Projects
In this laboratory we study the genetic control of hematopoiesis and development of the immune system using mouse models. Our current focus is on ETS proteins and their study on:
- Transcriptional control of the development and proliferation of lymphocytes (T and NK cells). Role of ETS proteins (ELF subfamily, particularly ELF4) in lymphoproliferative disorders.
- Control of the proliferation of hematopoietic stem cells and their response to depletion of blood cells (i.e. chemotherapy). Study of different progenitor and mature cells involved in the hematological recovery.
Overview
Hematopoietic stem cells (HSCs) are immature cells in the bone marrow that have the capacity to differentiate into all types of mature blood cells. Most blood cells complete their development in the bone marrow whereas T-cell progenitor cells mature in the thymus. Cell fate (differentiation, proliferation, cell death) is regulated by transcription factors that turn "on" or "off" specific genes. We are studying one member of the ETS family of transcription factors known as ELF4 (MEF) and its role in normal and malignant development and function of lymphocytes and hematopoietic stem cells (Figure 1).
Figure 1:Study the role of the transcription factor ELF4/MEF in lymphoid proliferation, blood formation (at steady state and post radiation or ablation) and tumor formation
We found in ELF4-deficient mice normal αβTCR development but fewer NK and NK-T cells. ELF4 deficiency also impaired the function of the NK cells that did develop: these cells could not lyse tumor cell targets largely due to defective perforin gene expression. Promoter studies and chromatin immunoprecipitation experiments revealed that ELF4 directly binds to the perforin promoter to regulate its activity (Lacorazza et al, article featured on the cover of Immunity). Therefore, ELF4 contributes to the state of readiness of NK cells by regulating the constitutive expression of perforin. As a sign of deregulated lymphocytic proliferation, we often found B and T cells infiltrated in different tissues of aged ELF4-deficient mice. This and the control of perforin gene expression support our current study on patients suffering non-malignant lymphoproliferative disorders.
Recent reports have shown that ELF4 level is reduced in patients with acute myeloid leukemias, therefore, we decided to study the effect of loss of ELF4 in hematopoietic primitive progenitors. ELF4-null mice accumulated quiescent HSCs with the capacity for repopulation and demonstrated enhanced resistance to the effects of chemotherapeutic drugs and radiation (Lacorazza et al., article featured on the cover of Cancer Cell). This finding suggests that this transcription factor regulates the quiescence of HSCs, a state that protects them from differentiation although stem cells can be recruited to promote a restoration of depleted blood cells (Figure 2). This feature can be also helpful to maintain HSCs in an undifferentiated state during gene and cell therapy protocols.
Figure 2: ELF4 controls quiescence of primitive hematopoietic progenitors (Cancer Cell, March 13th, 2006).
We are currently investigating how ELF4 and other ETS-proteins are involved in the control of lymphoid proliferation (i.e. T and NK cells) and the mechanism by which ELF4 controls the quiescence of hematopoietic stem cells and the process of blood formation. We are particularly interested in the recovery of the bone marrow after ablation. Specifically, we would like to know how ELF4 gene is regulated, what are the target genes, and how a deregulated expression could lead to abnormal proliferation (Figure 3). To study the effect of a specific target gene (gene X, identified from a microarray study) on the proliferative capacity of primitive progenitor cells at steady state or post myeloid suppression (e.g. treatment with 5-fluorouracil, 5-FU), we use retroviral gene transfer into bone marrow cells from donor mice and bone marrow transplant into lethally irradiated hosts (Figure 4).
Our work will contribute to the general knowledge of the genetic control of cell proliferation and how this process could be targeted in carcinogenesis. In the long run, we would like to improve the hematological recovery post treatment-induced myelosuppression (i.e. chemotherapy, radiation) by modulating the expression of specific transcription factors and consequently the expression of their target genes.
Figure 3: Role of ELF4 in hematopoiesis and development of the immune system
Figure 4: Experimental design used in our laboratory to study the effect of specific genes on hematopoiesis
