Epigenetic effects of NFE2 and JAK2V617F mutations in MPN

Project Summary

We have defined distinct classes of NFE2 mutations in patients with myeloproliferative neoplasms (MPN) and could demonstrate that elevated expression of the transcription factor NFE2 in MPN patients is regulated by epigenetic pathways. Now we will integrate changes in the transcriptome and histone modifications conferred by wt-NFE2 and the NFE2 mutations, to understand how NFE2 alters the epigenetic landscape to promote leukemic transformation. These data will allow us to discriminate between two alternative pathophysiological models of disease initiation and progression.

Selected project-relevant publications

• Staehle A.M., Peeken J.C., Vladimirov G., Hoeness M.E., Bojtine Kovacs S., Karantzelis N., Gruender A., Koellerer C., Jutzi J.S., Pahl H.L. and Staehle H.F. (2023) The histone demethylase JMJD2C constitutes a novel NFE2 target gene that is required for the survival of JAK2(V617F) mutated cells. Leukemia 37, 919-923.
• Staehle H.F., Pahl H.L. and Jutzi J.S. (2021) The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies. Biomolecules 11, doi 10.3390/biom11121911.
• Basu T., Bertrand H., Karantzelis N., Gründer A. and Pahl H.L. (2021) Pharmacological Inhibition of Insulin Growth Factor-1 Receptor (IGF-1R) Alone or in Combination With Ruxolitinib Shows Therapeutic Efficacy in Preclinical Myeloproliferative Neoplasm Models. Hemasphere 5, e565.
• Vorbach S., Gründer A., Zhou F., Koellerer C., Jutzi J.S., Simoni M., Riccetti L., Valk P.J., Sanders M.A., Müller-Tidow C., Nofer J.R., Pahl H.L. and Potì F. (2020) Enhanced expression of the sphingosine-1-phosphate-receptor-3 causes acute myelogenous leukemia in mice. Leukemia 34, 721-734.
• Staehle H.F., Heinemann J., Gruender A., Omlor A.M., Pahl H.L. and Jutzi J.S. (2020) Jmjd1c is dispensable for healthy adult hematopoiesis and Jak2V617F-driven myeloproliferative disease initiation in mice. PLoS One 15, e0228362.
• Siegwart L.C., Schwemmers S., Wehrle J., Koellerer C., Seeger T., Gründer A. and Pahl H.L. (2020) The transcription factor NFE2 enhances expression of the hematopoietic master regulators SCL/TAL1 and GATA2. Exp Hematol 87, 42-47.e41.
• Böckelmann L.C., Basu T., Gründer A., Wang W., Breucker J., Kaiser S., Pichler A. and Pahl H.L. (2020) Concomitant constitutive LNK and NFE2 mutation with loss of sumoylation in a case of hereditary thrombocythemia. Haematologica, doi: 10.3324/haematol.2020.246587.
• Jutzi J.S., Basu T., Pellmann M., Kaiser S., Steinemann D., Sanders M.A., Hinai A.S.A., Zeilemaker A., Bojtine Kovacs S., Koellerer C., Ostendorp J., Aumann K., Wang W., Raffoux E., Cassinat B., Bullinger L., Schlegelberger B., Valk P.J.M. and Pahl H.L. (2019) Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations. Blood 133, 1766-1777.
• Peeken J.C., Jutzi J.S., Wehrle J., Koellerer C., Staehle H.F., Becker H., Schoenwandt E., Seeger T.S., Schanne D.H., Gothwal M., Ott C.J., Grunder A. and Pahl H.L. (2018) Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms. Blood 131, 2065-2073.
• Gothwal M., Wehrle J., Aumann K., Zimmermann V., Grunder A. and Pahl H.L. (2016) A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy. Haematologica 101, 1054-1064.
• Aumann K., Werner M. and Pahl H.L. (2016) Immunohistochemical staining of transcription factor NFE2 for the discrimination of primary myelofibrosis from essential thrombocythemia. Hum Pathol 53, 195-196.
• Jutzi J.S. and Pahl H.L. (2015) The Hen or the Egg: Inflammatory Aspects of Murine MPN Models. Mediators Inflamm 2015, 101987.
• Gajer J.M., Furdas S.D., Grunder A., Gothwal M., Heinicke U., Keller K., Colland F., Fulda S., Pahl H.L., Fichtner I., Sippl W. and Jung M. (2015) Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo. Oncogenesis 4, e137.
• Rheinemann L., Seeger T.S., Wehrle J. and Pahl H.L. (2014) NFE2 regulates transcription of multiple enzymes in the heme biosynthesis pathway. Haematologica 99, e208-210.
• Jutzi J.S., Bogeska R., Nikoloski G., Schmid C.A., Seeger T.S., Stegelmann F., Schwemmers S., Grunder A., Peeken J.C., Gothwal M., Wehrle J., Aumann K., Hamdi K., Dierks C., Kamar Wang W., Dohner K., Jansen J.H. and Pahl H.L. (2013) MPN patients harbor recurrent truncating mutations in transcription factor NF-E2. J Exp Med 210, 1003-1019.
• Bogeska R. and Pahl H.L. (2013) Elevated nuclear factor erythroid-2 levels promote epo-independent erythroid maturation and recapitulate the hematopoietic stem cell and common myeloid progenitor expansion observed in polycythemia vera patients. Stem Cells Transl Med 2, 112-117.
• Aumann K., Frey A.V., May A.M., Hauschke D., Kreutz C., Marx J.P., Timmer J., Werner M. and Pahl H.L. (2013) Subcellular mislocalization of the transcription factor NF-E2 in erythroid cells discriminates prefibrotic primary myelofibrosis from essential thrombocythemia. Blood 122, 93-99.
• Kaufmann K.B., Grunder A., Hadlich T., Wehrle J., Gothwal M., Bogeska R., Seeger T.S., Kayser S., Pham K.B., Jutzi J.S., Ganzenmuller L., Steinemann D., Schlegelberger B., Wagner J.M., Jung M., Will B., Steidl U., Aumann K., Werner M., Gunther T., Schule R., Rambaldi A. and Pahl H.L. (2012) A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. J Exp Med 209, 35-50.