Key Points• The intensified standard-ofcare regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations.• MCLs with TP53 mutations should be considered for alternative frontline treatment.Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P < .0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P < .0001) and MIPI-c high-risk (HR, 2.6; P 5 .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P < .0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction-and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents. (Blood. 2017;130(17):1903-1910

Mantle cell lymphoma (MCL) is defined pathologically by the detection of CD20, CD5, and most importantly cyclin D1 (CCND1). Its distinction from other lymphomas is important for prognosis and appropriate therapy, but occasional cases may fail to express CCND1 and morphologic simulators may express CD20 and CD5 but not CD23. In this study, we show that the transcription factor Sox11 is specifically expressed in the nucleus of MCL compared with other lymphomas and benign lymphoid tissue. Although the role of Sox11 presently is not known in lymphocyte ontogeny, it is normally expressed in the developing central nervous system in the embryo and shows sequence homology with Sox4, a transcription factor crucial for B lymphopoiesis. Sox11 mRNA is increased in gliomas compared with healthy brain tissue, suggesting a role in malignant transformation and/or cell survival. Our novel finding of specific overexpression of Sox11 mRNA and nuclear protein in both cyclin D1-positive and -negative MCL may be useful for the diagnosis of MCL as a complement to cyclin D1 and also suggests a functional role for Sox11 in MCL. IntroductionB-cell lymphomas (BCLs) are divided into several subgroups depending on their morphologic and phenotypic properties, 1 and accurate diagnosis is necessary for prognosis and targeted therapy. Mantle cell lymphoma (MCL) accounts for 5% to 10% of BCLs and is characterized by overexpression of cyclin D1 (CCND1) due to the specific translocation t(11;14)(q13;q32), which brings the cyclin D1 (BCL1/CCND1) gene under the control of the immunoglobulin heavy chain enhancer. MCL may be distinguished from potential morphologic mimics, including chronic lymphocytic leukemia/small cell lymphoma (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) based on immunohistochemical staining (IHC) for CD5, CD23, and CD10. MCL and CLL both express CD5 but MCL, in contrast to CLL, generally lacks CD23 by immunohistochemistry. FL lacks both CD5 and CD23 but most often expresses CD10, whereas MZL is typically negative for all 3 antigens. Nevertheless, cases of CD23 Ϫ CLL occur and rare instances of CD5 ϩ MZL have been described. Follicular dendritic cell networks are characteristically expanded in MCL, but this occurs also in FL and MZL. CCND1 overexpression is thus the hallmark of MCL even though approximately 10% of MCLs lack CCND1 expression and may be misdiagnosed by overreliance on CCND1 IHC. 2,3 For these reasons, fluorescence in situ hybridization (FISH) targeting the specific translocation probably affords the most sensitive detection of MCL, although it is not widely performed and the results may be more easily affected by technical factors than modern IHC. Thus, specific markers that can aid in stratification and diagnosis of lymphomas in general and MCL in particular would be of major interest.In this study, we demonstrate that the transcription factor Sox11 is specifically up-regulated in MCL and distinguishes MCL from other B-cell lymphomas. Sox11 belongs to the Sox gene family and is mapped to chrom...

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BackgroundWe surveyed lymphomas to determine the range of expression of the mantle cell lymphoma-associated SOX11 transcription factor and its relation to cyclin D1. Design and MethodsOn hundred and seventy-two specimens were immunostained for the SOX11 N and C termini. Cyclin D1 was detected by immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction; in situ hybridization for t(11;14) was applied when needed. ResultsNuclear SOX11 was strongly expressed in most B and T-lymphoblastic leukemia/lymphomas and half of childhood Burkitt's lymphomas, but only weakly expressed in some hairy cell leukemias. Chronic lymphocytic leukemia/lymphoma, marginal zone, follicular and diffuse large B-cell lymphomas were negative for SOX11, as were all cases of intermediate Burkitt's lymphomas/diffuse large B-cell lymphoma, myeloma, Hodgkin's lymphomas and mature T-cell and NK/T-cell lymphomas. ConclusionsIn addition to mantle cell lymphoma, SOX11 is strongly expressed only in lymphoblastic malignancies and Burkitt's lymphomas. Its expression is independent of cyclin D1 (except for weak expression in hairy cell leukemias) and unlikely to be due to translocations in lymphoid neoplasia.Key words: lymphoid, SOX11 transcription factors, lymphoblastic neoplasms, mantle cell lymphoma, Burkitt's lymphoma. 's lymphoma. Haematologica 2009; 94:1563-1568. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Dictor M, Ek S, Sundberg M, Warenholt J, György C, Sernbo S, Gustavsson E, AbuAlsoud W, Wadström T, and Borrebaeck T. Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and BurkittStrong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkitt's lymphoma

BackgroundThe transcription factor SOX11 plays an important role in embryonic development of the central nervous system (CNS) and is expressed in the adult immature neuron but is normally not expressed in any other adult tissue. It has recently been reported to be implicated in various malignant neoplasms, including several lymphoproliferative diseases, by its specific expression and in some cases correlation to prognosis. SOX11 has been shown to prevent gliomagenesis in vivo but the causes and consequences of aberrant expression of SOX11 outside the CNS remain unexplained.ResultsWe now show the first function of SOX11 in lymphoproliferative diseases, by demonstrating in vitro its direct involvement in growth regulation, as assessed by siRNA-mediated silencing and ectopic overexpression in hematopoietic malignancies. Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction. Furthermore, promoter analysis revealed that SOX11 is silenced through DNA methylation in B cell lymphomas, suggesting that its regulation is epigenetically controlled.ConclusionsThe data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation. Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

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Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment-related morbidity, additional parameters need to be evaluated to enable risk-adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki-67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.

The dynamical properties of an InP photonic crystal nanocavity are experimentally investigated using pump-probe techniques and compared to simulations based on coupled-mode theory. Excellent agreement between experimental results and simulations is obtained when employing a rate equation model containing three time constants, that we interpret as the effects of fast carrier diffusion from an initially localized carrier distribution and the slower effects of surface recombination and bulk recombination. The variation of the time constants with parameters characterizing the nanocavity structure is investigated. The model is further extended to evaluate the importance of the fast and slow carrier relaxation processes in relation to patterning effects in the device, as exemplified by the case of all-optical wavelength conversion.