Differential diagnosis of non-atherosclerotic left main coronary artery stenosis.

A left main coronary artery (LMCA) stenosis without any atherosclerotic changes elsewhere in the coronary artery tree is a rare finding, and some uncommon reasons for luminal narrowing should be considered. An unusual case of non-atherosclerotic LMCA stenosis is reported.A middle-aged patient presented with acute myocardial infarction. An immediate coronary angiography was ordered and revealed a subtotal mid LMCA stenosis. A drug-eluting stent was successfully implanted in the LMCA.Operative revascularisation was recommended. Routine surgery was performed and surprisingly revealed an extended mass of a mediastinal tumour surrounding the aortic root. Histopathological examination of the tumour revealed a poorly differentiated squamous cell carcinoma.Postoperatively, the patient was treated with chemotherapy (carboplatin and docetaxel). Five years after the first admission to our hospital, the patient died as a result of ventricular fibrillation.The differential diagnosis of non-atherosclerotic LMCA stenoses is discussed.

Flt3-dependent transformation by inactivating c-Cbl mutations in AML.

In acute myeloid leukemia (AML), mutational activation of the receptor tyrosine kinase (RTK) Flt3 is frequently involved in leukemic transformation. However, little is known about a possible role of highly expressed wild-type Flt3 in AML. The proto-oncogene c-Cbl is an important regulator of RTK signaling, acting through its ubiquitin ligase activity and as a platform for several signaling adaptor molecules. Here, we analyzed the role of c-Cbl in Flt3 signal transduction and myeloid transformation. C-Cbl physically interacted with Flt3 and was tyrosine phosphorylated in the presence of Flt3-ligand (FL). Overexpression of a dominant-negative form of c-Cbl (Cbl-70Z) inhibited FL-induced Flt3 ubiquitylation and internalization, indicating involvement of c-Cbl in Flt3 signaling. DNA sequencing of AML bone marrow revealed a case with a c-Cbl point mutation (Cbl-R420Q). Cbl-R420Q inhibited Flt3 internalization and ubiquitylation. Coexpression of Cbl-R420Q or Cbl-70Z with Flt3 induced cytokine-independent growth and survival of 32Dcl3 cells in the absence of FL. Also, the mutant Cbl proteins altered the amplitude and duration of Flt3-dependent signaling events. Our results indicate an important role of Cbl proteins in Flt3 signal modulation. Also, the data suggest a novel mechanism of leukemic transformation in AML by mutational inactivation of negative RTK regulators.