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MYST3/CREBBP (MOZ/CBP) and CREBBP/MYST3 (CBP/MOZ) transcripts in AML with t(8;16)(p11;p13)

We read with interest the article by Rozman et al. (2004) on acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13). In this study, a previously described (Panagopoulos et al., 2000) as well as a new RT-PCR assay (Rozman et al., 2004) were applied to detect the t(8;16)(p11;p13)-specific MYST3/CREBBP (MOZ/CBP) and CREBBP/ MYST3 (CBP/MOZ) fusion transcripts. In response to this study, we would like to make the following comments. First, for the detection of MYST3/CREBBP types I and II fusion transcripts, a two-step RT-PCR reaction was performed (Rozman et al., 2004) using the constant MYST3 forward primer MOZ3558F and the nested CREBBP primers CBP1201R and CBP1047R. The first CREBBP reverse primer, CBP1201R, was initially described (Panagopoulos et al., 2000) in the wrong orientation and subsequently used in the study by Rozman et al. (2004). Due to the forward orientation of this primer, the reaction is unable to amplify either the type I or the type II MYST3/CREBBP transcript. We recently studied four AML cases with t(8;16)(p11;p13) (Schmidt et al., 2004) using the same one-step RT-PCR reaction for the MYST3/CREBBP types I and II transcripts as initially described (Panagopoulos et al., 2000), but with the MYST3 forward primer MOZ3558F and the correct CREBBP reverse primer, CBP1201R, 5 -GTTGCAATTGCTTGTGTGGGTAC-3 , and were able to amplify both MYST3/CREBBP fusions in only one of three positive cases (Schmidt et al., 2004). Subsequently, Rozman et al. (2004) developed a more sensitive one-step RT-PCR assay for the detection of the MYST3/CREBBP type I transcript, and with a similar approach, we were able to amplify the MYST3/ CREBBP type I transcript in three of our four cases (Schmidt et al., 2004). Second, in the study by Rozman et al. (2004), the reciprocal CREBBP/MYST3 fusions were not detected in any of the six MYST3/CREBBP-positive cases, in contrast to the finding that all five MYST3/ CREBBP positive cases (type I with or without type II transcript) in two other studies (Panagopoulos et al., 2000; Schmidt et al., 2004) showed reciprocal CREBBP/MYST3 fusion transcripts. It cannot be excluded that this discrepancy is due to technical reasons. This question has some relevance, as it is still unclear whether it is the MYST3/CREBBP or the CREBBP/MYST3 transcript that is relevant for leukemogenesis. One study (Borrow et al., 1996) revealed an in-frame MYST3/CREBBP fusion concomitant with an out-of-frame CREBBP/MYST3 fusion, whereas another (Panagopoulous et al., 2002) identified an alternative MYST3/CREBBP fusion without the reciprocal CREBBP/MYST3 fusion. In the other five cases with reciprocal RNA chimeras, in-frame MYST3/CREBBP as well as in-frame CREBBP/MYST3 fusions harboring functional protein domains were found (Panagopoulos et al., 2000; Schmidt et al., 2004). Thus, more cases need to be analyzed for identification of the relevant pathogenetic fusion transcript in this entity. Third, the breakpoints in CREBBP chimeras are not solely restricted to CREBBP intron 2, but have also been reported in intron 3 in cases with t(8; 16)(p11;p13) as well as in cases with other translocations involving CREBBP (Schmidt et al., 2004). Apart from these comments, we fully agree with Rozman et al. (2004) that the breakpoints in t(8; 16)(p11;p13)-positive leukemias seem to cluster in MYST3 intron 16 and CREBBP intron 2. The described RT-PCR reactions for the reciprocal fusion transcripts may be valuable for the routine detection of t(8;16)(p11;p13) in AML FAB M4/5.