Anti-MEGF8 (internal region) polyclonal antibody

Background: Chronic myeloid leukemia (CML) is driven by the fusion kinase Bcr-Abl. Bcr-Abl tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), revolutionized CML therapy. Nevertheless, about 20 % of CMLs display primary or acquired TKI resistance. TKI resistance can be either caused by mutations within the Bcr-Abl kinase domain or by aberrant signaling by its effectors, e.g. Lyn or Gab2. Bcr-Abl mutations are frequently observed in TKI resistance and can only in some cases be overcome by second line TKIs. In addition, we have previously shown that the formation of Gab2 complexes can be regulated by Bcr-Abl and that Gab2 signaling counteracts the efficacy of four distinct Bcr-Abl inhibitors. Therefore, TKI resistance still represents a challenge for disease management and alternative therapies are urgently needed. Findings: Using different CML cell lines and models, we identified the clinically approved TKIs sorafenib (SF) and axitinib (AX) as drugs overcoming the resistance mediated by the Bcr Abl(T315I) mutant as well as the one mediated by Gab2 and Lyn(Y508F). In addition, we demonstrated that AX mainly affects the Bcr-Abl/Grb2/Gab2 axis, whereas SF seems to act independently of the fusion kinase and most likely by blocking signaling pathways up-and downstream of Gab2. Conclusion: We demonstrate that SF and AX show potency in various and mechanistically distinct scenarios of TKI resistance, including Bcr-Abl(T315I) as well as Lyn- and Gab2-mediated resistances. Our data invites for further evaluation und consideration of these inhibitors in the treatment of TKI resistant CML.

Laterality disease is frequently associated with congenital heart disease (CHD). However, it is unclear what is behind this association, a pleiotropic effect of common genetic causes of laterality diseases or the impact of abnormal left-right patterning on the downstream cardiovascular development. MEGF8 is a disease gene of Carpenter syndrome characterized by defective lateralization and CHD. Here we performed spatial and temporal deletion to dissect the tissue and time requirements of Megf8 on cardiovascular development. None of conditional deletions in cardiomyocytes, endothelium/endocardium, epicardium, cardiac mesoderm or neural crest cells led to cardiovascular defects. More surprisingly, temporal deletion with a ubiquitous Cre driver at embryonic day 7.5 (E7.5), a time point before symmetry break and cardiogenesis, causes preaxial polydactyly (PPD) and exencephaly, but not laterality and cardiovascular defects. These data suggested that Megf8 was dispensable for cardiac organogenesis. Only with E6.5 deletion, we observed aortic arch artery defects including right aortic arch, an indicator of reversed left-right patterning. The concurrence of laterality and cardiovascular defects in pre-streak stage deletion rather than cardiac organogenesis stage deletion indicates that the laterality defect may directly impact heart development. Interestingly, the latent effect of Megf8 on the left-right patterning suggests that the regulation of laterality may be much earlier than we previously thought.