Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

Thivakaran, Aniththa; Botezatu, Lacramioara; Hönes, Judith; Schütte, Judith; Vaßen, Lothar; Al-Matary, Yahya; Patnana, Pradeep Kumar; Zeller, Amos; Heuser, Michael; Thol, Felicitas; Gabdoulline, Razif; Olberding, Nadine; Frank, Daria; Suslo, Marina; Köster, Renata; Lennartz, Klaus; Görgens, André; Giebel, Bernd; Opalka, Bertram; Khandanpour, Cyrus

doi:10.3324/haematol.2017.167288

Cited by 22 publications

(28 citation statements)

References 51 publications

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“…Growth factor independence 1b (GFI1B) encodes a key transcription factor regulating dormancy and proliferation of hematopoietic stem cells (HSCs) and the development of erythroid and megakaryocytic cells (31,32). Recent studies had revealed its critical role as a tumor suppressor in AML, as low GFI1B expression is associated with poor patient survival (33). Consistent with previous studies, the 6 patients with GFI1B enhancer mutation have significantly shorter time to relapse ( Figure 3F).…”

Section: Risk Enhancer/promoter Snvs and Small Indelssupporting

confidence: 84%

Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

Gao

Ding

et al. 2019

Preprint

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Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here we developed a computational framework to identify risk noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as candidate risk mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation signatures can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.

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Section: Risk Enhancer/promoter Snvs and Small Indelssupporting

confidence: 84%

Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

Gao

Ding

et al. 2019

Preprint

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“…However, the role of GFI1B in AML is uncertain. Despite GFI1B often being increased in AML patients (29)(30)(31)(32), a recent study suggests that low GFI1B expression correlates with poor patient outcome and that in mice, Gfi1b depletion accelerates progression to AML from myelodysplasia driven by a NUP98-HOXD13 fusion protein (33). Collectively, these observations suggest widespread contributions by GFI family proteins to lineage allocation during normal hematopoiesis and both oncogenic and oncosuppressor roles in hematologic malignancies.…”

mentioning

confidence: 99%

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

McClellan

Casey

Bareyan

et al. 2019

Molecular and Cellular Biology

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Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1B’s obligate effector, lysine-specific demethylase 1 (LSD1). We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin-remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2, and ZNF217) in an LSD1-dependent manner to control acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.

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“…The results showed that a putative binding site of growth factor independent 1B transcriptional repressor (GFI1B) was present in the promoter region of PGM5-AS1 ( Supplementary Table S1). GFI1B is an inhibitory transcription factor that regulates the quiescence of hematopoietic stem cells and differentiation of red blood cells and platelets [26]. Plasmid (pcDNA-GFI1B) was used to overexpress GFI1B, and small interfering RNA (si-GFI1B) assisted in knocking down GFI1B ( Figure S1B).…”

Section: Resultsmentioning

confidence: 99%

PGM5-AS1 Inhibits the Malignant Phenotype of Colon Cancer Cells by Regulating PAEP and NME1

Hui

Chen

Wang

et al. 2020

Preprint

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Background: An increasing number of long non-coding RNAs (lncRNAs) is recognized to be associated with drug resistance in CRC.Methods: For identifying differentially expressed target genes regarding PGM5-AS1, RNA transcriptome sequencing was performed. The mechanism by which PGM5-AS1 regulates its target genes was explored by performing experiments such as fluorescent in situ hybridization assay, dual luciferase reporter gene assay and RNA immunoprecipitation. Results: The lncRNA PGM5-AS1 was identified by analyzing data from the original microarray data set of colon cancer (GSE75970). PGM5-AS1 additionally suppressed acquired oxaliplatin resistance in CRC cells. Malignant phenotype of PGM5-AS1 was inhibited by recruiting SRSF3 to activate alternative splicing and being a sponge specific to hsa-miR-423-5p.Conclusions: Downregulation of PGM5-AS1 in oxaliplatin-resistant colon cancer tissues and cell lines is induced by transcriptional inhibition of GFI1B. PGM5-AS1 recruited SRSF3 to activate alternative splicing to downregulate the expression of PAEP. In addition, PGM5-AS1 could competitively bind with hsa-miR-423-5p to upregulate the expression of NME1. PGM5-AS1 inhibits the proliferation, invasion, migration and acquired oxaliplatin resistance of colon cancer cells through these two pathways.

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Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome

Cited by 22 publications

References 51 publications

Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers

Growth Factor Independence 1B-Mediated Transcriptional Repression and Lineage Allocation Require Lysine-Specific Demethylase 1-Dependent Recruitment of the BHC Complex

PGM5-AS1 Inhibits the Malignant Phenotype of Colon Cancer Cells by Regulating PAEP and NME1

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