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.
Highlights
Dysregulation of tumor suppressors and oncogenes can influence gene expression either directly or indirectly by altering the structure of chromatin and/or DNA methylation patterns, thereby reshaping the epigenome with consequences for a myriad of cellular functions
NPM can 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
Summary
Dysregulation of tumor suppressors and oncogenes can influence gene expression either directly or indirectly by altering the structure of chromatin and/or DNA methylation patterns, thereby reshaping the epigenome with consequences for a myriad of cellular functions. This phenomenon is well described in acute myeloid leukemia (AML) [1, 2], where characteristic mutations or chromosomal translocations frequently affect the function of transcriptional regulators. The frameshift mutation of NPM1 exon 12 that promotes de novo creation of a nuclear export signal and promotes NPM cytoplasmic accumulation (NPMc+) [3], influences the transcriptome in hematopoietic cells [4, 5]. NPM1 is one of the most commonly mutated/rearranged genes in hematological malignancies
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