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Tomasz Cierpicki

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Primary Appointment: Pathology Department
Primary PIBS Dept.: Molecular and Cellular Pathology
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 DESCRIPTION OF RESEARCH
  Research interest

The research in Cierpicki laboratory is focused on understanding the structure and function of proteins related to cancer and design small molecule inhibitors of protein-protein interaction.

Current projects

1. Menin as oncogenic co-factor and tumor suppressor
Menin is a tumor-suppressor protein encoded by the Men1 (Multiple Endocrine Neoplasia I) gene which mutations are associated with tumors of the parathyroids, pancreas, and anterior pituitary. Menin also functions as a critical co-factor for MLL fusion oncoproteins in their leukemogenic activity. Interaction of menin with MLL fusion proteins is required for constitutive up-regulation of Hox genes which impair proliferation and differentiation of hematopoietic cells. Translocations of MLL gene frequently occur in aggressive human acute leukemias, both in children and adults. Patients with leukemias harboring MLL translocations have a very unfavorable prognosis (20 % event free survival at 3 years) and poorly respond to available treatments. Therefore, it is clear that novel therapeutic strategies are urgently needed to treat these leukemias.

Our goal is to understand the molecular basis of menin interactions which are critical for both MLL leukemogenesis and for menin function as a tumor suppressor. We are using broad range of biochemical, biophysical and structural biology methods to characterize the interactions of menin with its physiological partners, to determine the three dimensional structure of menin and menin complexes. In a long term goal we plan to develop small molecules targeting menin and blocking menin interactions essential for leukemogenesis to reverse the oncogenic potential of MLL fusions.

2. Understanding the interaction of CEBPa with NF-kB transcription factors

CEBPa is a transcription factor encoded by CBEPA gene which specifically recognizes CAATT sequences. CEBPa is expressed in myeloid cells and is required for hematopoiesis (development of blood cells) by regulating granulocyte differentiation. The CEBPA gene is mutated in 10% of acute myeloid leukemia (AML) cases. CEBPa interacts directly with NF-kB proteins and induce expression of anti-apoptotic Bcl-2 proteins. Our goal is to understand structural basis of CEBPa-NF-kB interaction. Ultimately, development of small molecule compounds inhibiting this interaction may represent a strategy to downregulate expression of anti-apoptotic Bcl-2 proteins.

3. Development of NMR methodology facilitating drug discovery

We are interested in development and application of modern NMR approaches to identify small molecule inhibitors of protein-protein interactions. Our goal involves experimental determination of protein “druggability”, prediction of small molecule binding mode, design of modifications to improve the binding affinity. To efficiently carry our projects the laboratory is equipped in state of the art NMR spectrometer (Bruker 600MHz) suited with cryogenic probe and automatic sample changer.