Functional studies of the transcription factors KLF4, ETS2 and JAK2 mutation in myeloproliferative disorder

Loading...
Thumbnail Image
Date
2010
Authors
Soon Siong, Teo
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Haematopoiesis is a complex and well-ordered process that assures the regeneration of terminally blood cells from a common stem cell. Myeloproliferative disorders (MPD) are characterized by elevated nwnbers of fully differentiated myeloid and erythroid cells and platelets in peripheral blood. The etiology of this clonal stem cell disorder remains unknown. Increased sensitivity. of progenitors towards cytokines, such as erythropoietin and thrombopoietin, and partial resistance to inhibitory signals such as transforming growth faetor beta are characteristics ofMPD. The objectives of this thesis were to examine the functional effects of transcription factors, Kruppel-like factor 4 (KLF4), V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and Janus kinase 2 (JAK2) mutation in MPD. Using high-density oligonucleotide affymetrix chips, a set of 15 genes that are highly elevated in Polycythemia Vera patients were identified. PRV-1, previously known to be highly expressed in MPD was also included in this study. Unfortunately, in this.study, there was none of the marker when considered separately could achieve 1 00% discrimination between Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Idiopathic Myelofibrosis (IMF). For comparison, 88% to 92% of PV patients showed to be Haptoglobin (HP), Haptoglobin-related protein (HPR), KLF4 and PRV- • 1 high-expressed. The best markers of ET were HP (83%) and Suppressor of cytokine signaling 3 (SOCS3) (83%) and for IMF would be SOCS3 (83%) and Chromosome 1 open reading frame 29 (C1ort29) (83%). ETS2 and KLF4 were transcription factors that had been extensively studied in prostate, breast and colon cancer; but none of these two genes are well studied in vu • • MPD. Present study showed that about 75% and 88% of PV patients have highelevated expression of ETS2 and KLF4 respectively. Interestingly, about 90% of PV patients who have elevated KLF4 also elevated in p21 WAFI/CIPI expression, this finding further support previous study that showed the growth arrest property of KLF4 was due to the activation ofp21WAFI/Cipl promoter. Cell proliferation assay and gene expression of p21 WAFI/Cipi of transient transfected-KLF4 in UT7/TPO cell line showed the same phenomenon. However, transient and stable transfected of ETS2 proto-onc()gene do . not show visible difference in cell proliferation assay when compared t~ vector-only transtected cells. In vitro functional studies of recently described JAK2 V617F mutation indicate that transfected V617F cells give survival advantages (cytokine-independent) and showed hypersensitive to low concentrations cytokines (TPO, EPO, and miL3). However, forced expression of JAK2 V617F protein does not show significant difference on 15 MPD markers.
Description
Keywords
Transcription factors KLF4, ETS2 , Myeloproliferative disorder
Citation