Combined effects of the two reciprocal t(4;11) fusion proteins MLL.AF4 and AF4.MLL confer resistance to apoptosis, cell cycling capacity and growth transformation.

The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL.AF4, AF4.MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.

[Improving the visibility of intracranial vessels with the echo-enhancing substance Levovist in duplex sonography]. / Verbesserung der Darstellbarkeit intrakranieller Gefässe mit farbkodierter Duplexsonographie durch den Echosignalverstärker Levovist.

AIM: To evaluate the diagnostic advantages of Levovist for contrast enhancement of intracranial arteries in a routine clinical setting. METHOD: Routine cerebrovascular extracranial Doppler- and duplex-sonography was performed in 3990 patients (1791 female, 2189 male, mean age 50.4 years). In addition 879 trans-temporal, 990 trans-foraminal and 99 trans-orbital trans-cranial colour-coded duplex investigations were performed on these patients. Signal quality was classified in the categories: 'no signal', 'insufficient signal' and 'sufficient signal'. Patients classified as having 'no' or 'insufficient' signal quality underwent an additional examination after application of Levovist. RESULTS: 879 patients underwent trans-temporal examination. In 89 (9.1%) of these patients signal quality in the trans-temporal examination proved to be insufficient, thus indicating the use of Levovist. 346 of the examined vessels (72%) were originally classified as showing 'no signal'; this number could be reduced to 82 (23.9%) after applying Levovist. Of the 99 arteries (21%) falling into the category 'insufficient signal', only 4 (4%) did not show signal improvement after application of Levovist. 990 patients were examined by the trans-foraminal approach, and Levovist was given to just 26 patients (2.6%). Without enhancement, 20 basilar arteries (77%) showed 'no' or 'insufficient' signal, whereas after injecting Levovist only 4 (13.25%) remained in these categories. Of 13 vertebral arteries (25%) with 'no' or 'insufficient' signal intensity, 3 (5.8%) showed no improvement in imaging quality after application of Levovist. CONCLUSION: Imaging problems of intracranial arteries are dramatically reduced by Levovist.