p<0.001).Conclusion:Our results confirmed the unique characters and poor outcome associated with DEL and DHL mandated the need for more intense therapy and not the standard protocol. Moreover, the significant correlation between protein overexpression and gene rearrangement may open the door for the possibility to use IHC instead of RT-PCR in developing countries.

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Section: Discussionsupporting

confidence: 93%

C-MYC and BCL2: Correlation between Protein Over-Expression and Gene Translocation and Impact on Outcome in Diffuse Large B Cell Lymphoma

Mohammed

Rashed

Abdelrahman

et al. 2019

Asian Pac J Cancer Prev

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“…High expression of PVT1 can increase c-Myc expression by regulating c-Myc stability, and they can also interact with each other to regulate their expression, which synergistically promotes the occurrence and development of tumors [7,24]. MYC, a proto-oncogene, was first discovered as the cellular homolog of the Avian virus myelocytomatosis oncogene and plays various roles in protein synthesis, metabolism, and cellular differentiation [25,26]. C-Myc, a transcription factor, is thought to regulate the expression of 15% of all genes by binding enhancer box sequences (E-boxes) [27].…”

Section: Introductionmentioning

confidence: 99%

“…C-Myc, a transcription factor, is thought to regulate the expression of 15% of all genes by binding enhancer box sequences (E-boxes) [27]. Moreover, c-Myc can lead to genomic instability, gene amplification, cellular proliferation, and repression of apoptosis, which is observed in various tumors, including breast, lung, colon, and prostate cancers [25,27]. Although numerous studies have examined the interaction of PVT1 and MYC, the detailed mechanisms of the interaction between them remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA PVT1 interacts with MYC and its downstream molecules to synergistically promote tumorigenesis

Jin

Wang

Zhang

et al. 2019

Cell. Mol. Life Sci.

117

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Numerous studies have shown that non-coding RNAs play crucial roles in the development and progression of various tumor cells. Plasmacytoma variant translocation 1 (PVT1) mainly encodes a long non-coding RNA (lncRNA) and is located on chromosome 8q24.21, which constitutes a fragile site for genetic aberrations. PVT1 is well-known for its interaction with its neighbor MYC, which is a qualified oncogene that plays a vital role in tumorigenesis. In the past several decades, increasing attention has been paid to the interaction mechanism between PVT1 and MYC, which will benefit the clinical treatment and prognosis of patients. In this review, we summarize the coamplification of PVT1 and MYC in cancer, the positive feedback mechanism, and the latest promoter competition mechanism of PVT1 and MYC, as well as how PVT1 participates in the downstream signaling pathway of c-Myc by regulating key molecules. We also briefly describe the treatment prospects and research directions of PVT1 and MYC.

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“…In 2016, the World Health Organization (WHO) defined a new pathologic lymphoma entity entitled "High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations" (Swerdlow et al, 2016). These "double -hit" lymphomas (DHLs) represent 6-9% of all DLBCL cases and are characterized by MYC translocations in concert with BCL2 (80%) or BCL6 (20%) (Craig et al, 2018;Riedell and Smith, 2018). "Triple-hit" lymphomas (THLs) that contain translocations of all three genes have also been described and are included in the new WHO entity (Rosenthal and Younes, 2017;Wang et al, 2015).…”

Section: Double-hit Lymphomamentioning

confidence: 99%

“…Importantly, DHLs are different than so called "double-expressor" lymphomas (DELs), which are defined as being positive for MYC and BCL-2 proteins expression by immunohistochemistry (Burotto et al, 2016;Riedell and Smith, 2018). Indeed, 95% of DHLs are GC-DLBCL by gene expression profiling while the majority of DELs are ABC-DLBCL (Aukema et al, 2011;Ennishi et al, 2017;Riedell and Smith, 2018;Scott et al, 2018). Notably, most GC-DLBCLs but not DHLs have a favorable outcome with R-CHOP treatment (McPhail et al, 2018;Sarkozy et al, 2015).…”

Section: Double-hit Lymphomamentioning

confidence: 99%

Harnessing the Tumor Microenvironment for the Treatment of Double Hit Lymphoma

Lossos

Liu

Christie

et al. 2016

Blood

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Double Hit Lymphomas (DHL) constitute 6-9% of all newly-diagnosed Diffuse Large B-cell Lymphomas (DLBCL) and are defined by MYC translocation in concert with BCL2 (80%) or BCL6 (20%) rearrangement. DHL is characterized by poor upfront response to standard chemoimmunotherapies. The development of more effective treatment for DHL has been limited by the lack of models that accurately recapitulate the biology of this disease. To faithfully model bona fide human DHL, we generated two patient-derived xenografts (PDXs) in NSG mice from patients with DHL who relapsed after or were refractory to R-CHOP. Both PDXs had low/negative expression of surface CD20, in line with previous reports of DHL, and high surface expression of CD52. Importantly, these features recapitulated the original tumor phenotypes. We reasoned that immunologic approaches that target DHLs may help overcome their resistance to cytotoxic chemotherapy. Given the surface expression of CD52 on both PDXs, we treated xenografted mice with the anti-CD52 antibody Alemtuzumab (2x5mg/kg) when >2% tumor was detected in peripheral blood, a time corresponding to marked splenomegaly and ~30% bone marrow involvement. In both models, Alemtuzumab markedly reduced tumor involvement in the peripheral blood and spleen; however, the bone marrow was largely refractory to Alemtuzumab treatment. This is in line with previous results (Pallasch et al. Cell 2014) who also observed bone marrow-specific resistance to Alemtuzumab using a humanized transgenic model of DHL. In the latter model, Alemtuzumab resistance was successfully overcome by high-dose cyclophosphamide (CTX, 100mg/kg), which induced a tumor secretory response that induced macrophage-mediated phagocytosis of tumor cells. Thus, we treated both PDX models with vehicle, CTX 100mg/kg, Alemtuzumab or CTX+Alemtuzumab. While CTX monotherapy was able to partially reduce bone marrow tumor burden, in both PDXs, a single dose of CTX+Alemtuzumab was highly synergistic and eradicated nearly all bone marrow disease (Figure 1), which resulted in significantly extend murine survival compared to either CTX or Alemtuzumab alone alone (p<0.01). In contrast, high-dose Doxorubicin (DOX, 5mg/kg) had minimal effect on bone marrow DHL and DOX+Alemtuzumab was not synergistic. Strikingly, CD11b+F4/80+CD11c- macrophages comprised 20-40% of bone marrow cellularity 8 days after CTX treatment of xengorafted mice. DHL cells isolated from treated mice were next examined for changes in surface protein expression. At 16 hours after treatment, bone marrow DHL cells in mice receiving CTX (but not those receiving DOX or vehicle) had significantly reduced levels of surface CD47, the “don't eat me” signal that suppresses macrophage phagocytosis. By 48 hours after treatment, bone marrow DHL cells in mice receiving CTX (but not those receiving DOX or vehicle) had significantly increased expression of the pro-phagocytic proteins CD31 and Calreticulin. Next, we performed cytokine array analysis on bone marrow from mice engrafted with DHL PDXs at 16 hours after treatment. CTX-treated (but not vehicle- or DOX-treated) bone marrow had significantly increased levels of human IL-16 and CCL4, cytokines known to promote monocyte recruitment, as well as VEGF, PDGF and TNFα. Ex-vivo phagocytosis assays using murine bone marrow-derived macrophages confirmed that recombinant human VEGF and TNFα each enhanced macrophage phagocytosis of Alemtuzumab coated Raji lymphoma cells. Findings from RNA-seq studies on tumor cells and macrophages from the spleen and bone marrow as well as therapy induced changes in these respective niches will be further discussed at the meeting. In summary, we have demonstrated that high-dose CTX induces a phenotypic and secretory response from human DHL cells in vivo that promotes phagocytosis of Alemtuzumab-opsinized cells. As a result, we are initiating a clinical trial of this combination in patients with relapsed/refractory DHL. Figure 1. Percent tumor cells isolated from bone marrow of mice xenografted with DHL #61614 (left) or #63014 (right) on day 8 after treatment with cyclophosphamide (CTX), alemtuzumab (Alem) or the combination. Each marker indicates a mouse. Figure 1. Percent tumor cells isolated from bone marrow of mice xenografted with DHL #61614 (left) or #63014 (right) on day 8 after treatment with cyclophosphamide (CTX), alemtuzumab (Alem) or the combination. Each marker indicates a mouse. Disclosures No relevant conflicts of interest to declare.

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Double hit and double expressors in lymphoma: Definition and treatment

Cited by 141 publications

References 70 publications

C-MYC and BCL2: Correlation between Protein Over-Expression and Gene Translocation and Impact on Outcome in Diffuse Large B Cell Lymphoma

C-MYC and BCL2: Correlation between Protein Over-Expression and Gene Translocation and Impact on Outcome in Diffuse Large B Cell Lymphoma

Long non-coding RNA PVT1 interacts with MYC and its downstream molecules to synergistically promote tumorigenesis

Harnessing the Tumor Microenvironment for the Treatment of Double Hit Lymphoma

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