quantitative-mass-spectrometric-profiling-cancer-cell-proteomes

Quantitative Mass Spectrometric Profiling of Cancer-cell Proteomes Derived From Liquid and Solid Tumors

In-depth analyses of cancer cell proteomes are needed to elucidate oncogenic pathomechanisms, as well as to identify potential drug targets and diagnostic ...

Goethe University of Frankfurt

Spleen tyrosine kinase (Syk) induces cell survival and proliferation in a high proportion of acute myeloid leukemia (AML) blasts, but the underlying molecular events of Syk signaling have not been investigated. Proteomic techniques have allowed us to identify the multiprotein complex that is nucleated by constitutively active Syk in AML cells. This complex differs from the B-lymphoid Syk interactome with respect to several proteins, especially the integrin receptor Mac-1, the Fc-γ receptor I (FcγRI), and the transcription factors STAT3 and STAT5. We show in several AML cell line models that tonic signals derived from the Fc-γ chain lead to Syk-dependent activation of STAT3 and STAT5, which in turn induces cell survival and proliferation. Moreover, stimulation of Mac-1 or FcγRI intensifies the constitutive Syk-mediated STAT3/5 activation in AML cells, a scenario likely to take place in the bone marrow niche. In accordance with these findings, we observed that β2 integrins, including Mac-1, trigger proliferation of AML cells in an AML cell/stroma coculture model. Taken together, we identified an oncogenic integrin/Syk/STAT3/5 signaling axis that might serve as a therapeutic target of AML in the future.

β2 integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis.

This paper, analyzing interviews with men that donate their semen in Denmark, explores what it means to be a sperm donor. Breaking with the assumption that men have a specific and clearly identifiable motivation to become sperm donors, this paper leaves the confinement of such an accountable actor model implied in asking for men's motivations to donate semen. Instead, the author describes the experiences of sperm donors to show how the moral, organizational, and biomedical-technological context of sperm donation in Denmark makes for enactments of moral selves as well as specific embodiments of masculinity. Instead of looking for motivations that can be accounted for, the author engages with the question of how donating semen affords men the experience of moral and gendered selves.

Beyond motivation: on what it means to be a sperm donor in Denmark.

Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. While many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton's tyrosine kinase (BTK) in AML. BTK was frequently expressed and its inhibition strongly impaired the proliferation and survival of AML cells - also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context-dependent. In FLT3-ITD-positive AML, BTK mediates FLT3-ITD-dependent Myc- and STAT5 activation and combined targeting of FLT3-ITD and BTK showed additive effects. In FLT3-ITD-negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to NFκB and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and point for the first time to a role of TLR9 in AML. Clinical evaluation of BTK inhibitors in AML seems warranted.

FLT3-ITD and TLR9 employ Bruton's tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation.

Danish sperm donors face a particular kind of kinship trouble: they find themselves in a cultural and organizational context that offers different and contrary ways of how to make connections to donor-conceived individuals meaningful. Whereas Danish sperm banks and Danish law want sperm donors to regard these connections as contractual issues, the dominant kinship narrative in Denmark asks sperm donors to also consider them as family and kinship relations. Based on interviews with Danish sperm donors and participant observation at Danish sperm banks, I argue in this article that Danish sperm donors make sense of connections to donor-conceived individuals as a particular kind of relatedness that cannot be reduced to either contractual or kinship relations. Making sense of these connections, sperm donors negotiate their social significance and thereby participate in opening a space which offers avenues for new kinds of sociality.

Sebastian Mohr

Department of Hematology/Oncology

Goethe University of Frankfurt

Quantitative Mass Spectrometric Profiling of Cancer-cell Proteomes Derived From Liquid and Solid Tumors