PROJECT SUMMARY

Our understanding of the development of blood cancers in general, and myelodysplastic syndromes (MDS) in particular, has improved markedly over the past decades. Importantly, the finding that specific mutations are sequentially acquired in individual genes has shed light on how blood cancers develop from healthy blood cells. The Majeti lab has contributed to our understanding of blood cancer development by identifying the initiating mutations in blood stem cells, termed pre-leukemic stem cells. Others have subsequently shown similar findings, and importantly were able to show that these initiating mutations can even be found in a significant proportion of healthy individuals, a condition termed clonal hematopoiesis. In these individuals, blood stem cells carrying these initiating mutations can ultimately lead to the development of myeloid malignancies, but in most cases do not. One of the frequently mutated genes in clonal hematopoiesis is ASXL1, which is thought to act as a regulator for how genes are activated. In patients with myeloid malignancies including MDS, the presence of a mutation in ASXL1 is associated with very poor prognosis including poor treatment response. Our understanding of ASXL1 mutations remains limited, most likely due to the lack of representative model systems, and to date, no treatment approaches for blood cancers with mutant ASXL1 have been developed. The goal of this project is thus to:

1. Develop a better understanding of how mutations in ASXL1 change the function of the protein
2. Determine whether external stressors such as inflammation or the availability of stem cell niches contribute to the development of ASXL1-mutant malignancies
3. Determine whether a computational approach developed in the Majeti lab based on synthetic lethality might yield promising therapeutic targets for ASXL1-mutant malignancies

Recently, we have developed a novel model of mutant ASXL1 using primary human blood stem cells from normal donors. We are able to efficiently introduce mutations into the ASXL1 gene, and are able to show that the presence of the mutation alters the behavior of these blood stem cells, by initiating increased expansion of myeloid blood precursors. In addition, using a xenograft mouse model and our modified cells, we show that our model allows for the development of disease in a subset of mice – similar to the finding in humans that only a subset develop myeloid malignancies while most do not. This model uniquely allows us to advance our understanding of mutant ASXL1 and potentially develop therapeutic strategies.