Identification of activated Tnk1 kinase in Hodgkin's lymphoma

Abstract

To test this hypothesis, we extracted genomic DNA from one peripheral blood and 25 bone marrow samples of AML patients with t(8;21) from the University Medical Centers Freiburg, Germany and Nijmegen, The Netherlands. All patients had provided ethic board approved informed consent. The blast count in the peripheral blood sample was 35% and in bone marrow samples 470% in the majority of samples (range: 25-90%). In addition, to explore the mutation status in a homogeneous blast population, we investigated two AML cell lines bearing t(8;21), Kasumi-1 and SKNO. We amplified a 268-bp fragment of AML1-ETO encompassing the entire coding region of the NHR4 domain (aa658-707) (Table 1, Figure 1) and applied bidirectional sequencing (GATC Biotech, Konstanz, Germany). However, we identified no mutations within the NHR4 coding genomic sequence of these AML patients or the two cell lines. With the limitations of a cohort of 26 patient samples, we conclude that mutations within the NHR4 domain of AML1-ETO are probably a very infrequent event in patients with t(8;21). Our results also support the idea that in vivo, other mechanisms than NHR4 mutations, for example, a dysfunctional SON protein might be a reason for hampered interaction of AML1-ETO and SON. Conflict of interestThe authors declare no conflict of interest. AcknowledgementsThis study was in part supported by a grant from the Deutsche Krebshilfe (108397 to BH). We thank Dong-Er Zhang, University of California, San Diego, USA for her very helpful comments with this study.

Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells

“…Among these peptides, we have fortunately found five IRF4 phosphorylation sites, including Y124, -176, -191, -180, and -427 (Table 1). Consistent with our results, phosphorylation of Y124 and Y427 and of Y191 of endogenous IRF4 was also identified by phosphoproteome profiling in Hodgkin's lymphoma cells (42) and multiple myeloma cells (41), respectively. In contrast, phosphorylation of Y37, Y121, and Y439, which were identified in Hodgkin's lymphoma cells (42), was not identified in EBV-transformed cells in our assays with the same strategy.…”

“…2). Although phosphorylation of Y61 has not been identified by phosphoproteome profiling, phosphorylation of Y124 has also been identified in Hodgkin's lymphomas (42). Thus, Y124 is a convincing phosphorylation site at least important for IRF4-associated lymphomas.…”

“…Many proteins involved in signal transduction are tyrosine phosphorylated. Interestingly, a few limited high-throughput profiling studies have identified several tyrosine phosphorylation sites on IRF4 in different cancer contexts, including Y191 in MM (41) and Y36, Y121, Y124, Y427, and Y439 in Hodgkin's lymphomas (42).…”

LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required

“…In addition to LMP1 signaling, other unidentified lymphocyte-specific pathways may also impact the outcomes of IRF4 transcriptional activation, considering the following facts: (i) IRF4 is also phosphorylated in other contexts, such as human T-cell leukemia virus-1-infected cells, Hodgkin’s lymphoma cells 50 and multiple myeloma cells, 51 where LMP1 is absent; (ii) we have previously shown that, in addition to Src, other kinases including Alk and TNK also stimulate IRF4 transcriptional activity. 36 Thus, IRF4 may be activated through different lymphocyte-specific signaling pathways that involve distinct kinases in different contexts; (iii) in the context of EBV latent infection, in addition to LMP1, LMP2A also activates the PI3K/Akt pathway in response to BCR signaling.…”

PARP12, an Interferon-stimulated Gene Involved in the Control of Protein Translation and Inflammation

“…Since both cytoplasmic localizations could be observed in untransfected cells lines expressing the wild type form of the protein, it is tempting to speculate that the subcellular distribution of PARP12 may be regulated by a signaling event leading to the post-translational modification of the N-terminal domain of the protein. Accordingly, several studies have identified PARP12-derived N-terminal peptides displaying phosphorylated residues (61,62). PARP12 may therefore represent an ISG with dual functional properties both of which may contribute to the establishment of an antimicrobial state in cells exposed to IFNs.…”