Lisa M Rimsza

The University of Arizona, Tucson, Arizona, United States

Are you Lisa M Rimsza?

Claim your profile

Publications (142)1536.94 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 08/2015; DOI:10.1200/JCO.2014.60.2383 · 18.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The anaplastic lymphoma kinase ALK is chromosomally rearranged in a subset of certain cancers, including of 2-7% non-small cell lung cancers (NSCLC) and ~70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK+ NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ~10 months. Kinase domain mutations are detectable in 25-37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 05/2015; DOI:10.1158/0008-5472.CAN-14-3437 · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mediastinal involvement is considered essential for the diagnosis of primary mediastinal large B-cell lymphoma (PMBL). However, we have observed cases of diffuse large B-cell lymphoma (DLBCL) with features of PMBL but without detectable mediastinal involvement. The goal was to assess our previously established gene expression profiling (GEP) signature for PMBL in classifying these cases. In a large series of DLBCL cases, we identified 24 cases with a GEP signature of PMBL, including 9 cases with a submission diagnosis of DLBCL consistent with PMBL (G-PMBL-P) and 15 cases with a submission diagnosis of DLBCL. The pathology reviewers agreed with the diagnosis in the 9 G-PMBL-P cases. Among the other 15 DLBCL cases, 11 were considered to be PMBL or DLBCL consistent with PMBL, 3 were considered to be DLBCL, and 1 case was a gray-zone lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. All 9 G-PMBL-P and 9 of the 15 DLBCL cases (G-PMBL-M) had demonstrated mediastinal involvement at presentation. Interestingly, 6 of the 15 DLBCL cases (G-PMBL-NM) had no clinical or radiologic evidence of mediastinal involvement. The 3 subgroups of PMBL had otherwise similar clinical characteristics, and there were no significant differences in overall survival. Genetic alterations of CIITA and PDL1/2 were detected in 26% and 40% of cases, respectively, including 1 G-PMBL-NM case with gain of PDL1/2. In conclusion, PMBL can present as a nonmediastinal tumor without evidence of mediastinal involvement, and GEP offers a more precise diagnosis of PMBL.
    The American journal of surgical pathology 05/2015; DOI:10.1097/PAS.0000000000000473 · 4.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning anti-apoptotic proteins BCL2 and MCL1 are frequently expressed. Here, we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find clinical samples have frequent co-expression of MCL1 and BCL2, suggesting therapeutic strategies targeting only one will lead to treatment failures due to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest anti-tumor activity against most DLBCL lines and resulted in compensatory up-regulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent anti-tumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.Leukemia accepted article preview online, 17 April 2015. doi:10.1038/leu.2015.99.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2015; 29(8). DOI:10.1038/leu.2015.99 · 9.38 Impact Factor
  • Lisa M Rimsza
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular classification of diffuse large B-cell lymphoma (DLBCL) is a critical biologic, prognostic, and predictive distinction. Since the discovery of two molecular types of DLBCL in otherwise morphologically indistinguishable cases, numerous methodologies for making this distinction have been published. A method and technical platform may now be reaching consensus. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(10). DOI:10.1158/1078-0432.CCR-15-0253 · 8.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome. SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography-tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS). After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort). Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 03/2015; 33(13). DOI:10.1200/JCO.2014.57.5092 · 18.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We studied the global miRNA expression in diffuse large B-cell lymphoma (DLBCL; n=79), Burkitt lymphoma (BL; n= 36), primary mediastinal B-cell lymphoma (PMBL; n=12), B-cell lines (n=11), and normal subsets of naïve B-cells (N), centroblasts (CB), and peripheral blood B-cells along with their corresponding gene expression profiles (GEP). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared to ABC-DLBCL (p=0.002). We identified a 27-miRNA signature that included MYC targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155 which significantly associated with R-CHOP response failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to AKT inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; 125(7). DOI:10.1182/blood-2014-04-566778 · 10.43 Impact Factor
  • Lisa M Rimsza · Melba C Jaramillo
    [Show abstract] [Hide abstract]
    ABSTRACT: As shown with gene expression profiling (GEP), the development and progression of follicular lymphoma (FL) involves complex interactions between neoplastic B cells and the surrounding microenvironment. GEP further reveals that the tumor microenvironment may predict survival in patients with FL and influence the response to therapy and the risk of transformation. Here, we briefly review GEP technology and summarize the role of the tumor microenvironment in FL diagnosis, prognosis, and transformation. Genes expressed by infiltrating T cells and macrophages appear to be the most important predictors of survival, clinical behavior, and outcome. These findings provide a basis for future studies into the pathogenesis and pathophysiology of FL and may ultimately provide guidance in the choice of therapy and the identification of potential therapeutic targets. © 2014 by The American Society of Hematology. All rights reserved.
    Hematology 12/2014; 2014(1):163-8. DOI:10.1182/asheducation-2014.1.163 · 2.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Effective treatment of diffuse large B cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in an R-CHOP-treated DLBCL cohort to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA-seq data revealed novel deletions in RCOR1 to be associated with unfavorable progression free survival (P = 0.001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising of 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (OS) (P = 0.023). The prognostic significance of the 233-gene signature for OS was reproduced in an independent cohort comprising 195 R-CHOP treated patients (P = 0.039). Additionally, we discovered that within the IPI low risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. Taken together, we present a novel and reproducible molecular subgroup of DLBCL, impacting risk-stratification of R-CHOP treated DLBCL patients and revealing a possible new avenue for therapeutic intervention strategies.
    Blood 11/2014; 125(6). DOI:10.1182/blood-2013-06-507152 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare two alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in two independent DLBCL cohorts E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse OS. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in-situ hybridization (Dual ISH) as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence ISH for translocation but a higher amplification frequency, indicating that BCL2 amplification may be under-reported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false-negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies.
    Human pathology 10/2014; 45(10). DOI:10.1016/j.humpath.2014.06.005 · 2.81 Impact Factor
  • Nature 09/2014; · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) is a common malignancy yet the signaling pathways deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of GC B cells3,4. Recent GCB-DLBCL deep sequencing studies have revealed mutations in a large number of genes in this cancer, including in GNA13 (encoding Gα13) and S1PR25-7. Here we show using in vitro and in vivo assays that GCB-DLBCL associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse GC B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed GC B cell-derived lymphoma. GC B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to GC B cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1-deficiency also led to GC B cell dissemination. The incomplete phenocopy of Gα13- and S1PR2-deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another GC B cell-derived malignancy, Burkitt lymphoma (BL), also represses GC B cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of GC B cells that is frequently disrupted in GC B cell-derived lymphoma.
    Nature 08/2014; 516(7530):254-258. DOI:10.1038/nature13765 · 42.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Detection of B cell clonality is useful for assisting in the diagnosis of B cell lymphomas. Clonality assessment can be accomplished through evaluation of KAPPA and LAMBDA light chain expression. Currently, only slide based methods are available for the majority of patient biopsies and do not detect light chain protein or mRNA in many B-cell lymphomas. Herein we evaluated a new method, known as colorimetric in situ hybridization (CISH), with improved sensitivity and multiplexing capacity, for its usefulness in clonality detection in mature B cell malignancies. The KAPPA and LAMBDA ISH was performed on a Ventana Benchmark XT utilizing two color chromogenetic detection. The probes comprised 2 haptenated riboprobes each approximately 500 base pairs long directed against the conserved regions of either KAPPA or LAMBDA mRNA. The dual colors consisted of silver deposition (black) for KAPPA light chain and a novel (pink) chromogen for LAMBDA light chain. Following optimization, CISH allowed visualization of mRNA in benign B cells in reactive tissues including germinal center, mantle zone, and post-germinal center cells. We then identified 79 cases of B cell lymphoma with formalin-fixed paraffin-embedded (FFPE) biopsies including: follicular (36 cases), mantle cell (6 cases), marginal zone (12 cases), lymphoplasmacytic (6 cases), small lymphocytic (4 cases), and diffuse large B cell (15 cases), which were selected on the basis of either prior flow cytometry or immunohistochemistry (IHC) results to serve as the predicate, "gold standard," comparator. 39/79 (49.4%) cases were classified as KAPPA and 29/79 (36.7%) as LAMBDA light chain restricted; while 9/79 (11.3%) cases were classified as indeterminate. Of the 70 cases with KAPPA or LAMBDA light chain restricted CISH, 69/70 (98.6%) were concordant with the reference method, while 1/70 (1.4%) was discordant. Optimized CISH detected lower levels of mRNA than can be visualized with current slide based methods, making clonality assessment in FFPE biopsies possible for mature B cell neoplasms. In this preliminary study, CISH was highly accurate compared to flow cytometry or IHC. CISH offers the possibility of wider applicability of light chain ISH and is likely to become a useful diagnostic tool. Virtual Slides The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 07/2014; 9(1):144. DOI:10.1186/1746-1596-9-144 · 2.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphoma cells are subject to higher levels of oxidative stress as compared to their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase II study of imexon (Amplimexon/NSC-714597), a pro-oxidant molecule, in patients with relapsed / refractory B-cell non-Hodgkin lymphomas (NHL). Imexon was administered at 1000 mg/m2 intravenously daily for 5 days in 21-day cycles. Gene expression analysis performed on pre-treatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n=9), diffuse large B-cell (DLBCL) (n=5), mantle cell (n=3), transformed follicular (n=2), small lymphocytic (n=2) and Burkitt (n=1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%: including responses in follicular lymphoma (4/9) and DLBCL (2/5). Gene expression analyses revealed CD68 and the redox related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. To our knowledge, this is the first demonstration of clinical activity with a pro-oxidant molecule in lymphoma. Pre-treatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This study was registered at as #NCT01314014.
    Blood 07/2014; 124(8). DOI:10.1182/blood-2014-04-570044 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Variable survival outcomes are seen following treatment for aggressive non-Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B-cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress-related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline-based therapies. Their associations with progression-free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top 3 SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR]=1.87, 95% confidence interval [CI]=1.14-3.06, P = 0.013), AKR1C3 rs10508293 (HR=2.09, 95% CI=1.28-3.41, P=0.0032) and NCF4 rs1883112 (HR=0.66, 95% CI=0.43-1.02, P=0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR=0.66, 95% CI=0.44-1.01, P=0.05) and the meta-analysis was significant (HR=0.66, 95% CI=0.49-0.89, P<0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta-analysis remained significant (HR=1.64, 95% CI=1.12-2.41). These two SNPs showed similar trends with OS in the meta-analysis (for NCF4, HR=0.72, 95% CI 0.51-1.02, P=0.07 and for MPO, HR=2.06, 95% CI 1.36-3.12, P<0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL.
    American Journal of Hematology 06/2014; 89(6). DOI:10.1002/ajh.23709 · 3.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The clinicopathologic findings in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) may show significant overlap, and MYC abnormalities, found in all BLs, also occur in a subset of DLBCL. The 2008 World Health Organization classification introduced the category of "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (BCLU) in recognition of this overlap, but the clinical significance of BCLU (ie, "high-grade") morphology and the relationship between BCLU morphology and MYC abnormalities remains unclear. In this study, we identified 260 cases of non-Burkitt, diffuse aggressive B-cell lymphomas from SWOG S9704, a phase 3 randomized study of standard immunochemotherapy versus autologous stem cell transplantation. Of these, 31 cases (12%) showed BCLU morphology, and 229 (88%) showed typical DLBCL morphology. Of 198, 27 (14%) were positive for MYC by immunohistochemistry. BCLU morphology was associated with an increased incidence of MYC expression but otherwise was not associated with distinct clinicopathologic features or significantly decreased survival. MYC-positive cases were morphologically and phenotypically heterogenous and were associated with poor progression-free and overall survival in multivariate analysis. These findings confirm that BCLU does not represent a distinct clinicopathologic entity and demonstrate that BCLU morphology alone does not significantly impact survival compared with typical DLBCL. In contrast, MYC protein expression is a poor prognostic factor that may be associated with either BCLU or DLBCL morphology, and MYC immunohistochemistry is suggested for routine prognostic evaluation ( identifier: NCT00004031).
    The American journal of surgical pathology 04/2014; 38(4):494-501. DOI:10.1097/PAS.0000000000000147 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical-outcome. Currently 50% of PTCLs are not-classifiable (PTCL-NOS).Gene-expression profiles on 372 PTCLs were analyzed and findings were validated by immunohistochemistry and mutation analysis. Robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including angioimmunoblastic T-cell lymphoma (AITL; n=114), anaplastic lymphoma kinase (ALK)-positive (n=31) and ALK-negative anaplastic large cell lymphoma (n=48), adult T-cell leukemia/lymphoma (n=14) and extranodal NK/T-cell lymphoma (ENKTL). ENKTL were further separated into NK-cell (n=23) and γδT-cell lymphomas (n=21). We re-classified 37% of morphologically-diagnosed PTCL-NOS cases into other specific subtypes by molecular signatures. Pathologic re-examination, immunohistochemistry and IDH2 mutation analysis supported the validity of re-classification. The remaining PTCL-NOS cases (n=121) were classified into two major molecular subgroups, characterized by high expression of either GATA3 (33%;40/121) or TBX21 (49%;59/121) and corresponding target genes. GATA3-subgroup was significantly associated with poor overall-survival (p=0.01), and also revealed distinct enriched oncogenic pathways. However, high expression of cytotoxic gene-signature within TBX21-subgroup showed poor clinical-outcome (p=0.05). In AITL, high expression of pan B-cell signatures correlated with favorable-outcome (p=0.01), whereas high monocytic-signature was associated with inferior-survival (p=0.017). Combined prognostic score was predictive of AITL survival in independent cohort (p=0.004), suggesting role of tumor microenvironment.
    Blood 03/2014; 123(19). DOI:10.1182/blood-2013-11-536359 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.
    Nature Genetics 02/2014; 46(4). DOI:10.1038/ng.2900 · 29.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), owing to upstream signals from the B cell receptor (BCR) and MyD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase γ, a necessary event in some pathways that engage NF-κB. Two germ line polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11/MALT1/BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RFN31-RBCK1 binding, decreased NF-κB and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.
    Cancer Discovery 02/2014; 4(4). DOI:10.1158/2159-8290.CD-13-0915 · 19.45 Impact Factor

Publication Stats

8k Citations
1,536.94 Total Impact Points

Top Journals


  • 1996–2015
    • The University of Arizona
      • • Department of Pathology
      • • Department of Medicine
      Tucson, Arizona, United States
  • 2013
    • The Rockefeller University
      • Laboratory of Developmental Genetics
      New York City, NY, United States
    • Barts Cancer Institute
      Londinium, England, United Kingdom
  • 2012
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2009–2011
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
    • Cancer Research UK
      Londinium, England, United Kingdom
    • Roswell Park Cancer Institute
      • Department of Immunology
      Buffalo, NY, United States
  • 2010
    • National Institutes of Health
      • Branch of Metabolism
      Bethesda, MD, United States
  • 2004–2008
    • University of Rochester
      Rochester, New York, United States
  • 2006
    • University of Oslo
      Kristiania (historical), Oslo, Norway
    • University of Nebraska Medical Center
      • Department of Pathology and Microbiology
      Omaha, Nebraska, United States
  • 1998–2006
    • University of Florida
      • • Department of Pediatrics
      • • Department of Plant Pathology
      • • Department of Pathology, Immunology, and Laboratory Medicine
      • • College of Medicine
      Gainesville, FL, United States
  • 2005
    • Arizona Research Center
      Phoenix, Arizona, United States