Date of Award
Master of Science
Microbiology and Immunology
Dr. Rodney DeKoter
Acute Myeloid Leukemia (AML) is associated with reduced levels or activity of the transcription factor PU.l in mice and humans. However, little is known about how reduced levels of this essential regulator of hematopoiesis causes AML. We hypothesize that reduced levels of PU.l cause AML by promoting self-renewal of myeloid progenitors through cell-cycle deregulation. Using mice homozygous for an allele of PU.l (encoded by Sfpil) which expresses PU.l at -20% of normal levels (Sfpilm/m), we show that these mice are runted and display an abnormal skeletal phenotype. This is due to an absence of TRAP+osteoclasts and a failure to upregulate p57kip2in chrondrocytes. In addition to the skeletal phenotype, a large expansion of immature myeloid cells occurs in the spleen of newborn SfpilBWm mice suggesting unregulated cell cycle in vivo. SfpilBN/BNmyeloid precursors had indefinite colony formation ability when grown in differentiating media, which suggests self-renewal. Next, restoration of PU.l using a retroviral vector opposed self-renewal and promoted differentiation in vitro seen by an increase in CDlib and a decrease in c-Kit levels. We have identified E2fl as a target gene of PU. 1, which regulates cell cycle progression. This model system will allow us to further understand the mechanisms behind hematopoiesis and leukemia. Manipulation of PU.l levels might be used as a treatment to promote myeloid differentiation and cell cycle arrest.
Gruca, Marek R., "THE ROLE OF THE TRANSCRIPTION FACTOR PU.l IN REGULATION OF SELF-RENEWAL IN ACUTE MYELOID LEUKEMIA" (2011). Digitized Theses. 3607.