JAK2 V617F-Dependent Upregulation of PU.1 Expression in the Peripheral Blood of Myeloproliferative Neoplasm Patients

Irino, Tamotsu; Uemura, Munehiro; Yamane, Hitomi; Umemura, Shigeto; Utsumi, Takahiko; Kakazu, Naoki; Shirakawa, Taku; Ito, Mitsuhiro; Suzuki, Takeshi; Kinoshita, Kazuo

doi:10.1371/journal.pone.0022148

Cited by 16 publications

(15 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This mutant works mainly through master hematopoietic regulator SPI1 ( PU.1 ) (34). In agreement with this, SPI1 is upregulated in JAK2 V617F-positive MPNs (56). …”

Section: Gfi1b and Malignancysupporting

confidence: 70%

See 1 more Smart Citation

Transcription Factor GFI1B in Health and Disease

et al. 2017

View full text Add to dashboard Cite

Many human diseases arise through dysregulation of genes that control key cell fate pathways. Transcription factors (TFs) are major cell fate regulators frequently involved in cancer, particularly in leukemia. The GFI1B gene, coding a TF, was identified by sequence homology with the oncogene growth factor independence 1 (GFI1). Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain. Gfi1 is essential for neutrophil differentiation in mice. In humans, GFI1 mutations are associated with severe congenital neutropenia. Gfi1 is also required for B and T lymphopoiesis. However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages. Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function. Loss of Gfi1b in adult mice increases the absolute numbers of hematopoietic stem cells (HSCs) that are less quiescent than wild-type HSCs. In keeping with this key role in cell fate, GFI1B is emerging as a gene involved in cancer, which also includes solid tumors. In fact, abnormal activation of GFI1B and GFI1 has been related to human medulloblastoma and is also likely to be relevant in blood malignancies. Several pieces of evidence supporting this statement will be detailed in this mini review.

show abstract

“…This mutant works mainly through master hematopoietic regulator SPI1 ( PU.1 ) (34). In agreement with this, SPI1 is upregulated in JAK2 V617F-positive MPNs (56). …”

Section: Gfi1b and Malignancysupporting

confidence: 70%

“…Other genes have been related to malignancy both when upregulated and functionally inactivated, including key regulators of hematopoiesis CEBPA (64) and SPI1 ( PU.1 ) (56, 65, 66). This may be the case with GFI1B too.…”

Section: Gfi1b and Malignancymentioning

confidence: 99%

Transcription Factor GFI1B in Health and Disease

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In addition, this finding may support the model recently proposed by Irino et al [23]. These authors, focusing on genes involved in the JAK-STAT signaling pathway, identified two upregulated genes in MPN patients: SOCS3 , a known target of the JAK-STAT axis and a potentially novel target, and SPI1 , encoding PU.1 .…”

Section: Discussionsupporting

confidence: 88%

A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms

Fantasia¹,

Capua²,

Cenfra

et al. 2013

Ann Hematol

View full text Add to dashboard Cite

In Ph− myeloproliferative neoplasms, the quantification of the JAK2V617F transcripts may provide some advantages over the DNA allele burden determination. We developed a q-RT-PCR to assess the JAK2WT and JAK2V617F mRNA expression in 105 cases (23 donors, 13 secondary polycythemia, 22 polycythemia vera (PV), 38 essential thrombocythemia (ET), and 9 primary myelofibrosis (PMF)). Compared with the standard allele-specific oligonucleotide (ASO)-PCR technique, our assay showed a 100 % concordance rate detecting the JAK2V617F mutation in 22/22 PV (100 %), 29/38 (76.3 %) ET, and 5/9 (55.5 %) PMF cases, respectively. The sensitivity of the assay was 0.01 %. Comparing DNA and RNA samples, we found that the JAK2V617F mutational ratios were significantly higher at the RNA level both in PV (p = 0.005) and ET (p = 0.001) samples. In PV patients, JAK2WT expression levels positively correlated with the platelets (PLTs) (p = 0.003) whereas a trend to negative correlation was observed with the Hb levels (p = 0.051). JAK2V617F-positive cases showed the lowest JAK2WT and ABL1 mRNA expression levels. In all the samples, the expression pattern of beta-glucoronidase (GUSB) was more homogeneous than that of ABL1 or β2 microglobulin (B2M). Using GUSB as normalizator gene, a significant increase of the JAK2V617F mRNA levels was seen in two ET patients at time of progression to PV. In conclusion, the proposed q-RT-PCR is a sensitive and accurate method to quantify the JAK2 mutational status that can also show clinical correlations suggesting the impact of the residual amount of the JAK2WT allele on the Ph− MPN disease phenotype. Our observations also preclude the use of ABL1 as a housekeeping gene for these neoplasms.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-013-1920-0) contains supplementary material, which is available to authorized users.

show abstract

“…43 Interestingly, up-regulation of NF-E2 and PU.1 expression was observed in MPN. 48,49 In addition, it has been found recently that overexpression of NF-E2 induces MPN in mice and vorinostat treatment can reduce NF-E2 expression. 50 Therefore, it is plausible that vorinostat may inhibit the growth of JAK2V617F-expressing hematopoietic progenitors by inhibiting the expression of transcription factors that control erythropoiesis and myelopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of vorinostat in a murine model of polycythemia vera

Akada¹,

Akada²,

Gajra³

et al. 2012

Blood

View full text Add to dashboard Cite

The discovery of the JAK2V617F mutation in most patients with Ph-negative myeloproliferative neoplasms has led to the development of JAK2 kinase inhibitors. However, JAK2 inhibitor therapy has shown limited efficacy and dose-limiting hematopoietic toxicities in clinical trials. In the present study, we describe the effects of vorinostat, a small-molecule inhibitor of histone deacetylase, against cells expressing JAK2V617F and in an animal model of polycythemia vera (PV). We found that vorinostat markedly inhibited proliferation and induced apoptosis IntroductionMyeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic malignancies that include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). 1,2 These diseases are characterized by excessive proliferation of myeloid/erythroid lineage cells. A somatic point mutation (V617F) in the JAK2 tyrosine kinase has been found in most patients with PV and in 50%-60% patients with ET and PMF. [3][4][5][6] JAK2V617F is a constitutively active tyrosine kinase that can transform factor-dependent hematopoietic cell lines into cytokine-independent cells. 3,4 Expression of the JAK2V617F mutant activates multiple downstream signaling pathways, such as Stat, Erk, and PI3K/Akt pathways. 3,7,8 Current therapies for MPNs include phlebotomy and myelosuppressive therapy (eg, hydroxyurea and anagrelide) for PV and ET and transfusions and supportive care for PMF. However, these empiric treatments are unlikely to cure or offer remission to patients with MPNs, so there is a clear need for new therapies for MPNs. The discovery of the JAK2V617F mutation in PV, ET, and PMF has led to the development of inhibitors of JAK2. Several JAK2 inhibitors are undergoing clinical trials. Although JAK2 inhibitors are effective in reducing splenomegaly and improving constitutional symptoms, significant hematopoietic toxicities, including anemia and thrombocytopenia, are observed in the majority of patients after this treatment, 9,10 which is consistent with the known function of JAK2 in normal hematopoiesis. 11,12 Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved for the treatment of myelofibrosis. However, a recent report on long-term outcomes with Ruxolitinib treatment found improvement in constitutional symptoms, but no significant benefit in survival for myelofibrosis patients. 13 In addition, there is an increased rate of discontinuation of Ruxolitinib therapy because of severe hematopoietic toxicities or lack of response. 13 It is also possible that drug resistance may emerge in some patients treated with JAK2 inhibitors, similar to what is observed with the ABL inhibitor imatinib in CML patients. 14 Therefore, identifying additional new therapies targeting JAK2V617F or pathways downstream of JAK2V617F would be beneficial for the treatment of patients with MPNs.Acetylation is an important posttranslational modification that serves as a key modulator of chromatin structure and gene transcription, and provides a me...

show abstract

JAK2 V617F-Dependent Upregulation of PU.1 Expression in the Peripheral Blood of Myeloproliferative Neoplasm Patients

Cited by 16 publications

References 30 publications

Transcription Factor GFI1B in Health and Disease

Transcription Factor GFI1B in Health and Disease

A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms

Efficacy of vorinostat in a murine model of polycythemia vera

Contact Info

Product

Resources

About