Mismatch repair (MMR) deficiency is a common feature of acute lymphoblastic leukaemia (ALL) cell lines and in some cases is due to the mutations of hMLH1 which affect mRNA splicing. Therefore, we have analysed alternative splicing of hMLH1 in a cohort of children with ALL. We show that alternative splicing of hMLH1 is highly variable in normal and leukaemic cells and can occur by exon skipping or by the use of an alternative splice site, both serving to down-regulate the amount of full-length hMLH1 mRNA/protein produced. Aberrant splicing was found in one child with an aggressive leukaemia in which there was a predominant hMLH1Delta6 form and an associated loss of wild-type hMLH1 protein but this was not accompanied by microsatellite instability. Functional analysis of one of the most abundant spliced forms, hMLH1Delta9/10, was shown to have a significant dominant negative effect on the functionality of the MMR pathway but again was similarly expressed in ALL and normal cells.
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