Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

Abstract

Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor a, JAK2, and STAT5, but not of STAT6. Genomewide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. Cancer Res; 71(3); 693-704. Ó2010 AACR.

The molecular pathogenesis of primary mediastinal large B-cell lymphoma

“…In PMBCL, gene expression profiling revealed high levels of IL13 receptor expression and downstream effectors, such as JAK2 and STAT1, indicating up-regulation of pathway genes. 3,41,58 Moreover, constitutive STAT6 activation has been identified as a characteristic feature of PMBCL compared with DLBCL and, in contrast to cHL, this is probably not the result of autocrine IL-4 or IL-13 production. 8,59 Genomic amplification of a subtelomeric region of chromosome 9 (9p24.1) involving several genes, including JAK2, has been consistently reported in more than half of cases and can be considered as one of the hallmark genetic alterations in PMBCL 10,46,60,61 (Table 1).…”

“…As treatment recommendations are historically linked to DLBCL, the relative specificity of JAK-STAT, 8 NF-B pathway activation, 9 overexpression of PD-1 ligands, 3 and the histone-modifying genes JAK2 and JMJD2C 61 stand out as the most rational targets for specifically tailored future therapies in PMBCL. In vitro studies in MedB-1 cells demonstrate proof of principle that JAK pathway inhibition and reduction of STAT5 phosphorylation are toxic to the cells, 58 raising hope that similar approaches of JAK-STAT pathway inhibition might be a promising approach. Similarly, NF-B pathway inhibition has yielded promising results in preclinical models.…”

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

“…Furthermore, STAT6 is a critical regulator in IL-4-mediated B-cell differentiation. Previous work has shown that B cells from mice lacking STAT6 failed to produce significant amounts of IgE and IgG1 after infection with the nematode parasites (Raia et al, 2011;Turqueti-Neves et al, 2014). The binding sites of STAT6 have been found in the target regions of a variety of IL-4-mediated genes, including CD23 (Cooper et al, 2012), IL-4R (Jenkins et al, 2013), eotaxin-1 (Waddell et al, 2013), eotaxin-3 (Nakayama et al, 2010), FIZZ1 (Dasgupta et al, 2011), and in Ig germline e (Lu et al, 2007) promoters.…”

New developments in the pathology of malignant lymphoma: a review of the literature published from November 2010–January 2011

“…Raia et al [2] used such expression data from cell lines of HL and primary mediastinal diffuse large B cell lymphoma (PMDLBL), tumor types with quite some similarities, including the constitutive activation of the JAK/STAT signaling pathway. They compare the data with those from normal B cells and find an increased level of STAT5 and 6.…”