There are three main related projects in the laboratory:
1. Genetic control of cell intrinsic and environmental factors that regulate stem cell quiescence at steady state and during regenerative hematopoiesis.
The fate of hematopoietic stem cells can take different turns at the end of the cell cycle: differentiation, self-renewal, death, senescence (irreversible cell-cycle arrest), or quiescence (Figure 2). Quiescence is a reversible cell cycle arrest that protects tissue-specific progenitor cells from differentiation and metabolic/genetic damage. The observation that growth factors increase metabolic activity and cell proliferation supported for many years the paradigm that quiescence is a default state due to absence of nutrients. However, the emerging model is that both cell intrinsic factors and environmental cues actively regulate quiescence in specialized niches. We previously described that the transcription factor ELF4 negatively regulates HSC quiescence during homeostasis but not during regenerative hematopoiesis (Cancer Cell, 2006). We are currently investigating additional regulators of stem cell quiescence using loss-of-function mouse models.
2. Transcriptional regulation of development, function, and maintenance of memory T cells.
Following infection, antigen-specific naïve T-cells expand to eradicate a pathogen and most die shortly after to restore homeostasis, with exception of a small number of T cells that remains as immunological memory (Figure 3). The mechanism underlying longevity of memory T cells is largely unknown although believed to resemble the process of stem cell self-renewal. We described that the transcription factor ELF4 induces cell cycle arrest in naïve T cells by activating the tumor suppressor KLF4 downstream of the T cell receptor (TCR) and the mammalian target of rapamycin (mTOR) signaling (Nature Immunology, 2009; Journal of Immunology, 2010). Thus, loss of ELF4 leads to increased immunological memory induced by vaccination with peptide-pulsed dendritic cells. We are further investigating the role of genes regulated by ELF4 or KLF4 in the development and maintenance of memory T cells.
3. Role of proliferation brakes in the development of pediatric acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is the most prevalent hematological malignancy in children. Even though these patients have good prognosis, still 20-25% relapse after standard treatment, the most common cause of cancer-related deaths in children. The lack of clear understanding of ALL pathobiology is a major roadblock in the development of alternative therapies for high-risk patients. Even though specific chromosomal translocations and mutations have been identified in ALL patients, these cannot faithfully recapitulate human disease in mouse models suggesting that the outgrowth of pre-leukemic cells might require cooperative genetic aberrations. We are testing whether inhibitors of T cell proliferation are inactivated in leukemic cells to promote expansion of pre-leukemic cells and tissue invasion in organs such as central nervous system and testis. To test this hypothesis, we are generating several leukemic mouse models of acute lymphoblastic leukemia by deleting specific genes before and after retroviral transformation of bone marrow cells (Figure 4). Identification of cooperative genes will provide novel molecular targets to develop new therapeutic approaches for relapsed patients.