We showed that DAP kinase
was frequently methylated in MM samples, whereas p14
were not. Therefore, abrogation of the putative tumour suppressor genes involved in the DAP kinase
‐related apoptotic pathway in some cases might collaborate with other antiapoptotic signals from the microenvironment to enhance the survival of neoplastic plasma cells.1,2
Moreover, as concomitant abrogation of multiple tumour suppressors of this apoptosis pathway does not confer additional survival benefit, our findings suggested that hypermethylation of tumour suppressor components of this apoptosis pathway appears to be mutually exclusive.
Despite the sensitivity of DAP kinase MSP being only 1 in 103, the methylation status of the neoplastic plasma cells should preferably be studied by CD138‐sorted plasma cells.
- Death‐associated protein (DAP) kinase, a tumour suppressor gene regulating p53‐mediated apoptosis, is potentially important in myeloma pathogenesis because of its frequent methylation.
- DAP kinase hypermethylation might be of prognostic significance.
In the myeloma cell lines WL2 and HS‐Sultan, DAP kinase hypermethylation was associated with the absence of transcript, which was re‐expressed after 5‐AC treatment. As 5‐AC is a DNA methyltransferase inhibitor, and thus a demethylating agent, re‐expression of the transcript after 5‐AC treatment confirmed gene silencing‐associated gene promoter hypermethylation.
In this study, DAP kinase hypermethylation was associated with an inferior OS but not with Durie–Salmon stage. The latter could be due to the retrospective nature of the study, the small number of patients and the heterogeneity of treatment. For instance, 29 (52.7%) of our patients have undergone bone marrow transplantation. Therefore, the prognostic value of DAP kinase methylation needs verification in future prospective clinical trials with a larger number of patients receiving uniform treatment.
The oncogenic role of DAP kinase/p14/Apaf‐1
has been demonstrated in previous studies. DAP kinase expression was shown to suppress the metastatic potential of tumour cells in animal models.21
Modest frequency of DAPkinase
hypermethylation (10–20%) has been identified in lung, colon, and head and neck cancers.22
In contrast, frequent (66–72%) DAP kinase
hypermethylation was demonstrated in B‐cell lymphoma and MM.23,24
Moreover, DAP kinase
has been shown to be methylated in patients with monoclonal gammopathy of undetermined significance at a frequency comparable with that with MM.25p14
hypermethylation was found in 10–30% of renal, gastric and colorectal cancers.22
In haematological malignancies, p14
hypermethylation was present in 40% of chronic myeloid leukaemia cases in acceleration,26
but in only 8% of acute lymphoblastic leukaemia cases,27
and in none of the therapy‐related myelodysplastic syndrome/acute myeloid leukaemia cases.28
In MM, one previous study showed p14
hypermethylation in 9% of the patients.29
The infrequent p14
hypermethylation was consistent with results from another study, which showed p14 expression in MM.30
Furthermore, as the p14/p16
locus was not found to be deleted in MM,31p14
does not appear to be targeted in MM. Finally, while hypermethylation of Apaf‐1
has been detected in melanoma,32
and recently in leukaemia,26
this is the first report demonstrating the absence of Apaf‐1
hypermethylation in MM.
In conclusion, of the putative tumour suppressor genes in the DAP kinase/p14/HDM2/p53/Apaf‐1 apoptosis pathway, only DAP kinase is frequently methylated in MM, which is associated with gene silencing. p14 and Apaf‐1 were not methylated in MM. The high sensitivity of DAP kinase MSP might be a useful marker for monitoring of minimal residual disease.