Molecular Modulators of Hematopoiesis and Leukemogenesis

Abstract

Hematopoietic stem and progenitor cells proliferate and differentiate to reconstitute all lineages of functional blood cells. They are regulated by intricate cellular and molecular signals, on both genetic and epigenetic levels. Alterations in these regulatory signaling networks can lead to hematopoietic dysfunction, as well as transformation of hematopoietic cells and induction of leukemogenesis. This thesis focuses on uncovering molecular modulators that are crucial for the proper regulation of hematopoietic stem/progenitor cells. In Chapter II, I describe studies investigating functional roles of the histone demethylase UTX in normal and malignant hematopoiesis, using a short hairpin RNA-mediated knockdown approach. My data revealed that UTX is required for proliferation, self-renewal and differentiation of hematopoietic progenitor cells ex vivo through transcriptional regulation of hematopoiesis- specific transcriptional factors. I also discovered that UTX is critical for the proliferation of leukemia cells, implicating UTX as a possible target for clinical therapy. In Chapter III, I focus on understanding the process of leukemogenesis by generating and characterizing a novel model of myeloid sarcoma and acute myeloid leukemia in mice. This model induces these hematopoietic malignancies by introduction of multiple oncogenetic lesions (specifically, p16/p19-/-;Kras(G12V)) into bone marrow cells, and subsequent transplantation of these gene-modified cells into immunodeficient NOD.SCID mice. This model is very rapid and reproducible, and represents the first transplantable myeloid sarcoma model reported. Moreover, the disease induced in mice recapitulates the pathological progression of myeloid sarcoma in patients, providing a powerful model for dissection of critical leukemogenic events and discovery of new candidate therapeutic targets. Together, these studies help to reveal novel molecular modulators required for normal hematopoiesis, and offer potential animal model and drug target for therapeutic applications.