NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes

English version

Autoři: Anaïs Darracq ^aff001; Helen Pak ^aff001; Vincent Bourgoin ^aff001; Farah Zmiri ^aff001; Graham Dellaire ^aff003; El Bachir Affar ^aff001; Eric Milot ^aff001
Působiště autorů: Maisonneuve Rosemont Hospital Research Center, CIUSSS Est de l’Île de Montréal, boulevard l’Assomption, Montreal, Quebec, Canada ^aff001; Molecular Biology Program, University of Montreal, Montreal, Quebec, Canada ^aff002; Departments of Pathology and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada ^aff003; Department of Medicine, University of Montreal, Boulevard Edouard-Montpetit, Montréal, Quebec, Canada, Montreal, Quebec, Canada ^aff004
Vyšlo v časopise: NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008463
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008463

Souhrn

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.

Klíčová slova:

Acute myeloid leukemia – Antibodies – Co-immunoprecipitation – DNA transcription – Gene expression – Gene regulation – Chromatin – Transcriptional control

Zdroje

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