A novel model for differentiation therapy of leukaemia [Abstract]

Zaker, F., May, A., Al-Sabah, AIa and Burnett, Alan Kenneth 1996. A novel model for differentiation therapy of leukaemia [Abstract]. British Journal of Haematology 93 (S2) , p. 43. 10.1111/j.1365-2141.1996.tb08988.x

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Abstract

The evaluation of established and potential differentiation inducers as antileukaemic agents requires the ability to study their effects both in vitro and in vivo. Chemically induced rat erythroleukemia cell lines have a natural host (Long Evans rats) thereby providing a potentially useful model system. To explore this possibility three different cell lines (RELC7, RELCl and D5A1) were studied for in vitro proliferation and differentiation and two of them (RELC7 and D5A1) for in vivo tumorigenicity. Using inducers of differentiation (DMSO and HMBA) a dose-dependent inhibition of proliferation was observed in vitro, the clonogenic potential of the cells was suppressed and FACS analysis showed accumulation in the GO/Gl phase of the cell cycle. D5A1 produced the most overt signs of erythroid differentiation (decreased cell size, changes in nuclear morphology and haemoglobin production) and the greatest decrease in cell numbers. Gene expression changes were analysed by Northern blot. All three showed induction of ALAS-E mRNA by day 2, subsequently increasing markedly only in D5A1. D5A1 also showed a simultaneous decrease in ALAS-N mRNA. The two oncogenes, c-myc and c-myb, thought to be involved in both proliferation and differentiation, were studied first. In the presence of inducer c-myc mRNA levels decreased transiently (after 2 hr in D5A1 and after 4 hr in RELC7/RELCl) returning to control values by 24 hr. c-myb mRNA levels also showed a transient decrease, returning to and staying at control values in RELC7/RELCI but decreasing again in D5A1. That the early decrease in c-myc mRNA has functional significance is suggested by a corresponding but proportionally smaller decrease in intracellular c-myc protein levels. Significant effects on tumorigenesis were observed after in vitro treatment of the cells with inducer. Kaplan Meier survival curves and the log rank statistic were used to assess differences over time of cumulative tumour development. In two separate experiments treatment of D5A1 with HMBA in vitro for up to 4d caused a time-related decrease of tumorigenicity detectable by 48 hr treatment. In vitro treatment for 4-5d of RELC7 with DMSO likewise inhibited tumorigenesis (x2 experiments). These data demonstrate that this combination of cell lines and their in vivo host provides a useful model for the study of molecular events involved in leukemogenesis and the action of differentiation agents in the treatment of leukaemia.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Additional Information:	Supplement 2. Abstracts of papers presented at the Second Meeting of the European Haematology Association, Paris, France, 29 May-1 June 1996. Article 170.
Publisher:	Wiley-Blackwell
ISSN:	0007-1048
Last Modified:	18 Sep 2017 09:49
URI:	https://orca.cardiff.ac.uk/id/eprint/58809

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