Research Overview
Hematopoiesis is the development of blood cells, which is highly regulated through both intrinsic and
extrinsic factors. Transcription factors are critical for normal proliferation and differentiation
of blood cells. Growth factors and the bone marrow microenvironment are also critical for normal
hematopoiesis. Specific diseases of hematopoiesis result from defects in transcription or protein
synthesis.
The overall goal of our laboratory is to understand the molecular regulation of hematopoiesis and how
aberrancies result in diseases of hematopoiesis, including leukemia, bone marrow failure, and
myeloproliferative disease.
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Transcriptional regulation in leukemogenesis
CREB is a leucine zipper transcription factor that controls cell proliferation, differentiation,
and survival. CREB is overexpressed in bone marrow cells from the majority of patients with acute
lymphoblastic and myeloid leukemia. CREB transgenic mice develop myeloproliferative disease, i.e.
preleukemia, but not acute leukemia. Therefore, CREB is an oncogene that requires additional mutations.
We are studying other cooperating oncogenes that contribute to leukemogenesis. In addition, downstream
target genes are being explored.
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Targeted therapy for leukemia and other cancers
In collaboration with pharmaceutical companies, we are testing novel compounds to target specific
signaling molecules in AML. Among the small molecules being studied in vitro and in vivo are inhibitors
of receptor tyrosine kinases, aurora kinases, and anti-apoptotic proteins. We are also collaborating with
investigators at MIT/Broad Institute and Dana Farber Cancer Institute to study inhibitors of the aggresome
pathway in ALL. Mechanistic pathways are being investigated.
Protacs are chimeric molecules to target cancer causing proteins for ubiquitination and degradation. We
have demonstrated the feasibility of using this approach in prostate and breast cancer cell lines to
target the androgen and estrogen receptors for ubiquitination and degradation, resulting in apoptosis.
Approaches are being developed to design Protacs for clinical trials in humans.
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Signaling Pathways in bone marrow failure syndromes
Defects in ribosome biogenesis have been associated with specific bone marrow failure syndromes, such
as Diamond Blackfan Anemia. We are studying the signaling pathways that are altered by deficiency in
specific ribosomal protein subunits. Zebrafish, mouse, and human cells are being used to characterize
p53-dependent and –independent pathways mediating aberrant erythropoiesis and increased risk of cancer
in these patients.
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