scholarly journals Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q− syndrome

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4666-4673 ◽  
Author(s):  
Madhu S. Kumar ◽  
Anupama Narla ◽  
Atsushi Nonami ◽  
Ann Mullally ◽  
Nadya Dimitrova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Erythroid Differentiation ◽  
Deletion Syndrome ◽  
Chromosomal Deletion ◽  
Reciprocal Effect ◽  
Protein Coding ◽  
Megakaryocytic Differentiation ◽  
Molecular Abnormalities ◽  
Human Malignancy ◽  
The Common

Abstract Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q− syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q− syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q− syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q− syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q− syndrome.

Coordinate Loss of a MicroRNA Mir 145 and a Protein-Coding Gene RPS14 Cooperate in the Pathogenesis of 5q- Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 947-947 ◽  
Author(s):  
Madhu Kumar ◽  
Anupama Narla ◽  
Atsushi Nonami ◽  
Brian Ball ◽  
Christine Chin ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Macrocytic Anemia ◽  
Erythroid Differentiation ◽  
Deletion Syndrome ◽  
Disease Genes ◽  
Reciprocal Effect ◽  
Protein Coding ◽  
Molecular Abnormalities ◽  
Human Malignancy

Abstract Abstract 947 Large hemizygous chromosomal deletions are among the most common molecular abnormalities in cancer, but the identification of critical haploinsufficiency disease genes within the deleted regions has been difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a well-studied chromosomal deletion syndrome characterized by a consistent clinical phenotype with macrocytic anemia and thrombocytosis. We have previously shown that while hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not account for the thrombocytosis. Evaluation of the effects of all protein coding genes in the CDR on hematopoietic differentiation showed no genes other than RPS14 altered the ratio of megakaryocytic to erythroid cells, either alone or in combination with RPS14. We therefore examined the 5q- syndrome CDR for non-coding RNAs and identified a microRNA, miR-145, which targets Fli-1, a transcriptional factor that regulates megakaryocyte development. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 in CD34+ cells decreases megakaryocyte production, while inhibition of miR-145 or overexpression of Fli-1 has the reciprocal effect. These findings have been validated in vivo using transgenic mice. Moreover, the combined loss of miR-145 and RPS14 cooperate to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate for the first time that coordinate deletion of a microRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis

Blood ◽  
2021 ◽  
Author(s):  
Oriol Alejo-Valle ◽  
Karoline Weigert ◽  
Raj Bhayadia ◽  
Michelle Ng ◽  
Hasan Issa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Repression ◽  
Reverse Genetics ◽  
Erythroid Differentiation ◽  
Chromosome 21 ◽  
Hematopoietic Stem ◽  
Megakaryocytic Differentiation ◽  
Megakaryoblastic Leukemia ◽  
Multiple Routes ◽  
Induced Apoptosis

Given the plasticity of hematopoietic stem/progenitor cells, multiple routes of differentiation must be blocked during acute myeloid leukemia pathogenesis - the molecular basis of which is incompletely understood. Here we report that post-transcriptional repression of the transcription factor ARID3A by miR-125b is a key event in megakaryoblastic leukemia (AMKL) pathogenesis. AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing this disease. We show that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncover Arid3a as the main miR-125b target behind this synergy. We demonstrate that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFβ-induced apoptosis and cell cycle arrest in complex with SMAD2/3. While Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a dual megakaryocytic/erythroid differentiation blockade and subsequently AMKL. Inversely, restoring ARID3A expression relieves the megakaryocytic differentiation arrest in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of post-transcriptional gene regulation can interplay to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease.

Novel Role for EKLF in Megakaryocyte-Erythroid Differential Lineage Commitment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4205-4205
Author(s):  
Maria Pilar Frontelo ◽  
Deepa Manwani ◽  
Mariann Galdass ◽  
Holger Karsunky ◽  
Patrick G. Gallagher ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Erythroid Differentiation ◽  
Lineage Commitment ◽  
Loss Of Function ◽  
Erythroid Precursor ◽  
Molecular Analyses ◽  
Lineage Decision ◽  
Quantitative Examination ◽  
The Common ◽  
First Time

Abstract Megakaryocytes and erythroid cells are thought to derive from a common progenitor. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We have used gain- and loss-of-function studies, expression profiling, and molecular analyses to show that EKLF, a transcription factor whose crucial role in erythroid gene regulation is well established, plays an unexpected function in the lineage decision between megakaryopoiesis and erythropoiesis. It achieves this by inhibiting the formation of megakaryocytes derived from the common megakaryocyte-erythroid precursor (MEP) cell, while at the same time stimulating erythroid differentiation. Quantitative examination of EKLF expression during hematopoiesis reveals that, unlike genes whose presence is required for establishment of both lineages, EKLF expression is uniquely down-regulated in megakaryocytes after formation of the MEP. Microarray and molecular analyses support these observations and suggest that megakaryocytic inhibition is achieved, at least in part, by EKLF repression of Fli-1 message levels. These results reveal for the first time that EKLF plays a directive role in erythroid and megakaryocyte lineage decisions prior to establishment of the red cell compartment and suggest a model for transcription factor antagonism in MEP differential lineage commitment. Tests as predicted by this model will be discussed.

scholarly journals The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis

2021 ◽  
Author(s):  
Oriol Alejo-Valle ◽  
Karoline Weigert ◽  
Raj Bhayadia ◽  
Michelle Ng ◽  
Stephan Emmrich ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Repression ◽  
Reverse Genetics ◽  
Erythroid Differentiation ◽  
Chromosome 21 ◽  
Hematopoietic Stem ◽  
Megakaryocytic Differentiation ◽  
Megakaryoblastic Leukemia ◽  
Multiple Routes ◽  
Induced Apoptosis

Given the plasticity of hematopoietic stem/progenitor cells, multiple routes of differentiation must be blocked during acute myeloid leukemia pathogenesis - the molecular basis of which is incompletely understood. Here we report that post-transcriptional repression of transcription factor ARID3A by miR-125b is a key event in megakaryoblastic leukemia (AMKL) pathogenesis. AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing this disease. We show that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncover Arid3a as the main miR-125b target underlying this synergy. We demonstrate that during normal hematopoiesis this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFbeta-induced apoptosis and cell cycle arrest in complex with SMAD2/3. While Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a dual megakaryocytic/erythroid differentiation blockade and subsequently AMKL. Inversely, restoring ARID3A expression relieves the megakaryocytic differentiation arrest in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of post-transcriptional gene regulation interplay to block multiple routes of hematopoietic differentiation and cause leukemia. Surmounting this differentiation blockade in megakaryoblastic leukemia by restoring the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease.

Knockdown of transcription factor forkhead box O3 (FOXO3) suppresses erythroid differentiation in human cells and zebrafish

2015 ◽  
Vol 460 (4) ◽  
pp. 923-930 ◽  
Author(s):  
Hai Wang ◽  
Yanming Li ◽  
Sifeng Wang ◽  
Qian Zhang ◽  
Jiawen Zheng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Erythroid Differentiation ◽  
Human Cells ◽  
Forkhead Box

Abstract 14308: Integrative Epigenomic Analysis Identifies Enhancer Modifying Variants Linked to Cardiomyopathy Genes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anthony M Gacita ◽  
Dominic Fullenkamp ◽  
Joyce C Ohiri ◽  
Tess Pottinger ◽  
Megan Puckelwartz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Clinical Care ◽  
Phenotypic Expression ◽  
Transcription Factor Binding ◽  
Clinical Feature ◽  
Protein Coding ◽  
Human Cardiomyocytes ◽  
Factor Binding ◽  
Enhancer Function

Introduction: Inherited cardiomyopathy is caused by mutations in more than 100 genes. A well-recognized clinical feature of genetic cardiomyopathy is varying phenotypic expression. Even with identical primary mutations, there is a range of clinical outcomes. Genetic variants in protein coding regions have been shown to alter the phenotypic expression of primary cardiomyopathy-causing mutations. However, the contribution of noncoding variation has been less well studied. Methods and Results: We used an integrative analysis of >20 publicly-available heart enhancer function and enhancer target datasets to identify genomic regions predicted to regulate the cardiomyopathy genes, MYH7 and LMNA . We identified two candidate enhancer clusters around the MYH7 gene and three clusters around the LMNA gene. We tested enhancers in these clusters using reporter assays and CRISPr-mediated deletion in human cardiomyocytes derived from induced pluripotent stem cells (iCMs). We identified a super enhancer upstream of MYH7 that is necessary for high MYH7 expression in iCMs. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. We created an informatic pipeline that extended this strategy genomewide to identify an additional enhancer modifying variant upstream of MYH7 . This variant disrupts a transcription factor binding site upstream of MYH7 and limits MYH7 upregulation. We extended these analyses by examining clinical correlates, finding that this variant correlated with a more dilated left ventricle over time in patients with cardiomyopathy. Conclusions: We identified two enhancer regions important for MYH7 expression in iCMs. These enhancer regions may be utilized to induce MYH7 during human development and heart failure. MYH7 changes in heart failure have been linked to cardiomyopathy phenotypes. The variant upstream of MYH7 likely alters these changes and results in a more severe phenotype. These findings demonstrate that noncoding variants have clinical utility and targeted assessment of noncoding modifiers may become integrated into clinical care.

Malan Syndrome

2019 ◽  
pp. 153-162
Author(s):  
Manuela Priolo ◽  
Martin Zenker ◽  
Raoul C. Hennekam
Keyword(s):  
Transcription Factor ◽  
Differential Diagnosis ◽  
Intellectual Disability ◽  
Bone Age ◽  
Nuclear Factor ◽  
Connective Tissues ◽  
Causative Gene ◽  
Molecular Abnormalities ◽  
Large Head ◽  
Visual Problems

The chapter discusses the clinical phenotype and the molecular abnormalities in Malan syndrome, an overgrowth condition caused by mutations in the NFIX gene. Overgrowth in Malan syndrome can be present at birth, especially in terms of large head circumference, and it continues after birth, although statural growth velocity decreases with age. The syndrome is also characterized by dysmorphic facial traits, skeletal abnormalities, intellectual disability, visual problems, and advanced bone age. This condition is allelic to another overgrowth disorder, Marshall-Smith syndrome, with which it shares several clinical features and should be considered in the differential diagnosis. The causative gene for both conditions, NFIX, encodes the nuclear factor one X-type transcription factor, which regulates the growth of several types of connective tissues.

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