6 research outputs found
ILK Induction in Lymphoid Organs by a TNFalpha-NF-kappaB-Regulated Pathway Promotes the Development of Chronic Lymphocytic Leukemia
The proliferation of chronic lymphocytic leukemia (CLL) cells requires communication with the lymphoid organ microenvironment. Integrin-linked kinase (ILK) is a multifunctional intracellular adaptor protein that transmits extracellular signals to regulate malignant cell motility, metastasis, and cell-cycle progression, but is poorly characterized in hematologic malignancies. In this study, we investigated the role of ILK in the context of CLL and observed high ILK expression in patient samples, particularly in tumor cells harboring prognostic high-risk markers such as unmutated IGHV genes, high Zap70, or CD38 expression, or a signature of recent proliferation. We also found increased numbers of Ki67 (MKI67)-positive cells in regions of enhanced ILK expression in lymph nodes from CLL patients. Using coculture conditions mimicking the proliferative lymph node microenvironment, we detected a parallel induction of ILK and cyclin D1 (CCND1) expression in CLL cells that was dependent on the activation of NF-kappaB signaling by soluble TNFalpha. The newly synthesized ILK protein colocalized to centrosomal structures and was required for correct centrosome clustering and mitotic spindle organization. Furthermore, we established a mouse model of CLL in which B-cell-specific genetic ablation of ILK resulted in decelerated leukemia development due to reduced organ infiltration and proliferation of CLL cells. Collectively, our findings describe a TNFalpha-NF-kappaB-mediated mechanism by which ILK expression is induced in the lymph node microenvironment and propose that ILK promotes leukemogenesis by enabling CLL cells to cope with centrosomal defects acquired during malignant transformation. Cancer Res; 76(8); 2186-96. (c)2016 AACR
Combined CXCR3/CXCR4 measurements are of high prognostic value in chronic lymphocytic leukemia due to negative co-operativity of the receptors.
Combined CXCR3/CXCR4 measurements are of high prognostic value in chronic lymphocytic leukemia due to negative co-operativity of the receptors
Persistent CD49d engagement in circulating CLL cells: A role for blood-borne ligands?
CD49d, the \u3b1-chain of the integrin heterodimer \u3b14\u3b21 (CD49d/CD29) is expressed on cell surface of ~40% of chronic lymphocytic leukemia (CLL) cases. It mediates both cell\u2013cell and cell\u2013matrix adhesion through binding to the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN), respectively. These interactions regulate CLL cell recirculation from the blood stream to tissue sites, as well as the transmission to CLL cells of signals of pro-survival and resistance to drug-induced apoptosis.1 Consistent with this functional role in CLL, a recent worldwide meta-analysis carried out on a large patient cohort, definitely demonstrated the independent prognostic relevance of CD49d in this diseas
In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment
Chemokine receptor oligomerization to tweak chemotactic responses
Chemokine receptors guide cell migration by responding to local chemokine gradients during immune surveillance and inflammation. Similar to other G protein-coupled receptors, chemokine receptors can form oligomeric complexes that might have distinct pharmacological and biochemical properties as compared to their individual constituents. The majority of evidence for chemokine receptor oligomers came from transfected cells using tagged receptors to monitor their close proximity or physical association. However, translation of these observations to (patho)-physiological consequences is puzzling for the majority of chemokine receptor oligomers due to experimental limitations and challenges to distinguish oligomer- from downstream signaling-mediated crosstalk. Recent methodological advances allow in situ validation of chemokine receptor oligomers in native cells, disruption of oligomers, and detection of oligomer-mediated signaling. Chemokine receptor oligomerization modulates cell migration in (patho)-physiology and consequently offers novel therapeutic targets