Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Epigenetic dysregulation of transcription factor NF-E2 expression in thepathophysiology of myeloproliferative neoplasms

Myeloproliferative Neoplasms (MPN) constitute a group of malignant, hematological disorders that predispose to the development of acute leukemia. Despite recent advances in our understanding of MPN etiology, brought on by the discovery of the JAK2V617F mutation, a central problem remains unsolved: the molecular mechanisms by which JAK2V617F contributes to the development of MPNs have not been elucidated. This shortcoming appears especially relevant in light of the limited efficacy of JAK2 inhibitors observed in recent clinical trials. Recently, a novel, STAT-independent, epigenetic pathway of JAK2 activity was described, that involves histone phosphorylation by JAK2 and subsequent modulation of chromatin binding proteins.We have demonstrated that the transcription factor NF-E2 is overexpressed in MPN patients and that elevated NF-E2 levels cause an MPN phenotype in a mouse model including spontaneous transformation to acute leukemia. However, the molecular mechanisms causing NF-E2 overexpression have not been delineated.

In preliminary data, we have demonstrated that NF-E2 is epigenetically silenced in healthy controls and that this silencing is absent in MPN patients. The aims of this project are therefore to investigate the molecular mechanisms effecting dysregulated epigenetic NF-E2 silencing in MPN patients and to delineate the effects of the JAK2V617F mutation on NF-E2 expression. The following hypotheses will be investigated:Hypothesis 1: Both the Decitabine-mediated and the physiological, maturation induced decrease in NF-E2 expression, which is perturbed in MPN patients, are regulated by upstream signaling pathways and mediated by histone modification. Hypothesis 2: NF-E2 overexpression in MPN patients is effected by H3Y41-phosphorylation via the novel JAK2/phospho-H3Y41/HP-1alpha pathway.Hypothesis 3: NF-E2 overexpression in MPN patients is effected by altered activity of histone methylases or demethylases causing aberrant histone methylation in the NF-E2 promoter.
Elucidating the molecular mechanisms causing NF-E2 overexpression will lead to a better understanding of MPN disease etiology. Since targeting a transcription factor therapeutically is very challenging, the pathways identified as causal for NF-E2 overexpression may better lend themselves as drug targets.

  • Jutzi JS, Bogeska R, Nikoloski G, Schmid CA, Seeger TS, Stegelmann F, Schwemmers S, Gründer A, Peeken JC, Gothwal M, Wehrle J, Aumann K, Hamdi K, Dierks C, Kamar Wang W, Döhner K, Jansen JH, Pahl HL. MPN patients harbor recurrent truncating mutations in transcription factor NF-E2. J Exp Med. 2013 May 6;210(5):1003-19. PMID:23589569

  • Aumann K, Frey AV, May AM, Hauschke D, Kreutz C, Marx JP, Timmer J, Werner M, Pahl HL. Subcellular mislocalization of the transcription factor NF-E2 in erythroid cells discriminates prefibrotic primary myelofibrosis from essential thrombocythemia. Blood. 2013 Jul 4;122(1):93-9.. PMID:23670178

  • Heike Pahl

    University of Freiburg Medical Center
    Center for Clinical Research
    Breisacher Str 66
    79106 Freiburg, Germany
    Phone: +49 761 270 63400
    Fax: +49 761 270 63410