Zu den Inhalten springen

Klinik für Innere Medizin IHämatologie, Onkologie und Stammzelltransplantation

Overexpression of NF-E2 in vivo: A Murine Model of Myeloproliferative Neoplasms

The transcription factor nuclear factor erythroid-2 (NF-E2) is expressed in hematopoietic stem cells as well as in myeloid, erythroid and megakaryocytic precursors. NF-E2 deficient mice display marked anemia at birth and die perinatally due to thrombopenia, demonstrating an essential role for NF-E2 in both in erythropoiesis and platelet formation. We have previously shown that NF-E2 is overexpressed in the vast majority of patients with Myeloproliferative Neoplasms (MPNs). However, the effect of augmented transcription factor activity has not been studied in vivo. We therefore engineered two independent transgenic mouse lines expressing human NF-E2 under the control of the vav-Promoter, which has previously been shown to direct transgene expression in hematopoietic stem cells as well as in precursor cells of all lineages.

The two founder lines show overlapping but distinct phenotypes. Epo-independent colony formation, a pathognomonic feature of polycythemia vera, is significantly increased in NF-E2 transgenic animals. Bone marrow histopathology shows findings characteristically seen in MPNs, including the presence of increased megakaryopoiesis with cytologically abnormal forms, often in clusters. Both NF-E2 transgenic strains display significantly increased mortality. Upon autopsy, between 15 and 20% of mice in both strains present with major gastrointestinal bleeding in conjunction with splenic atrophy. Histopathological examination of all spleens revealed mild to moderately expanded red pulp with increased numbers of iron containing histiocytes. This observation indicates increased red cell destruction and may explain the fact that neither hematocrit nor hemoglobin are elevated in NF-E2 transgenic animals. At 18 months of age, one mouse developed acute leukemia, which is currently being phenotyped. In summary, in a murine model moderate NF-E2 overexpression causes a phenotype resembling Essential Thrombocythemia. In addition, our preliminary data indicate that NF-E2 overexpression may predispose to the development of acute leukemia.

Current Lab Members on Project

  • Dr. Albert Gründer, Post doc
  • Jonas Jutzi, M.D. 2013
  • Sandra Kaiser, Dipl.-Biol.
  • Titiksha Basu, B.A.

Alumni

  • Dr. med. Kai Kaufmann, (M.D. 2012)
  • Tobias Hadlich, (M.D. 2012)
  • Kien-Binh Pham, (M.D. pending)
  • Monika Gothwal, (Ph. D. 2012)
  • Sarah Kayser, (M.D. 2012)
  • Jan Marx, (M.D. 2012)
  • Laura Vandré, (M.D. 2012)

Literature

  1. Jutzi JS, Bogeska R, Nikoloski G, Schmid CA, Seeger TS, Stegelmann F, Schwemmers S, Gründer A, Peeken J, Gothwal M, Wehrle J, Aumann K, Hamdi K, Dierks, C, Wang W, Döhner K, Jansen JH, Pahl HL (2013) MPN patients harbor recurrent truncating mutations in transcription factor NF-E2, J. Ex. Med, 210: 1003 - 1019. (PDF-file)
  2. Kaufmann KB, Gründer A, Hadlich T, Wehrle J, Gothwal M, Bogeska R, Seeger TS, Kayer S, Pham KB, Jutzi JS, Ganzenmüller L, Steinemann D, Schlegelberger B, Wagner JM, Jung M, Will B, Steidl U, Aumann K, Werner M, Günther T, Schüle R, Rambaldi A, Pahl HL, (2012) Overexpression of transcription factor NF-E2: a novel murine model of myeloproliferative neoplasms, J. Exp. Med, 209 (1): 35 - 50.   (PDF-file)
  3. 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)
  4. 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