In summary, genome-wide DNA methylation profiling enabled us to separate pre-B ALL according to major subtypes, to map epigenetic biomarkers specific for the t(12;21) subtype, and through a combined methylome and transcriptome approach to identify downstream effects on candidate drivers of leukemogenesis.
In B-ALL KIBRA methylation was associated with ETV6/RUNX1 [t(12;21) (p13;q22)] chromosomal translocation (p = 0.0082) phenotype, suggesting that KIBRA may play an important role in t(12;21) leukemogenesis.
This indicates that the t(8;21) and t(12;21) fusion proteins inhibit transcriptional activation by the AML-1 transcription factor family, and in so doing contributes to leukemogenesis.
Thus, the t(12;21) fusion protein dominantly interferes with AML-1B-dependent transcription, suggesting that the inhibition of expression of AML-1 genes is critical for B-cell leukemogenesis.
The TEL-AML1 fusion RNA was found in all patients with the t(12;21) whereas the reciprocal AML1-TEL transcript was only found in a subset of patients, suggesting that only the protein product encoded by TEL-AML1 is likely to play a role in leukemogenesis.