MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

Abstract Background In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of microRNA (miRNA) was downregulated in transformed FL (tFL). Methods Differentially expressed miRNAs were systematically compared in 11 lymph nodes from patients at different stages of disease. Expression of miR-7e-5p was analyzed in 46 B-cell lymphomas, including 30 FL tissues and 16 DLBCL tissues. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitors treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

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MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

10.21203/rs.3.rs-38701/v3 ◽

2020 ◽

Author(s):

Xiaoli Lou ◽

Jianhong Fu ◽

Xin Zhao ◽

Xuemei Zhuansun ◽

Chao Rong ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Target Gene ◽

Fas Ligand ◽

B Cell Lymphoma ◽

Differentially Expressed ◽

Aggressive Lymphoma ◽

Low Grade ◽

M1 Macrophages ◽

M1 Macrophage

Abstract Background: In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of microRNA (miRNA) was downregulated in transformed FL. Methods: Differentially expressed miRNAs were systematically analyzed compared in eleven lymph nodes tissue samples from patients at different stages of disease. Expression of miR-7e-5p was analyzed in 46 B-cell lymphomas, including 30 FLs and 16 DLBCLs. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitor treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results: We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion: Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

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MiR-7e-5p downregulation promotes transformation of low-grade follicular lymphoma to aggressive lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

10.21203/rs.3.rs-38701/v2 ◽

2020 ◽

Author(s):

Xiaoli Lou ◽

Jianhong Fu ◽

Xin Zhao ◽

Xuemei Zhuansun ◽

Chao Rong ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Target Gene ◽

Fas Ligand ◽

B Cell Lymphoma ◽

Differentially Expressed ◽

Aggressive Lymphoma ◽

Low Grade ◽

M1 Macrophages ◽

M1 Macrophage

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MiR-7e-5p downregulation promotes malignant transformation of follicular lymphoma by modulating an immunosuppressive stroma through the upregulation of FasL in M1 macrophages

10.21203/rs.3.rs-38701/v1 ◽

2020 ◽

Author(s):

Xiaoli Lou ◽

Jianhong Fu ◽

Xin Zhao ◽

Xuemei Zhuansun ◽

Chao Rong ◽

...

Keyword(s):

Follicular Lymphoma ◽

Target Gene ◽

Fas Ligand ◽

B Cell Lymphoma ◽

Tumor Stroma ◽

Differentially Expressed ◽

M1 Macrophages ◽

Tissue Samples ◽

Transmission Electron ◽

M1 Macrophage

Abstract Background In follicular lymphoma (FL), histologic transformation to high-grade FL and diffuse large B-cell lymphoma (DLBCL) is a critical adverse step in disease progression. Activation of the oncogene c-MYC and tumor microenvironment remodeling account for FL progression. A panel of miroRNA (miRNA) was downregulated in transformed FL. Methods Differentially expressed miRNAs were systematically analyzed in tissue samples from patients at different stages of disease. In FL cells, transcriptional regulation of the oncogene c-MYC on its target miR-7e-5p was revealed by Chromatin Immunoprecipitation (ChIP) assay. Exosome, carrying differentially expressed miR-7e-5p was isolated and visualized by transmission electron microscope and fluorescence tracing. The effect of miR-7e-5p on recipient macrophage was determined by target gene quantification, flow cytometry, and TUNEL method in a cocultured system with miR-7e-5p-mimics or inhibitor treatment. Expression of miR-7e-5p targets, macrophage proportions, and clinical parameters were included for correlation analysis. Results We determined that downregulation of miR-7e-5p, driven by c-MYC overexpression, was associated with poorer prognosis in FL patients. The decreased expression of miR-7e-5p in lymphoma cells led to a reduced exosomal transfer to surrounding macrophages. As a result, the target gene of miR-7e-5p, Fas ligand (FasL), was upregulated and activated the caspase signaling, which led to the apoptosis of M1 macrophages in tumor stroma. Finally, in transformed FL tissues, overexpression of FasL and activation of caspase proteins was detected in tumor stromal macrophages. Downregulation of miR-7e-5p was associated with poorer clinical outcomes. Conclusion Downregulation of exosomal miR-7e-5p induces stromal M1 macrophage apoptosis, which leads to immunosurveillance and transformation of FL.

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Transformation of Follicular Lymphoma to Double Hit B-Cell Lymphoma Causing Hypercalcemia in a 69-Year-Old Female: A Case Report and Review of the Literature

Case Reports in Hematology ◽

10.1155/2014/619760 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Sakshi Kapur ◽

Miles B. Levin

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

Care Center ◽

Tertiary Care ◽

B Cell Lymphoma ◽

Low Grade ◽

Severe Hypercalcemia ◽

Double Hit

Double hit B-cell lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14;18)(q32;q21) involving BCL2. These tumors mostly occur in adults and carry a very poor prognosis. Double hit lymphomas can occur de novo, or arise from transformation of follicular lymphoma. We report a case of a 69-year-old female with abdominal distention and progressively worsening weakness over six months. Patient presented with severe hypercalcemia and multiple intra-abdominal/pelvic masses. Histopathology results of the abdominal mass were compatible with a double hit B-cell lymphoma. However, bone marrow biopsy results showed a low grade follicular lymphoma, thus suggesting peripheral transformation of follicular lymphoma to double hit B-cell lymphoma. Patient was transferred to a tertiary care center and was started on combination chemotherapy (EPOCH: doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisone). Our paper highlights not only transformation of follicular lymphoma to double hit B-cell lymphoma and the challenges encountered in diagnosing and treating these aggressive tumors, but also the association of new onset/worsening hypercalcemia in such patients.

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Clinical Significance of VEGF-A and Microvessel Density in Diffuse Large B-Cell Lymphoma and Low-Grade Follicular Lymphoma

Acta Clinica Croatica ◽

10.20471/acc.2017.56.04.02 ◽

2017 ◽

Author(s):

Labinot Shahini

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Clinical Significance ◽

Microvessel Density ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Low Grade ◽

Large B Cell Lymphoma ◽

Large B Cell

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Lymphoma Microenvironment Deconvolution Links M1 Macrophage Infiltration to Clinical Outcome in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-134867 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Mark Yan ◽

Yi Meng Chang ◽

Vibha Raghavan ◽

Estella Dong ◽

Christian Klein ◽

...

Keyword(s):

B Cell ◽

B Cell Lymphoma ◽

Cell Types ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Publicly Traded ◽

Private Company ◽

M1 Macrophages ◽

Large B Cell Lymphoma ◽

M1 Macrophage

Introduction: The lymphoma microenvironment is increasingly recognized as crucial to sustaining lymphoma cell growth and an important contributor to treatment outcome, especially in the context of immunotherapies. CD20-targeted monoclonal antibodies (e.g. obinutuzumab [G] and rituximab [R]) function by several mechanisms, including antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Immune effector cells, such as natural killer (NK) cells and phagocytes (i.e. macrophages and dendritic cells), and the Fc gamma receptor (FcγR) found on the surface of these cells, are critical to antibody treatment efficacy. Here we evaluated how the lymphoma microenvironment may affect clinical outcome in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) receiving immunochemotherapy. Methods: We leveraged two large Phase III clinical trials of pts with previously untreated DLBCL (GOYA [NCT01287741] and MAIN [NCT00486759]) to produce comprehensive lymphoma immune microenvironment profiles from 604 tissue biopsies from pts treated with R plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or G plus CHOP (G-CHOP) using the RNA-Seq deconvolution and marker gene methods: quanTIseq and xCell. The infiltration scores in each pt for various immune and stromal cell types were assessed, and their contribution to disease biology and treatment outcome was examined. Results: The extent of lymphoma microenvironment heterogeneity highlighted by the deconvolution analyses was consistent with previous studies (Figure A). Of the infiltrating cell types analyzed, the M1 macrophage signature quantified by either quanTIseq or xCell was most strongly associated with lower risk of progression (progression-free survival [PFS]; quanTIseq: HR, 0.596; 95% CI: 0.441-0.805; 24-month PFS: 82% [M1 high] vs 68% [M1 low] and xCell: HR, 0.627; 95% CI: 0.465-0.844; 24-month PFS: 80% [M1 high] vs 70% [M1 Low]; Figure B, C, D) and improved overall survival (OS; quanTIseq: HR, 0.465; 95% CI: 0.318-0.679; and xCell: HR, 0.527; 95% CI: 0.365-0.762). This finding was confirmed by both algorithms. This prognostic trend was stronger amongst G-treated pts than R-treated pts, consistent with the previous finding that G exhibits higher ADCC versus R (Mössner, et al. Blood 2010). Pts with PFS >24 months had significantly higher levels of M1 macrophage scores than pts with PFS <24 months. Despite the correlation with delayed disease progression, there was no differential enrichment of M1 macrophages in pts with complete response versus non-responders at end of treatment, or depending on International Prognostic Index. M1 scores did not significantly differ depending on cell of origin, although there was a trend for higher M1 macrophage scores in germinal center B-cell DLBCL. Aside from M1 macrophages, CD4+Th2 cells showed the strongest prognostic trend in DLBCL (PFS; HR, 0.745; 95% CI: 0.553-1.000; Figure C). In contrast to M1 macrophages, pts with M2 macrophage infiltration tended to have shorter PFS and OS although relatively low levels were observed for these signatures (Figure B, C). This suggests that lymphoma-infiltrating macrophages more commonly resemble the classically activated M1 polarization phenotype and are linked to prolonged PFS, while alternatively activated M2 macrophages, although their frequency is lower in DLBCL, are associated with shorter PFS. Consistent with previous work showing that programmed death-ligand 1 (PD-L1) levels correlate with a macrophage signature in DLBCL (McCord, et al. Blood Adv 2019), M1, but not M2, macrophage infiltration correlated with PD-L1 mRNA expression. M1 enrichment was highly correlated with CD8+ T cell signatures (including central and effector memory CD8+ T cells) in DLBCL. Conclusions: Data suggest macrophage polarization may be an important contributor to immunochemotherapy outcome in DLBCL. Previous studies aiming to link tumor-associated macrophages to R-CHOP outcome have yielded conflicting results, perhaps as most relied on CD68/CD163 staining alone as markers. Although R and G are thought to function via NK cell-mediated ADCC, FcγR-dependent stimulation of M1 macrophage-mediated ADCP may be key to sustaining their anti-lymphoma activity. Strategies facilitating the recruitment of M1 macrophages or macrophage repolarization may augment responses to immunochemotherapy in DLBCL. Disclosures Yan: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Chang:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Raghavan:F. Hoffmann-La Roche: Current Employment. Dong:In graduate school: University of Toronto, MSc Biostatistics: Ended employment in the past 24 months; F. Hoffmann-La Roche, Mississauga, Biometrics: Current Employment. Klein:Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Paulson:Genentech, Inc: Current Employment; F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company. Hatzi:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment.

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miR-17~92 Promotes Progression of ABC-DLBCL Lymphoma via Regulation of Canonical NF-kB Signaling

10.21203/rs.3.rs-691597/v1 ◽

2021 ◽

Author(s):

Xianhuo Wang ◽

Huaqing Wang ◽

Xiaoyan Zhang ◽

Chengfeng Bi ◽

Timothy W. McKeithan ◽

...

Keyword(s):

B Cell ◽

Therapeutic Strategy ◽

Target Gene ◽

Target Genes ◽

B Cell Lymphoma ◽

Aggressive Lymphoma ◽

Luciferase Reporter ◽

Loss Of Function ◽

Over Expression ◽

Dual Luciferase Reporter Assay

Abstract Background: Activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma characterized by constitutive NF-κB activation. Nevertheless, the role and mechanisms of miR-17~92 in contributing to the NF-κB activation in ABC-DLBCL are still elusive. Methods: The expression of miR-17~92 primary transcript (MIR17HG) and NF-κB target genes was determined using RNA-sequencing. The expression of miR-17~92 was performed using microarray analysis. Plasmids carrying conditional over-expression and loss-of-function of miR-17~92 were respectively constructed and dual-luciferase reporter assay was used to validate the target gene of miR-17~92. Immunoprecipitation and polyubiquitination were further used to the study of potential mechanisms.Results: Expression of MIR17HG was positively correlated with NF-κB activity, miR-17~92 activated the NF-κB signaling in ABC-DLBCL, and its over-expression promoted ABC-DLBCL cell growth, accelerated cell G1 to S phase transition and enhanced cell resistance to NF-κB inhibitor. Importantly, miR-17~92 promoted NF-κB activation through directly targeting multiple ubiquitin-editing regulators to lead to increase the K63-linked polyubiquitination and decrease the K48-linked polyubiquitination of RIP1 complex in ABC-DLBCL. We further found that miR-17~92 selectively activated IκB-α and NF-κB p65 but not NF-κB p52/p100, and high miR-17~92 expression was also associated with poorer outcome in ABC-DLBCL patients. Conclusions: Taken together, miR-17~92 selectively activate the canonical NF-κB signaling via targeting ubiquitin-editing regulators to lead to constitutively NF-κB activation and poorer outcome, which is an innovative function of miR-17~92 and previously unappreciated regulatory mechanism of NF-κB activation in ABC-DLBCL. Targeting miR-17~92 may thus provide a novel bio-therapeutic strategy for ABC-DLBCL patients.

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Critical influences on the pathogenesis of follicular lymphoma

Blood ◽

10.1182/blood-2017-11-764365 ◽

2018 ◽

Vol 131 (21) ◽

pp. 2297-2306 ◽

Cited By ~ 14

Author(s):

Ralf Küppers ◽

Freda K. Stevenson

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Posttranslational Modifications ◽

Somatic Hypermutation ◽

Early Stage ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Aggressive Lymphoma ◽

Surface Immunoglobulin ◽

Selection Of

Abstract The development of follicular lymphoma (FL) from a founder B cell with an upregulation of B-cell lymphoma 2 (BCL2), via the t(14;18) translocation, to a proliferating clone, poised to undergo further transformation to an aggressive lymphoma, illustrates the opportunistic Darwinian process of tumorigenesis. Protection against apoptosis allows an innocent cell to persist and divide, with dangerous accumulation of further mutational changes, commonly involving inactivation of chromatin-modifying genes. But this is not all. FL cells reflect normal B cells in relying on expression of surface immunoglobulin. In doing so, they add another supportive mechanism by exploiting the natural process of somatic hypermutation of the IGV genes. Positive selection of motifs for addition of glycan into the antigen-binding sites of virtually all cases, and the placement of unusual mannoses in those sites, reveals a posttranslational strategy to engage the microenvironment. A bridge between mannosylated surface immunoglobulin of FL cells and macrophage-expressed dendritic cell–specific ICAM-3–grabbing nonintegrin produces a persistent low-level signal that appears essential for life in the hostile germinal center. Early-stage FL therefore requires a triad of changes: protection from apoptosis, mutations in chromatin modifiers, and an ability to interact with lectin-expressing macrophages. These changes are common and persistent. Genetic/epigenetic analysis is providing important data but investigation of the posttranslational landscape is the next challenge. We have one glimpse of its operation via the influence of added glycan on the B-cell receptor of FL. The consequential interaction with environmental lectins illustrates how posttranslational modifications can be exploited by tumor cells, and could lead to new approaches to therapy.

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“Double hit” follicular lymphoma with low proliferation index: A unique case and literature review

Advances in Modern Oncology Research ◽

10.18282/amor.v3.i2.169 ◽

2017 ◽

Vol 3 (2) ◽

Author(s):

Pardis Vafaii ◽

Haipeng Shao

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Clinical Course ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Proliferation Index ◽

Low Grade ◽

Gene Rearrangements ◽

Double Hit ◽

Indolent Disease

“Double hit” lymphomas (DHLs) are aggressive B-cell lymphomas with concurrent c-MYC and BCL2 and/or BCL6 gene rearrangements. DHLs are usually classified morphologically as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, and less commonly as DLBCL. Follicular lymphoma (FL) is characterized genetically by the presence of IGH-BCL2 rearrangement. A subset of DHLs arises from FL by the acquisition of c-MYC gene rearrangement during disease progression, but FL with concurrent IGH-BCL2 and c-MYC gene initial rearrangements is rarely reported. The few reported cases had different clinical courses, including some with indolent disease. We report a case of “double hit” low grade FL with both c-MYC and BCL2 gene rearrangements but at low proliferation rate. Unlike the usual DHLs with aggressive clinical course, our patient showed at least partial response to intense chemotherapy. Review of the literature shows a few similar cases with variable clinical course, including a few indolent cases. These patients appear to respond better with more intense chemotherapy for DHL.

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Clinical and Pathological Features of Non-Hodgkin Lymphomas Harboring Concurrent t(14;18) and 8q24 Anomalies

Blood ◽

10.1182/blood.v116.21.3134.3134 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3134-3134

Author(s):

Ash A. Alizadeh ◽

Matthew Anderson ◽

Holbrook E Kohrt ◽

Ragini M Shyam ◽

Charles D. Bangs ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Small Sample ◽

World Health ◽

Fish Analysis ◽

Low Grade ◽

Cytogenetic Abnormalities

Abstract Abstract 3134 Background: Concurrent t(14;18) and 8q24 translocations involving BCL2 and MYC in non-Hodgkin lymphomas (NHL) are rare, but are associated with a inferior overall survival (OS) regardless of the presenting or antecedent histological features (Johnson N, et al. Blood 2009). We sought to confirm these observations in an independent cohort of patients with NHL. Methods: Metaphase karyotypes and/or fluorescence in-situ hybridization (FISH) were used to identify cases of NHL with cytogenetic abnormalities involving 18q21 and 8q24 (BCL2 and MYC). Clinical and cytogenetic characteristics of these patients were assessed for correlations with pathological and clinical variables including outcome. Histological diagnoses were determined according to the 2008 World Health Organization Classification. Overall survival (OS) was calculated from the date a biopsy demonstrated an abnormality involving MYC to the last follow up date or death, as some cases acquired these lesions during their clonal evolution. Result: Among ∼1700 NHL patients diagnosed and/or treated at Stanford University Medical Center on whom cytogenetic studies were routinely performed, we identified 26 patients with evidence for concurrent cytogenetic abnormalities involving BCL2 and MYC. The histological diagnoses at the time of BCL2 and MYC rearrangements were available for 25 of the patients and included follicular lymphoma (FL1-2, n=3; FL3A, n=4), diffuse large B-cell lymphoma (DLBCL, n=2), and B cell lymphoma, unclassifiable, with features intermediate between Burkitt Lymphoma and DLBCL (BCLU, n=16). Cytogenetic analysis revealed that 13/26 cases with both BCL2 and MYC rearrangements had MYC translocations involving the immunoglobulin (Ig) loci. However, in striking contrast to the <10% prevalence of IgL or IgK partners in NHL harboring Ig-MYC, without Ig-BCL2 rearrangements, 9 of these13 cases (69%) involved IgL t(8;22), and only 4 of these 13 cases (31%) involved IgH t(8;14). 9/26 MYC translocations involved various non-Ig loci (35%). One case (1/26) demonstrated amplification of ?both the BCL2 and the MYC loci by FISH, while one case showed trisomy 8 (1/26). Three cases had FISH analysis only, precluding assessment of the MYC rearrangement partner. No correlation between MYC partner and histology was observed, although this analysis was limited by small sample sizes. Non-FL histology correlated with significantly poorer than expected outcome, with a median OS of 4 months compared to 2 y for FL (p=0.003). Interestingly, we found cases with low-grade follicular lymphoma (FL1-2) histology which harbored both BCL2 and MYC rearrangements. To better define the frequency of 8q24 anomalies in an unselected cohort of follicular lymphoma cases, FISH for MYC and BCL2 rearrangements was performed on 192 independent low-grade follicular lymphoma (FL1-2) cases. While a subset of these cases (71) showed the expected frequency of BCL2 rearrangements (72%) by FISH, none showed concomitant 8q24 anomalies by FISH, suggesting that routine FISH analysis of low-grade follicular lymphoma for MYC rearrangements would have a low diagnostic yield. Conclusion: NHL with rearrangements of both BCL2 and MYC are under-recognized due to lack of routine karyotyping or FISH analysis. Comprehensive analysis of BCL2 and MYC status should be performed on all HGBCL in the new WHO (2008) classification, though the low frequency of these lesions among FL tumors precludes a similar conclusion for low grade NHL. Disclosures: No relevant conflicts of interest to declare.

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