Project Details
Description
Abstract:
The developmental mechanisms of human and Drosophila blood systems show
remarkable parallels. Most genes essential for the formation and maturation of
Drosophila hemocytes are conserved in humans, and the majority is associated with
hematopoietic malignancies.
We have identified a new gene, zfrp8, controlling cell proliferation of the
hematopoietic organs, the lymph glands. Several loss-of-function alleles in zfrp8 cause
enormous hyperplasia of the lymph glands, over-proliferation of immature blood cells,
and severe growth delay in other tissues.
Zfrp8 and its human ortholog, PDCD2, are >50% homologous. PDCD2 appears
to be involved in human blood malignancies. This conclusion is based on its regulation
by the BCL6 (B-cell lymphoma 6) oncogene and its chromosomal localization to a region
of chromosome 6q27, frequently deleted in human lymphomas. In some lymphomas,
PDCD2 is present in the cytoplasm of normal lymphocytes, but is not detected in
malignant lymphocytes, indicating that the gene may have similar function in cell
proliferation in Drosophila and humans.
In the bone marrow and blood of leukemia patients, we have detected a smaller
than normal form of PDCD2, PDCD2?33, that is not detected in samples from healthy
controls. PDCD2?33 is found in all the cancer cell lines we have tested and thus
correlates with increased levels of cell proliferation and oncogenesis. Because of the
Drosophila PDCD2/zfrp8 loss-of-function phenotype, strong hyperplasia of hemocytes,
and the high level of expression of PDCD2?33 in malignant tissues, we propose that
PDCD2?33 represents an abnormal/oncogenic form of the protein.
Our experiments are aimed at defining the function of zfrp8 in normal lymph
gland development and in growth of other tissues in Drosophila, and at characterizing
additional genes, a few of which we have already identified, functioning with zfrp8. We
also propose to define the gene products of PDCD2 in vertebrates, and to investigate
their function in normal and malignant cells.
Status | Finished |
---|---|
Effective start/end date | 9/1/08 → 8/31/09 |
Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development: $319,511.00
ASJC
- Genetics
- Cell Biology
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