A germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation

Dowdy, Christopher R.; Frederick, Dana; Zaidi, Sayyed K.; Colby, Jennifer L.; Lian, Jane B.; Wijnen, André J. van; Gerstein, Rachel M.; Stein, Janet L.

doi:10.1016/j.exphem.2013.06.006

Cited by 14 publications

(12 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TP53 mutation is independently associated with a poor prognosis, more frequently with complex karyotypes (50%) and del(5q) (15%‐20%), and may predict resistance or relapse to lenalidomide in MDS patients 4 . However, different degrees of gene mutations lead to different clinical phenotypes 26 . The clinical relevance of VAF for the majority of mutations is unknown.…”

Section: Discussionmentioning

confidence: 99%

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

Deng

Ling

et al. 2020

European J of Haematology

View full text Add to dashboard Cite

Tumor protein p53 (TP53) is frequently expressed in patients with myelodysplastic syndromes (MDS). Studies have already reported the poor prognostic impact of TP53 gene mutations in MDS patients. However, parts of this subgroup of patients with low-risk MDS still have relatively better survival and longer remission times. Therefore, we performed a meta-analysis to evaluate the prognostic difference intragene of variant allele frequency (VAF). The primary endpoint was overall survival (OS), and event-free survival (EFS) was selected as the secondary endpoint. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for OS and EFS from univariate and multivariate Cox proportional hazard models. A total of 4003 MDS patients and 1278 TP53-mutated patients from 13 cohorts of 11 studies up to February 24, 2020, were included in our meta-analysis. Pooled HRs suggested that a high mutant VAF had an adverse impact on OS (HR = 2.11, 95% CI: 1.48-3.01, P < .0001) but no impact on EFS (HR = 15.57, 95% CI: 0.75-324.44, P = .003) in MDS patients. Twenty percent is a proper threshold to set (HR = 2.02, 95% CI: 1.31-3.13, P = .001) and is a rough line between high clone burden and low clone burden, while 40% is an exact cutoff point (HR = 2.11, 95% CI: 1.26-3.55, P < .0001) to guide diagnosis and treatment. Beyond the traditional binary classification of gene mutation, we aimed to find a way to divide mutant molecular markers more specifically by VAF to provide clinical therapeutic values. Our meta-analysis indicates that a high VAF is an independent, adverse prognostic factor for OS in TP53 mutant MDS patients. Patients with mediate/low-frequency parts who could be treated like wide-type patients have relatively better survival and may choose allogeneic hematopoietic stem cell transplantation as conditions permitting. Further prospective studies are needed in the future, and a large subgroup analysis of the same cutoff point subgroups is needed to obtain a more reliable basis for the impact of other mutant gene VAFs on the prognosis of MDS.

show abstract

Section: Discussionmentioning

confidence: 99%

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

Deng

Ling

et al. 2020

European J of Haematology

View full text Add to dashboard Cite

show abstract

“…In addition to the recognized role in hematopoiesis and hematological malignancies [22,[27][28][29][30][31][32][33][34][35][36][37][38][39], RUNX1 has been recently identified as a key player in breast cancer development and tumor progression [40][41][42][43][44][45][46][47]. Findings from our group [48], reinforced by studies from others [49,50], have shown that RUNX1 plays a critical role in maintaining breast epithelial phenotype and prevents EMT.…”

Section: Introductionmentioning

confidence: 63%

“…We have shown that RUNX proteins reside in punctate subnuclear domains and their subnuclear localization is functionally linked with transcriptional activity [30,[82][83][84][85][86][87][88][89][90][91][92][93][94]. To investigate subcellular localization of RUNX1 in normal mammary epithelial cells, we performed immunofluorescence (IF) microscopy in actively proliferating MCF10A cells and imaged cells in interphase as well as those undergoing spontaneous mitoses.…”

Section: Runx1 Organizes As Punctate Foci In the Mammary Epithelial Cmentioning

confidence: 99%

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

et al. 2020

Self Cite

View full text Add to dashboard Cite

RUNX1 has recently been shown to play an important role in determination of mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal transition (EMT) are not known. Here, we report that interaction between RUNX1 and its heterodimeric partner CBFβ is essential for sustaining mammary epithelial cell identity. Disruption of RUNX1-CBFβ interaction, DNA binding, and association with mitotic chromosomes alters cell morphology, global protein synthesis, and phenotyperelated gene expression. During interphase, RUNX1 is organized as punctate, predominantly nuclear, foci that are dynamically redistributed during mitosis, with a subset localized to mitotic chromosomes. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and early G1 breast epithelial cells reveal RUNX1 associates with RNA Pol II-transcribed protein coding and long non-coding RNA genes and RNA Pol I-transcribed ribosomal genes critical for mammary epithelial proliferation, growth, and phenotype maintenance. A subset of these genes remains occupied by the protein during the mitosis to G1 transition. Together, these findings establish that the RUNX1-CBFβ complex is required for maintenance of the normal mammary epithelial phenotype and its disruption leads to EMT. Importantly, our results suggest, for the first time, that RUNX1 mitotic bookmarking of a subset of epithelial-related genes may be an important epigenetic mechanism that contributes to stabilization of the mammary epithelial cell identity.

show abstract

“…Our results suggest that RUNX1 is a target for positive regulation by RUNXOR. The RUNX1 gene is a Runt-related transcription factor, also known as AML1 (acute myelogenous leukemia 1), that regulates the expression of several important hematopoietic regulator genes [ 50 , 51 , 52 , 53 , 54 ], including genes regulating B-cell maturation [ 55 ], granulocyte differentiation, and megakaryocyte maturation [ 56 ]. The RUNX1 gene is frequently mutated in various hematological malignancies [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3–miR124 Axis

Thakuri

Zhang

Zhao

et al. 2020

Cells

View full text Add to dashboard Cite

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR–RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR–RUNX1–STAT3–miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.

show abstract

A germline point mutation in Runx1 uncouples its role in definitive hematopoiesis from differentiation

Cited by 14 publications

References 56 publications

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3–miR124 Axis

Contact Info

Product

Resources

About