POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature

Fortier, Julie M.; Payton, Jacqueline E.; Cahan, Patrick; Ley, Timothy J.; Walter, Matthew J.; Graubert, Timothy A.

doi:10.1038/leu.2010.61

Cited by 23 publications

(17 citation statements)

References 60 publications

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“…We found a small number of genes ( TRIB2 , NR4A2 , POU4F1 , HDC , and OTP ) that are hypermethylated in RAEB‐2 and that have expression that appears repressed in RAEB‐2 samples but is activated after in vitro AZA treatment. Both TRIB2 [45] and POU4F1 [46] have been implicated in the development of AML, although both are thought to act as oncogenes and are associated with progression of disease. Interestingly, Pou4f1 is thought to regulate transcription of Nr4a2 during mouse habenula development [47], suggesting that their expression may also be linked in the hematopoietic system.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

Wong

Micklem

Taguchi

et al. 2014

Stem Cells Translational Medicine

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Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-29-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease progression and how DNA methylation contributes to MDS remain unclear. We analyzed global DNA methylation in purified CD34+ hematopoietic progenitors from MDS patients undergoing multiple rounds of AZA treatment. Differential methylation between MDS phenotypes was observed primarily at developmental regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS patients. Haploinsufficiency in mice of one of these genes (NR4A2) has been shown to lead to excessive HSC proliferation, and our data suggest that suppression of NR4A2 by DNA methylation may be involved in MDS progression. STEM CELLS TRANSLATIONAL

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Section: Discussionmentioning

confidence: 99%

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

Wong

Micklem

Taguchi

et al. 2014

Stem Cells Translational Medicine

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“…51 Increased expression of SOX4 in human AML also occurs in patient samples containing the common MOZ-TIF2, AML1-ETO and NUP98-HOXA9 translocations. [52][53][54] These findings indicate that SOX4 acts as a proto-oncogene in both myeloid leukemia and lymphomas by acting in concert with a variety of distinct genetic lesions.…”

Section: Sox4-mediated Regulation Of Tumorigenesis and Tumor Progressionmentioning

confidence: 94%

The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe?

2012

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Development and progression of cancer are mediated by alterations in transcriptional networks, resulting in a disturbed balance between the activity of oncogenes and tumor suppressor genes. Transcription factors have the capacity to regulate global transcriptional profiles, and are consequently often found to be deregulated in their expression and function during tumorigenesis. Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) is a member of the group C subfamily of the SOX transcription factors and has a critical role during embryogenesis, where its expression is widespread and controls the development of numerous tissues. SOX4 expression is elevated in a wide variety of tumors, including leukemia, colorectal cancer, lung cancer and breast cancer, suggesting a fundamental role in the development of these malignancies. In many cancers, deregulated expression of this developmental factor has been correlated with increased cancer cell proliferation, cell survival, inhibition of apoptosis and tumor progression through the induction of an epithelial-to-mesenchymal transition and metastasis. However, in a limited subset of tumors, SOX4 has also been reported to act as a tumor suppressor. These opposing roles suggest that the outcome of SOX4 activation depends on the cellular context and the tumor origin. Indeed, SOX4 expression, transcriptional activity and target gene specificity can be controlled by signaling pathways, including the transforming growth factor-β and the WNT pathway, as well as at the post-translational level through regulation of protein stability and interaction with specific cofactors, such as TCF, syntenin-1 and p53. Here, we provide an overview of our current knowledge concerning the role of SOX4 in tumor development and progression.

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“…After the comparison of two databases, we got a list of highly expressed genes in AML (Supplementary Table 14). Among the top 10 genes, FLT3 is well-known, and POU4F1 has also been reported [55]. Moreover, half of them are lncRNA.…”

Section: Aml Target Searching Based On the Hclmentioning

confidence: 99%

A single-cell survey of cellular hierarchy in acute myeloid leukemia

Xiao

Sun

et al. 2020

J Hematol Oncol

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Background Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes. Methods Using Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells. Results From the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic “cancer attractor” that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape. Conclusions We identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.

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POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature

Cited by 23 publications

References 60 publications

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe?

A single-cell survey of cellular hierarchy in acute myeloid leukemia

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