Denzi Research Laboratory

Denzin Lab

Research Area 1Research Area 2

RESEARCH AREA 2:  The p15Paf oncogene

Specific recognition of MHC-peptide complexes results in extraordinary T cell proliferation, with doubling occurring approximately every 2–4 hours.  Data from my lab suggested that a poorly characterized PCNA interacting protein, p15PAF, might play role a role in this rapid expansion of antigen specific T cells.  Intriguingly, p15Paf, has also been shown to be substantially up-regulated in virtually every type of cancer and studies support that p15Paf is itself an oncogene. 

To determine the in vivo function of p15Paf in the immune system, my lab generated p15Paf deficient mice.  Genetic disruption of p15Paf by homologous recombination resulted in altered hematopoietic stem cell (HSC) function and subsequent progenitor development, directly impacting the peripheral T and B cell compartments.  Moreover, p15Paf controls the regulated proliferation of HSCs, keeping long-term-HSCs quiescent and protecting them from premature exhaustion.  Our results also show that p15Paf is necessary for the survival of Lymphoid primed multipotent progenitor and common lymphoid progenitor populations (Figure 5).

p15Paf is, therefore, a key regulator of HSC quiescence and multipotent progenitor differentiation and development.  Unlike many factors that have been shown to control HSC development, p15Paf does not appear to be a transcription factor, suggesting it works via a novel mechanism.  Indeed, recent microarray analyses of p15Paf deficient and wild type long-term HSCs suggest that p15Paf controls hematopoiesis via novel mechanisms.  Identification of how p15Paf functions to maintain effective hematopoiesis will likely yield information relevant for the treatment of cancers such as childhood leukemia and lymphoma. 

Research Goals:  Collectively, our studies have established an important role for p15Paf in HSC development and function.  Our long-term goals are to define the molecular mechanisms by which p15Paf functions in regulating hematopoiesis, immune cell development and function and tumorgenesis.