Epigenetic Mechanisms and Targeting in Hematological Malignancy
Jonathan Licht
MDUniversity of Florida
Project Term: October 1, 2024 - September 30, 2029
Blood cancers can be caused by aberrant regulation of genes that control cell growth and development. The root cause of this problem may be the presence of mutant regulator proteins in the cell and abnormal switching on or off of target genes. Our SCOR studies the molecular basis of this gene deregulation using cell cultured in the laboratory, in human specimen and animal models.
Melnick will study the complex of proteins evolve in looping DNA segments to put gene regulatory sequences in proximity of genes critical for the development of antibody producing B cells. Abnormalities of this apparatus lead to lymphoma. Roeder will study multi-protein complexes involved in “bookmarking” chromatin (the complex of DNA and histones found in the cell nucleus) by chemical modification. He studies the proteins that initiate transcription of DNA into RNA and that assure the passage of the polymerase that creates messenger RNA across genes. Soto-Feliciano studies TRIM28, a protein essential for growth of acute leukemia will identify its mechanisms and target genes. Licht will study the role of chromatin regulators in the response of the immune system to multiple myeloma and how inhibitors of chromatin regulator inhibitors affect the tumor immune response. Patel will study in explore the three-dimensional structures of these protein complexes critical for gene regulation in blood malignancies to understand their mechanisms and develop new small molecules to modulate their action.
Blood cancers may be caused by aberrant regulation of genes that control cell growth and development resulting from mutant regulator proteins. Our group studies mechanisms of gene deregulation using cultured cells, human specimen, and animal models to understand the mechanisms of gene deregulation and develop new strategies to reverse the process. Over 17 years the group has published their work in the highest quality scientific journals and stimulated the development of novel therapeutics including inhibitors of the EZH2 histone methyltransferase and Menin/MLL interaction (FDA approved) as well as NSD2, histone deacetylase and lysine demethylase inhibitors.
- Project 1: Melnick will study abnormal gene expression in lymphoma due to mutations in proteins that loop regulatory sequences from one part of a chromosome to genes critical for growth of antibody producing B cells. Mutations of these proteins reprograms lymphocytes for continuous growth and at the same time create new therapeutic vulnerabilities and potential therapeutic targets.
- Project 2: Roeder studies the biochemistry of gene transcription, the process by which DNA is transcribed to messenger RNA that guides assembly of proteins that control the cell. He will study proteins that maintain gene expression critical for growth of leukemia and lymphoma cells including the KMT2D and superelongation complexes and TRIM28.
- Project 3: Soto-Feliciano found that chromatin protein TRIM28 is essential for the growth of acute myeloid leukemia. She will characterize protein partners of TRIM28 and its ability to bind across the genome to activate target genes which in themselves may be therapeutic targets in AML. She will determine the structure of TRIM28 complexes which can aid discovery of new anti-leukemia agents.
- Project 4: Licht has studied the tumor suppressive and regulatory effects of the histone modifying KDM6A, SETD2, and NSD2 proteins in blood cancers. He will now determine how mutations of these proteins affect the ability of multiple myeloma cells to present themselves to the immune system and the effects of chemicals targeting chromatin regulators on the immune response to myeloma.
- Project 5: Patel will apply x-ray crystallography and electron microscopy approaches to understand the structure and the function of the multi-protein gene regulatory machines including the KMT2D complex, TRIM28, the chromatin looping apparatus and NSD2 bound to novel inhibitors.
Unique aspects of this SCOR include:
- A focus specific gene regulators malfunctioning in a range of blood cancers.
- Approaches spanning from structural biology, biochemistry, chemical methods to inhibit gene regulators, and use of genetically engineered cell culture and animal models.
- Expert epigenetic bioinformatics and chemical biology cores.
- Examination of the consequences of chromatin deregulation on the tumor immune response.
- Identification of chromatin pathways that have successfully been targeted for therapy.