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Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

Molecular etiology of NF-E2 and PRV-1 Overexpression in MPN

The transcription factor NF-E2 and the gene encoding PRV-1 are overexpressed in patients with polycythemia vera (PV). The recent description of a Jak2V617F mutation in PV patients raises the question whether this allele exerts its effect on the malignant clone in part through inducing NF-E2 expression. NF-E2 is a promising candidate in the pathophysiology of PV for several reasons: NF-E2 is overexpressed in stem cells as well as in all three cell lineages affected in PV. In murine cells NF-E2 overexpression leads to Epo-independent growth and differentiation. NF-E2 may thus play a pivotal role in causing the erythrocytosis of PV. However, both the molecular mechanism leading to NF-E2 overexpression and its effect on human hematopoiesis are not known. In addition, the cause of PRV-1 overexpression remains unclear. Therefore, it is the aim of this project to investigate the cause of NF-E2 and PRV-1 overexpression in PV and the effect of NF-E2 overexpression in hematopoietic cells. Based on the following hypotheses, the specific aims of this project are therefore:

Hypothesis 1: NF-E2 is required for the Epo-independent growth of PV cells or its overexpression modulates hematopoietic differentiation.

Specific Aim 1: To modulate NF-E2 expression via siRNA knock down and retroviral or lentiviral transduction and examine the consequences on Epo-dependent and independent growth in vitro.

Hypothesis 2: NF-E2 and PRV-1 overexpression in PV are mediated by the Jak2V617F allele.

Specific Aim 2: To introduce Jak2 wt and V617F alleles in vivo and in vitro and examine the effects on NF-E2 and PRV-1 expression in various models.

Hypothesis 3: NF-E2 and PRV-1 overexpression result from aberrant transcriptional activation.

Specific Aim 3: To characterize protein/DNA interaction on the NF-E2 and PRV-1 promoters in PV and healthy control cells to determine aberrantly activated transcription factors.

 

Current Lab Members on the Project

  • Dr. Wei Wang, Post doc (Ph. D. 2010)
  • Jakob Meyer, M.D. student

 

Literature

  1. Wang W, Schwemmers S, Hexner EO, Pahl HL (2010) AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2. Blood, 116: 254 - 266. (PDF-file)
  2. Temerinac S, Klippel S, Röder S, Lübbert M, Lange W, Azemar M, Meinhardt G, Pahl HL (2000) Cloning of PRV-1, a Novel Member of the uPAR Receptor Superfamily, which is Overexpressed in Polycythemia rubra vera. Blood, 95: 2569-2576.
    (PDF-File)
  3. Klippel S, Strunck E , Busse CE, Behringer D, Pahl HL (2002) Biochemical Characterization of PRV-1, a Novel Hematopoietic Cell Surface Receptor, which is Overexpressed in Polycythemia rubra vera., Blood, 100: 2441-2448
    (PDF-file)
  4. Klippel S, Strunck E, Temerinac S, Meinhardt G, Mohr U, Leichtle R, Griesshammer M, Heimpel H, Pahl HL (2003) Quantification of PRV-1 mRNA distinguishes Polycythemia vera from Secondary Erythrocytosis., Blood, 102: 3569-3574
    (PDF-File)

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