Extensive alternative splicing of PAX5has been described in both malignant and normal B-cells and the existence of disease-specific isoforms has been suggested (Santoro et al, 2009). Disturbingly, the PAX5 isoform expression patterns observed were inconsistent between studies, even in normal B-cells. Thus, it has been questioned whether these variations result from an irreproducible pattern of PAX5 alternative transcripts or distinct expression patterns that are associated with specific B-cell malignancies (Borson et al, 2002; Robi-chaud et al, 2004; Sadakane et al, 2007; Sekine et al, 2007).
While a recent study did not reveal any significant differences in thePAX5transcript patterns between normal and cancerous B-lymphocytes derived from chronic lymphocytic leukaemia and lymphoma (Arseneauet al, 2009), others claim that either a higher number or even leukaemia-specific isoforms are expressed in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) (Santoroet al, 2009).
Our own observation – that paediatric BCP-ALL bone marrow (BM) samples which had been shipped overnight expressed higher numbers of isoforms – and previous studies suggesting that ‘ageing’ of blood or cold shock conditions may induce illegitimate splicing (Gaytheret al, 1997; Arset al, 2000;
Wimmeret al, 2000; Liuet al, 2010) prompted us to investigate the expression ofPAX5isoforms under such stress conditions.
The analysis ofPAX5isoforms in cells isolated from freshly drawn blood from healthy donors as compared to those of
‘aged’ lymphocytes isolated from blood which was left at room temperature (RT) for 1–4 d (for details see Appendix S1), irrespective of the anticoagulant used, reproducibly revealed a progressive increase of alternative splice variants at the expense of full-length (FL) PAX5transcripts (Fig 1A, B). Both alter-native FL-PAX5transcripts comprising exons 1A-10 or exons 1B-10 (Fig 1A, B) were affected in the same way, and separate amplification of either the 5¢ region (exons 1A-6) or the 3¢
region (exons 5–10) of PAX5 (Fig 1C, D) verified this observation.
Although in fresh samples inter-individual differences in the PAX5expression patterns were found, FL-PAX5was always the predominant isoform. In our hands also the cell lines NALM6 and REH expressed mainly FL-PAX5, no matter which culture conditions, including starvation and suboptimal cell densities (for details see Appendix S1), were used (data not shown).
However, incubation of the B-cell line RAJI at RT for 24 or 48 h induced the expression ofPAX5isoforms and subsequent re-cultivation at 37!C reversed this process (Fig 1E), support-ing the hypothesis of cold shock-stimulated illegitimate splicing. These data corroborate the recent finding that FL-PAX5is always the predominant isoform (Arseneauet al, 2009), but contradict earlier studies in whichPAX5variants, rather than FL-PAX5, were expressed in some B-cell lines (Robichaudet al, 2004; Arseneauet al, 2009).
Cloning and sequencing of a number of splice variants amplified from ‘aged’ normal lymphocytes revealed that all isoforms identified corresponded to those previously described (Borson et al, 2002; Robichaud et al, 2004; Arseneau et al, 2009), including transcripts with various deletions of exons such as D2, D7/8, D2/7/8, D2/7/8/9, D2/4/8, and D2/3/4/8.
Importantly, also the PAX5D2 isoform, which has been recently suggested to play a role in the development of BCP-ALL (Santoro et al, 2009), was readily expressed in ‘aged’
normal lymphocytes.
The basis for age- and temperature-induced missplicing has not been studied in detail yet. Nevertheless, it has been proposed that the fidelity of splicing – at least for some genes – is affected in ‘aged’ lymphocytes (Wimmer et al, 2000; Liu et al, 2010), rather than caused by a general RNA degradation.
Accordingly, the transcript patterns of HPRT1, IKZF1, and RUNX1 were not affected by ‘ageing’ of the samples (Fig 1F–H). Together, these data strongly suggest that in
‘aged’ blood,PAX5is prone to abnormal isoform expression.
To further substantiate that PAX5 isoform expression patterns in BCP-ALL may be altered dependent on the elapsed
ª2011 Blackwell Publishing Ltd,British Journal of Haematology,155,268–280 277
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