Abstract
Introduction Acute leukemia is characterized by abnormalities affecting the self-renewal of hematopoietic stem cells and differentiation of myeloid or lymphoid lineages. Our lab is focused on developing a better understanding of the biology of acute leukemias involving the KMT2A-MLLT3 fusion that is commonly found in pediatric leukemias. Methods/Results By transducing healthy CD34+ cord blood cells with the KMT2A-MLLT3 fusion and xenografting them into immunodeficient mice, we can generate human acute leukemias where the genetic background of the initial donor is defined. We have used this model system to interrogate the epigenetic changes that occur at the earliest stages of leukemogenesis, something which is not possible with patient samples. Interestingly, two distinctive DNA methylation patterns were observed in model myeloid and lymphoid samples, although acute leukemias can arise from the same molecular events. Furthermore, our ChIP-seq and ATAC-seq data revealed that the KMT2A-MLLT3 induction has a significant impact on chromatin rearrangement and distribution of histone marks. By correlating these epigenetic data with gene expression data from patient and model leukemic cells, we identified novel potential biomarkers that are specifically highly expressed and epigenetically regulated in KMT2A-rearranged leukemias. The pharmacological inhibition of one of these genes, encoding a GPCR, leads to significant apoptosis in leukemic cell lines highlighting its essential role in leukemogenesis. Conclusion An epigenetic reprogramming is required for KMT2A-MLLT3 acute leukemia development. This study also highlights novel biomarkers that are not only of potential clinical interest, but also likely reflect important aspects of the underlying biology of KMT2A-translocated leukemias.
Published Version
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