Aberrations of the Wnt canonical pathway (WCP) are known to contribute to the pathogenesis of various types of cancer. We hypothesize that these defects may exist in mantle cell lymphoma (MCL). Both the upstream and downstream aspects of WCP were examined in MCL cell lines and tumors. Using WCP-specific oligonucleotide arrays, we found that MCL highly and consistently expressed Wnt3 and Wnt10. ␤-catenin, a transcriptional factor that is a downstream target of WCP, is localized to the nucleus and transcriptionally active in all 3 MCL cell lines examined. By immunohistochemistry, 33 (52%) of 64 MCL tumors showed nuclear localization of ␤-catenin, which significantly correlated with the expression of the phosphorylated/inactive form of GSK3␤ (p-GSK3␤; P ‫؍‬ .011, Fisher). IntroductionMantle cell lymphoma (MCL) is a specific type of non-Hodgkin B-cell lymphoma recognized by the World Health Organization (WHO) Classification Scheme. 1 The genetic hallmark of this disease is the recurrent chromosomal abnormality, the t(11;14)(q13;q32), which brings the cyclin D1 gene under the influence of the enhancer of the immunoglobulin heavy chain (IgH) gene, leading to cyclin D1 overexpression. 2 Although cyclin D1 overexpression is likely to be pathogenetically important in MCL, evidence suggests that additional biochemical defects are necessary for lymphomagenesis. For instance, using Ecyclin D1 transgenic mice, 2 research groups have previously shown that enforced cyclin D1 expression in B cells is not sufficient to induce tumor formation. 3,4 Furthermore, large-scale cDNA microarray studies using frozen MCL tumors have revealed a relatively large number of biochemical abnormalities in MCL, with these defects frequently implicated in the regulation of apoptosis, cell cycle progression, and DNA repair. [5][6][7][8][9][10] Examination of specific cellular signaling pathways also provided additional insights into the biology of these tumors. For instance, a relatively recent study reported constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in a subset of MCL tumors, particularly those with a blastoid morphology. 11 The Wnt canonical pathway (WCP) is important for normal cell growth and development. 12,13 Defects of this pathway have been shown to play roles in the pathogenesis of a variety of human cancers, particularly those of epithelial type. 14 Normally, WCP is activated via ligation of the Wnt proteins, which are secreted glycoproteins, to their respective dimeric cell surface receptors composed of the frizzled proteins and the low-density lipoprotein-receptor-related proteins (LRPs). 15 The binding of the Wnt proteins to their receptors is negatively regulated by the Wnt inhibitory factor and the sFRP proteins (sFRP1-5). Upon ligation to their receptors, the disheveled proteins (DvLs), a family of the upstream WCP signaling proteins, are phosphorylated. 16,17 In WCP, Wnt stimulation results in inactivation/phosphorylation of GSK3␤, as well as the dissociation of the "destruction comp...

Adult SOT recipients face a prolonged risk of late PTLD, whereas risk of early PTLD may have declined in recent years.

Central nervous system (CNS) relapse affects 5% of diffuse large B‐cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high‐dose methotrexate (HD‐MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD‐MTX in DLBCL patients aged 18–70 years treated in Alberta, Canada between 2012 and 2019. Provincial guidelines recommended HD‐MTX for patients at high‐risk of CNS relapse based upon CNS‐IPI score, double‐hit lymphoma, or testicular involvement. Among 906 patients with median follow‐up 35.3 months (range 0.29–105.7), CNS relapse occurred in 1.9% with CNS‐IPI 0–1, 4.9% with CNS‐IPI 2–3, and 12.2% with CNS‐IPI 4–6 (p < .001). HD‐MTX was administered to 115/326 (35.3%) high‐risk patients, of whom 96 (83.5%) had CNS‐IPI score 4–6, 45 (39.1%) had double‐hit lymphoma, and four (3.5%) had testicular lymphoma. The median number of HD‐MTX doses was two (range 1–3). Central nervous system relapse risk was similar with versus without HD‐MTX (11.2% vs. 12.2%, p = .82) and comparable to previous reports of high‐risk patients who did not receive CNS prophylaxis (10–12%). In multivariate and propensity score analyses, HD‐MTX demonstrated no association with CNS relapse, progression‐free survival, or overall survival. This study did not demonstrate a benefit of prophylactic HD‐MTX in this high‐risk patient population. Further study is required to determine the optimal strategy to prevent CNS relapse in DLBCL.

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