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NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes
- Source :
- PLoS Genetics, Vol 15, Iss 11, p e1008463 (2019), PLoS Genetics
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- Nucleophosmin (NPM1) is frequently mutated or subjected to chromosomal translocation in acute myeloid leukemia (AML). NPM protein is primarily located in the nucleus, but the recurrent NPMc+ mutation, which creates a nuclear export signal, is characterized by cytoplasmic localization and leukemogenic properties. Similarly, the NPM-MLF1 translocation product favors the partial cytoplasmic retention of NPM. Regardless of their common cellular distribution, NPM-MLF1 malignancies engender different effects on hematopoiesis compared to NPMc+ counterparts, highlighting possible aberrant nuclear function(s) of NPM in NPMc+ and NPM-MLF1 AML. We performed a proteomic analysis and found that NPM and NPM-MLF1 interact with various nuclear proteins including subunits of the chromatin remodeling complexes ISWI, NuRD and P/BAF. Accordingly, NPM and NPM-MLF1 are recruited to transcriptionally active or repressed genes along with NuRD subunits. Although the overall gene expression program in NPM knockdown cells is similar to that resulting from NPMc+, NPM-MLF1 expression differentially altered gene transcription regulated by NPM. The abnormal gene regulation imposed by NPM-MLF1 can be characterized by the enhanced recruitment of NuRD to gene regulatory regions. Thus, different mechanisms would orchestrate the dysregulation of NPM function in NPMc+- versus NPM1-MLF1-associated leukemia.<br />Author summary NPMc+ mutation is the most common mutation in acute myeloid leukemia (AML) with prevalence in one third of all AML cases. NPM can also be involved in leukemogenic translocation including the t(3;5)(q25;q34) NPM-MLF1 translocation, which is associated to bad clinical course but remains poorly defined. We are reporting that NPM and the leukemogenic NPM-MLF1 play central role in chromatin organization and gene regulation in hematopoietic cells. A proteomic analysis provided the evidence that NPM and NPM-MLF1 are interacting with the chromatin remodeling complexes NuRD, P/BAF and ISWI in hematopoietic cells. The NPM nuclear depletion, such as imposed by the leukemogenic NPMc+ mutation, or the expression of NPM-MLF1 favors the uncontrolled recruitment of the CHD4/NuRD to chromatin and the abnormal regulation of NPM-target genes. Our results suggest that the abnormal gene regulation forced by NPM-MLF1 is different than the loss of nuclear function imposed by NPMc+, and it can be characterized by the enhanced recruitment of CHD4/NuRD to genes. Thus, NPM-MLF1 is likely to promote hematopoietic malignancies by disruption of gene regulation imposed by the NuRD activity.
- Subjects :
- Proteomics
Cancer Research
Chromosomal Proteins, Non-Histone
Physiology
Gene Expression
Cell Cycle Proteins
QH426-470
Biochemistry
Translocation, Genetic
Hematologic Cancers and Related Disorders
0302 clinical medicine
Immune Physiology
Medicine and Health Sciences
Transcriptional regulation
Nuclear protein
Genetics (clinical)
Adenosine Triphosphatases
Regulation of gene expression
0303 health sciences
Immune System Proteins
integumentary system
Chromosome Biology
Transcriptional Control
Nuclear Proteins
Hematology
Myeloid Leukemia
Chromatin
Precipitation Techniques
Cell biology
DNA-Binding Proteins
Leukemia, Myeloid, Acute
Oncology
Epigenetics
Nucleophosmin
Mi-2 Nucleosome Remodeling and Deacetylase Complex
Research Article
Acute Myeloid Leukemia
NPM1
DNA transcription
Immunology
Biology
Research and Analysis Methods
Antibodies
Chromatin remodeling
03 medical and health sciences
Cell Line, Tumor
Leukemias
Genetics
Humans
Immunoprecipitation
Protein Interaction Domains and Motifs
Gene Regulation
Nuclear export signal
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Biology and Life Sciences
Cancers and Neoplasms
Proteins
Cell Biology
Chromatin Assembly and Disassembly
Co-Immunoprecipitation
Myelodysplastic Syndromes
Mutation
030217 neurology & neurosurgery
Transcription Factors
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- PLOS Genetics
- Accession number :
- edsair.doi.dedup.....4154b4201be619f739140b453d6f6864