Epigenetic Regulation of Hematopoiesis and Acute Leukemia

In this thesis we have explored chromatin regulation in acute leukemia and normal hematopoiesis. In doing so, we have focused on the H3K4 methyltransferase MLL1 and the H4K16 acetyltransferase MOF. MLL- and NUP98-translocations are quite common in acute leukemia and even more frequently found in certain forms of pediatric leukemia.
In Chapter 2 we discuss the current science and views with regard to therapeutically targeting the cancer epigenome.
In Chapter 3 we have shown that NUP98 fusion proteins encoded by NUP98 fusion genes such as NUP98-HOXA9 and NUP98-NSD1, physically interact with MLL1 and the NSL histone modifying complexes. Further functional assays indicate that MLL1 is crucial for NUP98-fusion leukemogenesis by recruiting the NUP98 fusion protein to its target gene loci.
In chapter 4 we have explored the role of MOF histone acetyltransferase activity in MLL-AF9 leukemogenesis and found MOF’s acetyltransferase activity to be indispensable for leukemia maintenance. In a normal hematopoietic context we found MOF histone acetyltransferase activity to be required for adult, but not early fetal hematopoiesis in mice.
These findings are discussed in chapter 5 and are further proof of how chromatin regulators are differentially involved at varying stages of hematopoietic development. Altogether we believe our findings indicate that both the MLL1 and MOF epigenetic pathway are candidate drug targets for NUP98-rearranged and MLL-rearranged leukemia respectively.