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Reactivation of transposable elements as novel enhancers in cohesin-mutant myeloid malignancies

Dr. Jann

Johann-Christoph Jann


Dana-Farber Cancer Institute

Project Term: July 1, 2023 - June 30, 2026

The reason why some patients with clonal hematopoiesis progress to overt myeloid malignancies is not understood. I will revert epigenetic changes in isogenic in-vitro and in-vivo models of stepwise progression of cohesin-mutant myeloid neoplasia to mechanistically address how changes in genome organization and enhancer regulation drive clonal selection. These studies will improve our understanding of myeloid disease progression and inform therapeutic options to intercept this step.

Lay Abstract

It takes years for leukemia cells to become dominant over healthy blood-producing cells in patients. Although we now have very detailed information about the genetic alteration in these cancer cells, the process that eventually selects the most aggressive cells is not well understood. Inflammation is increasingly thought to be critically important during this often very long-lasting process of disease development. A typical human cell contains about 2 meters of genetic material, which must be tightly packed to fit into the small nucleus of a cell. Cohesin complex is an essential cellular protein complex that controls organization of our genetic material. Patients with specific subtypes of leukemia that carry mutations in the cohesin complex lose the normal function of this complex and often have very poor outcomes. In our experiments using cells from leukemia patients and mouse models of blood cancer, we have recently found that cells with deficient cohesin proteins have high levels of inflammation. We believe that over a long time this could be the main mechanism that helps select for the most aggressive leukemia cells. Furthermore, cohesin loss is coupled with reopening of otherwise highly packed “dark” regions of the genome. We found that such regions are also becoming active in patients with leukemia. Activation of these dark regions of the genome has the potential to change gene expression programs in blood cancer cells and accelerate their growth. In the proposed project, I will plan to characterize these unpacked dark regions of the genome that may control gene expression across different leukemia patient samples. Once I identify the critical regions I will use cutting-edge genome engineering tools to re-silence these regions and test the rate of leukemic transformation and impaired blood production using mouse models that recapitulate leukemia disease development. In summary, improving our understanding of mechanisms of genome organization and inflammation has the potential to inform novel therapeutic approaches to cure leukemia.

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