Muntean Lab

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Research Interests

Broadly, the Muntean lab is interested in the epigenetic and transcriptional mechanisms driving acute myeloid leukemia and how these differ from normal blood cell development (hematopoiesis). We aim to define the molecular events that are critically required in leukemic cells, so that they may be exploited for better treatments for leukemia patients. We have focused our efforts on an epigenetic regulator complex, the Polymerase Associated Factor complex (PAFc), that we have shown is necessary for leukemogenesis. The PAFc critical role in regulating the transcription of specific gene sets, however the regulation of function of the complex in leukemia cells is not well understood. The major ongoing projects in the lab are in the following areas:

The transcriptional targets of the PAFc facilitating acute myeloid leukemia

Our laboratory has developed a mouse model of MLL-rearranged leukemia that is commonly found in infant and childhood leukemias. Using this in vivo model, as well as several cell-based model systems and high throughput DNA sequencing analysis we are investigating the gene expression program initiated and maintained by the PAFc in leukemic cells and how these contribute to the disease. We have discovered that the PAFc maintains a gene program that blocks myeloid differentiation of hematopoietic progenitor cells. We are currently exploring this program to determine how these individual target contribute to disease.

The biochemical regulation of the PAFc in normal and malignant blood cells

We have developed a mouse model carrying a conditional allele of the PAFc subunit cdc73. Using this resource we have been able to probe the structural make up of the PAFc in leukemic cells, as well as identifying novel protein interactions. We are aiming to identify and characterize novel PAFc-protein interactions that are used by the cell to regulate PAFc function during normal hematopoietic development. For example, we have characterized a direct protein interaction between the PAFc and the histone H3K4 methyltransferase MLL. Interestingly, we have found that leukemic cells are exquisitely sensitive to disruption of this interaction while normal hematopoietic stem cells remain less sensitive. We envision disruptions to these normal molecular mechanisms contribute to stalled differentiation and leukemia.

PAFc function in normal hematopoiesis

Using mouse models containing hematopoietic specific Cre drivers to study hematopoietic stem cell function, studies are aimed at understanding how the PAFc controls the self-renewal and/or differentiation of hematopoietic stem cells, progenitors and mature blood cells. These studies have uncovered a role for the PAFc in hematopoietic stem cells. The long-term goal of this project is to characterize the role of the PAFc in normal hematopoiesis and identify those epigenetic and transcriptional mechanisms that show differential requirements in normal and malignant hematopoiesis, which may serve as therapeutic targets for better leukemia treatment.