Abstract
Molecular pathogenesis of Chronic Lymphocytic Leukemia (CLL) is not fully elucidated. Genome wide association studies have linked Interferon Regulatory Factor 4 (IRF4) to the development of CLL. We recently established a causal relationship between low levels of IRF4 and development of CLL. However, the molecular mechanism through which IRF4 suppresses CLL development remains unclear. Deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL. Yet, the role of Notch signaling as well as its regulation during CLL development remains poorly understood. Previously, we demonstrated that IRF4 deficient mice expressing immunoglobulin heavy chain Vh11 (IRF4−/−Vh11) developed spontaneous CLL with complete penetrance. In this study, we show that elevated Notch2 expression and the resulting hyperactivation of Notch signaling are common features of IRF4−/−Vh11 CLL cells. Our studies further reveal that Notch signaling is indispensable for CLL development in the IRF4−/−Vh11 mice. Moreover, we identify E3 ubiquitin ligase Nedd4, which targets Notch for degradation, as a direct target of IRF4 in CLL cells and their precursors. Collectively, our studies provide the first in vivo evidence for an essential role of Notch signaling in the development of CLL and establish IRF4 as a critical regulator of Notch signaling during CLL development.
Highlights
Chronic Lymphocytic Leukemia (CLL) is a clinically heterogeneous B cell malignancy
Using westernblot analysis our studies revealed Notch2 protein as the predominant Notch paralogue expressed in Interferon Regulatory Factor 4 (IRF4)-/-Vh11 CLL cells (Figure 1B)
B cells from CD19creNotch2fl/fl mice showed efficient Notch2 deletion, accompanied with a dramatic downregulation of Hes1 (Figure S2B and S2C). These results indicate that Notch2 protein is the major contributor of Notch signaling in mature B cells and its loss leads to a profound abrogation of Notch signaling in vivo
Summary
Chronic Lymphocytic Leukemia (CLL) is a clinically heterogeneous B cell malignancy. Despite considerable progress in our current understanding of CLL, the molecular events underlying the complex pathogenesis of CLL have not been fully elucidated. Recent Whole Genome Sequencing studies have identified mutational activation of Notch signaling pathway as one of the most recurrent molecular events in human CLL [1,2,3,4,5]. Other than the mutational activation, studies have reported constitutively high expression of Notch and Notch leading to activation of Notch signaling in human CLL cells [8]. In vitro studies have provided evidence for a role of Notch signaling in promoting the survival and chemo-resistance of CLL cells [9, 10]. These studies have linked aberrant Notch signaling to the pathogenesis of CLL in vitro, whether Notch signaling is critical for CLL development in vivo remains unknown. The molecular pathways that lead to the deregulated Notch signaling in CLL cases without Notch mutations are still poorly defined
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