Abstract 674

The interplay between genetic and epigenetic regulators is a fundamental mechanism to ensure gene regulation and cell fate decision. Hematopoiesis and leukemia are excellent systems in which to study this process. The Mixed-Lineage Leukemia (MLL) protein, a Set1-like H3K4 methyltransferase, and the heterodimeric transcription factor RUNX1 (AML1)/CBFβ are critical for definitive and adult hematopoiesis. They are required for the generation of all hematopoietic lineages and act as tumor suppressors in human leukemia. PU.1 is a critical downstream target gene for AML1 in adult hematopoiesis. AML1 regulated PU.1 through 3 AML1 binding sites in the PU.1 URE region (1). AML1 is responsible for the H3K4me3 mark at PU.1 URE and promoter region. AML1-ETO represses PU.1 expression through PU.1 URE region (2). Dysregulation of PU.1 levels cause leukemia in both mouse and human. PU.1 is absolutely required for the normal development of monocytic and B cell lineages, in which the core binding factor (CBF) fusions (CBFβ-SMMHC or TEL-AML1) or MLL fusions (MLL-AF9 or MLL-AF4) have been high frequently identified in human acute leukemias. These suggested that AML1/CBFβ and MLL might regulate PU.1 expression and AML1/CBFβ or MLL fusions might dysregulate PU.1 expression at genetic and epigenetic levels and eventually develop similar leukemias. We found that the AML1-ETO/CBFβ complex interacts with MLL in a similar manner as AML1/CBFβ (3), while the AML1/CBFβ-SMMHC complex interacts with MLL more strongly. Surprisingly, the CBFβ-SMMHC by itself interacts with MLL through the junction region of the fusion protein. The interactions with MLL by these fusion proteins complexes, AML1-ETO/CBFβ and AML1/CBFβ-SMMHC, correlate with their ability to maintain H3K4me3 levels at PU.1 URE and promoter regions in 416B cell lines stable expressing AML1-ETO or CBFβ-SMMHC. Taken together, our data indicate that AML1-ETO/CBFβ complex preserves the interaction with MLL, while the AML1/CBFβ-SMMHC complex enhances it. This suggests that these two leukemogenic fusions downregulate PU.1 expression through different epigenetic mechanisms in the presence of H3K4me3 mark at PU.1 regulatory region. The effects of these differential interactions on the H3K4me3 mark maintenance and on target gene expression, particularly PU.1, may be critical for the aberrant regulation that underlies the etiology of M2 and M4Eo acute myelogenous leukemia (AML).

1. Huang G, et al. Nat. Genet. 2008; 40: 51-60

2. Zhang P, et al. Blood 2008; 112: 594.

3. Huang G, et al. Blood 2008; 112: 282.

Topics:
complex, core-binding factor, fusion proteins, leukemia, leukemia, acute, leukemia, myelocytic, acute, methyltransferase, oncogene proteins, regulatory sequences, nucleic acid, staphylococcal protein a
© 2009 by The American Society of Hematology
2009
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