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Our laboratory is focusing on the following topics:
Maintaining the stability of the genome is critical to cell survival and normal cell growth. The faithful repair of DNA damage, such as chromosomal double strand breaks (DSBs), is critical to preserving genomic integrity. Aberrant DSB repair results in chromosomal rearrangements − including translocations − that in turn promote mutagenesis, malignant transformation or cell death.
In contrast to terminally differentiated cells, stem cells pass on genetic mutations to progeny cells. Thus, mutations in somatic stem cells can lead to disease in more differentiated cells, or might be a first step in a “multihit” progression toward disease, especially in stem cell tissues like the hematopoietic system, skin or intestine. So far, there has been little evaluation of the role of DNA repair processes in the maintenance of both the hematopoietic stem cell phenotype and the long-term repopulation capacity after DNA damage. We assume that hematopoietic stem cells use DNA repair pathways in a unique fashion to protect their genome.
Hematopoietic stem and progenitor cells (HSPCs) reside in adult bone marrow (BM) and are largely absent from peripheral blood (PB). Systemic administration of cytokines, as well as chemokines or cytotoxic agents (like cyclophosphamide) or antibodies specific for adhesion molecules, mobilizes HSCs and HPCs from the BM into the PB.
Mobilization induced by the cytokine G-CSF is widely used in the clinical setting and has become the preferred way in the United States of harvesting HSPCs for clinical therapies. Besides this clinical significance, the pathways that regulate mobilization are not very well understood at the molecular level, hampering a rational and targeted approach to improving mobilization efficiency.
Using a forward genetic approach, we recently identified the EGF-EGFR-Cdc42 axis as a novel regulator of stem cell mobilization efficiency in response to G-CSF. We are currently investigating the role of EGFR signaling in hematopoiesis and are on the way to translating our findings into the clinic.
Continued progress in leukemia treatment requires a better understanding of the molecular mechanisms of diseases and pathways that confer resistance to chemotherapy. In general, genes that are now recognized as playing a role in cancer development can be divided into two groups: oncogenes and tumor suppressor genes. Oncogenes are mutated, hyperactive forms that cause normal cells to grow out of control. In contrast, tumor suppressor genes normally keep cells from dividing too quickly or uncontrolled. Thus, when tumor suppressor genes don’t work properly or are absent, cells can grow out of control. Such an inactivation of a tumor suppressor gene can either happen through repression of gene expression or loss of both functional copies of the gene through various mutational pathways.
The retinoblastoma (RB) tumor suppressor gene is such a gene; it is best known for its role in causing the childhood cancer retinoblastoma when both copies of the gene are deleted in retinal cells. The RB gene is also, together with the p53 gene, one of the best-studied tumor suppressor genes in various types of solid cancers. The role of these tumor suppressor genes in normal hematopoiesis, aging and leukemia development has been less well investigated.
We have shown that RB is thus critical for hematopoietic stem and progenitor cell function, localization and differentiation. We will further investigate the block in B-cell differentiation and determine the pathway of loss of self-renewal activity in RB-/- HSCs, and the contribution or loss of RB to disease progression in mouse models of B-cell leukemia.
Many organs with high cell turnover (e.g., skin, intestine, blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Aging causes these tissues to lose their ability to maintain homeostasis. Many theories regarding regulation of aging have been postulated; genetic, behavioral and environmental factors are all thought to be involved. Stem cells were initially thought to be endowed with unlimited self-renewal (“rejuvenation”) capacity, and thus exempt from aging. However, evidence accumulated over the past decade has demonstrated measurable and successive age-dependent decline in stem cell activity from adulthood to old age in various organ systems, including hematopoietic, intestinal and muscle systems. This age-associated decline in stem cell function leads to a decline in the regenerative capacity of humans and mice, which may limit lifespan.
Identifying conditions under which aged stem cells are activated to become phenotypically and functionally equivalent to young stem cells could be a first step toward designing treatments for age-associated imbalances in tissue homeostasis and tissue regeneration, thereby allowing for a more healthy aging process. We are currently investigating pathways of aging in hematopoiesis.
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