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Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

The role of transcription factor NF-E2 in the pathophysiology of MPNs

The molecular etiology of Polycythemia vera (PV) remains unknown, despite the recent description of a point mutation in the JAK2 kinase (JAK2V617F).Gene expression profiling has been successfully used to reveal candidate genes involved in disease development.We thus performed cDNA microarray analysis on 40 patients with PV 50 healthy controls and 12 patients with secondary erythrocytosis (SE) (Goerttler, 2005).253 genes upregulated and 391 genes downregulated more than 1.5-fold in PV compared to healthy controls (p < 0.01) were identified. Of these, the transcription factor NF-E2, is overexpressed between 2- and 40-fold in PV patients. In PV bone marrow, NF-E2 is overexpressed in megakaryocytes, erythroid and granulocytic precursors. It has been shown that overexpression of NF-E2 leads to the development of Epo-independent erythroid colonies and that ectopic NF-E2 expression can reprogram monocytic cells towards erythroid and megakaryocytic differentiation.Transcription factor concentration may thus control lineage commitment. We therefore propose that in PV patients elevated concentrations of NF-E2 lead to an overproduction of erythroid and, in select patients, megakaryocytic cells/platelets. In this model the level of NF-E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.The recent description of the 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.Both the molecular mechanism leading to NF-E2 overexpression and its effect on human hematopoiesis are not known. Therefore, it is the aim of this project to investigate the cause of NF-E2 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 

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

 

Current Lab Members on the Project

  • Dr. Ruzhica Bogeska, Post doc (Ph. D. 2012)
  • Laura Siegwart, M.D. student
  • Julius Wehrle, (M.D. 2013)
  • Lara Rheinemann


Alumni

  • Dr. Angela Magin
  • Manuel Mutschler, (M.D. 2009)
  • Roland Roelz, (M.D. 2010)
  • Martina Buerge, (M.D. 2011)
  • Christian Arnold, (M.D. 2013)
  • Aitomi Essig, (M.D. 2012)
  • Dr. Thalia Seeger, Post doc

 

Literature

  1. Mutschler M, Magin AS, Buerge M, Roelz R, Schanne DH, Will B, Pilz I, Migliaccio AR, Pahl HL (2009) NF-E2 Overexpression Delays Erythroid Maturation and Increases Erythrocyte Production. , Br. J. Haematol, 146: 203-217. (PDF-file)
  2. Goerttler PS, Kreutz C, Donauer J, Faller D, Maiwald T, März E, Rumberger B, Sparna T, Schmitt-Gräff A, Wilpert J, Timmer J, Walz G, Pahl HL (2005) Gene Expression Profiling in Polycythemia vera: Overexpression of transcription factor NF-E2., Br. J. Haematol, 129: 138-150. (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