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Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

Epigenetic effects of transcription factor NF-E2 in Myeloproliferative Neoplasms:pathophysiology and therapeutic target

Myeloproliferative neoplasms (MPN) constitute a group of pharmacologically incurable hematologic malignancies. We have previously shown that the expression of transcription factor “nuclear factor erythroid-2” (NF-E2) is aberrantly elevated in the vast majority of MPN patients. NF-E2 has been demonstrated to remodel chromatin, to establish histone marks and to recruit both histone acety-lases and the MLL2 methyltransferase complex. Our NF-E2 overexpressing transgenic (tg) mouse model shows a phenotype characteristic of MPNs in humans including thrombocytosis and trans-formation to acute leukemia. In addition, NF-E2 tg mice display alterations in histone modifications. Treatment with the histone deacetylase inhibitor Vorinostat normalized platelet counts in NF-E2 transgenic mice and reversed the altered histone acetylation. Finally, we have identified epigenetic modifiers as novel NF-E2 target genes. Based on these data, we will test the following hypotheses:

Hypothesis 1:The pathology of NF-E2 transgenic mice is mediated, at least in part, by epigenetic changes effected by overexpression of the NF-E2 protein.

Specific Aim 1:To investigate epigenetic changes (histone marks, chromatin occupancy) in NF-E2 overexpressing mice.2.

Hypothesis 2:The pathologic changes caused by NF-E2 overexpression can be reversed by treatment with inhibitors of chromatin modifying enzymes.

Specific Aim 2:To treat NF-E2 transgenic mice with SAHA (Vorinostat) and other inhibitors of histone modifying enzymes and to observe physiological parameters (blood counts, hematopoietic colony formation, bone marrow morphology and spleen size).

Hypothesis 3:Novel NF-E2 target genes mediate epigenetic modifications

Specific Aim 3:To characterizenovel NF-E2 target genes, such as JMJD1C and JMJD2C and their activity in NF-E2 tg mice and MPN patients.The long-term goals of this project are to demonstrate the pre-clinical efficacy of epigenetic therapy in a MPN model and to translate these results into a novel therapy for patients with MPN.

 

Current Lab Members on the Project

  • Jan Peeken, M.D. student

Alumni

  •  Dr. Thalia  Seeger

 

Principal Investigator

Prof. Dr. Heike L. Pahl

Prof. Dr. Heike L. Pahl

Chair: Section of Molecular Hematology
Department of Hematology / Oncology

Telefon+49 (0) 761 270-63400
Telefax+49 (0) 761 270-63410
heike.pahl@uniklinik-freiburg.de

Postal address:

Center for Tumor Biology
University Hospital Freiburg

Breisacher Str. 117
79106 Freiburg
Germany