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 α, JAK2, and STAT5, but not of STAT6. Genome-wide, 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.

Highlights

  • A deregulated activation of JAK (Janus kinase)/STAT pathway is frequently observed in 2 clinically different hematologic malignancies: primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma

  • We identified through establishment of data-based mathematical models major similarities and differences in the dynamic behavior of the JAK/STAT pathway in 2 lymphoma entities

  • Previous cytogenetic based [39, 40] and semiquantitative approaches using immunohistochemistry, Quantitative real-time PCR (qRT-PCR), immunoblotting, and ELISA [1, 41, 42] provided evidence for altered STAT, JAK2, and SHP1 levels in lymphomas compared with normal cells

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Summary

Introduction

A deregulated activation of JAK (Janus kinase)/STAT pathway is frequently observed in 2 clinically different hematologic malignancies: primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL). The STAT family member STAT6 is hyperphosphorylated in about 80% of PMBL [1] and cHL [2] patients, mutations of the negative regulator SOCS1 are common [3, 4] and chromosomal aberrations including gains of the JAK2 gene were observed in 35% of PMBLs and in 33% of Hodgkin lymphomas [5]. STAT5, another STAT family member, is phosphorylated in approximately 30% of cHL patients [6]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). A model description is in Supplementary Text S7. Details of MedB-1 and L1236 models are in Supplementary Text S8

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