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Background  Translocations of the  Mixed Lineage Leukemia  ( MLL ) gene occur in a subset (5%) of acute myeloid leukemias (AML), and in mixed phenotype acute leukemias in infancy - a disease with extremely poor prognosis. Animal model systems show that  MLL  gain of function mutations may contribute to leukemogenesis. Wild-type (wt)  MLL  possesses histone methyltransferase activity and functions at the level of chromatin organization by affecting the expression of specific target genes. While numerous MLL fusion proteins exert a diverse array of functions, they ultimately serve to induce transcription of specific genes. Hence, acute lymphoblastic leukemias (ALL) with  MLL  mutations ( MLL mu) exhibit characteristic gene expression profiles including high-level expression of  HOXA  cluster genes. Here, we aimed to relate  MLL  mutational status and tumor suppressor gene (TSG) methylation/expression in acute leukemia cell lines.    Results  Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification assay), methylation of 24 different TSG was analyzed in 28  MLL mu and  MLL wt acute leukemia cell lines. On average, 1.8/24 TSG were methylated in  MLL mu AML cells, while 6.2/24 TSG were methylated in  MLL wt AML cells. Hypomethylation and expression of the TSG  BEX2, IGSF4  and  TIMP3  turned out to be characteristic of  MLL mu AML cell lines.  MLL wt AML cell lines displayed hypermethylated TSG promoters resulting in transcriptional silencing. Demethylating agents and inhibitors of histone deacetylases restored expression of  BEX2, IGSF4  and  TIMP3 , confirming epigenetic silencing of these genes in  MLL wt cells. The positive correlation between  MLL  translocation, TSG hypomethylation and expression suggested that  MLL  fusion proteins were responsible for dysregulation of TSG expression in  MLL mu cells. This concept was supported by our observation that  Bex2  mRNA levels in  MLL-ENL  transgenic mouse cell lines required expression of the  MLL  fusion gene.    Conclusion  These results suggest that the conspicuous expression of the TSG  BEX2, IGSF4  and  TIMP3  in  MLL mu AML cell lines is the consequence of altered epigenetic properties of  MLL  fusion proteins.

Hypomethylation and expression of BEX2, IGSF4 and TIMP3 indicative of MLL translocations in Acute Myeloid Leukemia