| Leukemia is the most common form of cancer among children and adolescents, and approximately 2,000 infants per year are diagnosed within their first year of life. Infant survival rates are poor, reaching only 25-45% with current chemotherapy regimens. The Mixed Lineage Leukemia (MLL) gene translocation is present in 70-80% of infant leukemia cases and is the most significant biomarker for poor prognosis. MLL-gene translocations produce oncogenic fusion proteins, such as MLL-AF9 that bind and overactivate transcription of genes involved in normal hematopoiesis. One such gene that the MLL-AF9 fusion protein directly binds is MDS1-EVI1 (Myelodysplastic Syndrome-Ecotropic Virus Integration Site 1), a transcription factor critical for normal hematopoiesis. For our first aim, we determined whether MDS1-EVI1 DNA binding via specific zinc finger domains is required for MLL-AF9 leukemogenesis and identified genome-wide target genes. We discovered that MDS1-EVI1 DNA binding via its Zinc Finger 1 domain, is necessary for the development of MLL-AF9 leukemia in a mouse model. Using high-throughput sequencing techniques we identified several interesting key genes involving embryogenesis and cellular proliferation to be markedly upregulated in MDS1-EVI1 positive MLL- infant leukemia cells from primary patients. Furthermore, we found several target genes to be significantly overexpressed that may serve as potential druggable targets for novel therapies, or even potentially existing drug compounds. Furthermore, we explored whether MDS1-EVI1 HMT activity contributes to MLL-leukemia. For our second aim, we examined whether MDS1-EVI1 PR-domain HMT activity was aberrant in MLL-leukemic cells. A histone methyltransferase (HMT) assay did not demonstrate a significant difference in HMT activity in the presence of the MDS1-EVI1 PR-domain, and thus is not likely the major driving force of the PR-domain that induces MLL-leukemogenesis. In conclusion, we elucidated the one of the main mechanism by which MDS1-EVI1 contributes to malignant transformation in MLL-infant leukemic cells, and have identified critical molecular genes and pathways that may serve as future druggable targets. |
