Functional studies of the transcription factors KLF4, ETS2 and JAK2 mutation in myeloproliferative disorder
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Date
2010
Authors
Soon Siong, Teo
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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
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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.
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Keywords
Transcription factors KLF4, ETS2 , Myeloproliferative disorder