Reversibility of acute B-cell leukaemia induced by BCR-ABL1

Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukaemias initiated by a chromosomal translocation. We have taken a new approach to determine if ablation of the genetic abnormality is sufficient for reversion by generating a conditional transgenic model of BCR-ABL1 (also known as BCR-ABL)-induced leukaemia. This oncogene is the result of a reciprocal translocation and is associated with different forms of leukaemia. The most common form, p210 BCR-ABL1, is found in more than 90% of patients with chronic myelogenous leukaemia (CML) and in up to 15% of adult patients with de novoacute lymphoblastic leukaemia (ALL). Efforts to establish a useful transgenic model have been hampered by embryonic lethality when the oncogene is expressed during embryogenesis, by reduced penetrance or by extremely long latency periods. One model uses the 'knock-in' approach to induce leukaemia by p190 BCR-ABL1(ref. 10). Given the limitations of models with p210, we used a different experimental approach. Lethal leukaemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR-ABL1expression, even after multiple rounds of induction and reversion. Our results demonstrate that BCR-ABL1is required for both induction and maintenance of leukaemia.     

beta-Carboline-3-carboxylic acid ethyl ester antagonizes diazepam activity

Analogous to the progression of events in the opiate receptor-enkaphalin area, the first reports that benzodiazepines have selective and specific high-affinity binding sites in brain have stimulated a search for the endogenous 'ligand' or substance that might normally act at these sites. Braestrup and co-workers have extracted from human urine a gamma-fraction (ref. 10) which they have recently identified as beta-carboline-3-carboxylic acid ethyl ester (beta CEE). They reported that this substance is extremely potent in displacing 3H-diazepam from brain binding sites and proposed that a beta-carboline-3-carboxylic acid derivative might, in part, be the endogenous ligand for the brain benzodiazepine receptor. We have examined several synthetically derived beta-carboline-3-carboxylic acid analogues and now present data obtained from testing only the beta CEE described by Braestrup et al. In addition to confirming these workers' observation that this compound is a potent displacer of 3H-diazepam from brain tissue, our pharmacological data indicate that beta CEE has activity that is opposite to, rather than similar to, that of diazepam.     

Saccharin preference of butyraldoxime-treated C57BL mice

Zusammenfassung Butyraldoxim, das in C57BL-Mäusen bevorzugtes Alkoholtrinken vermindert, wurde im 2-Wahl-Vorzugsversuch in Wasser oder Saccharinlösung verabreicht und führte zu keiner konditionierten Aversion. Das Ergebnis bestätigt die Hypothese, der Butyraldoxim-Effekt beruhe auf spezifisch metabolischer Wechselwirkung mit Alkohol.