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PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes
- Source :
- Genes & Development. 31:973-989
- Publication Year :
- 2017
- Publisher :
- Cold Spring Harbor Laboratory, 2017.
-
Abstract
- Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell- and T-cell-specific factors. Additionally, Phf6KO cells show significant down-regulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.
- Subjects :
- 0301 basic medicine
Lineage (genetic)
Biology
Gene Knockout Techniques
Mice
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Leukemia, B-Cell
Genetics
Animals
Nucleosome
Cell Lineage
Gene
Transcription factor
ChIA-PET
Homeodomain Proteins
Lymphoma, Non-Hodgkin
Chromatin
3. Good health
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Repressor Proteins
Phenotype
030104 developmental biology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Homeobox
Developmental biology
Research Paper
Signal Transduction
Developmental Biology
Subjects
Details
- ISSN :
- 15495477 and 08909369
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Genes & Development
- Accession number :
- edsair.doi.dedup.....c25c181dbd6da37a42b34705e051e40b