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Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

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Nucleophosmin 1 Mutations in Acute Myeloid Leukemia G C A T T A C G G C A T genes Review Nucleophosmin 1 Mutations in Acute Myeloid Leukemia Jabra Zarka 1 , Nicholas J. Short 1, Rashmi Kanagal-Shamanna 2 and Ghayas C. Issa 1,* 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] (J.Z.); [email protected] (N.J.S.) 2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] * Correspondence: [email protected] Received: 19 May 2020; Accepted: 9 June 2020; Published: 12 June 2020 Abstract: Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations. Keywords: AML; nucleophosmin (NPM1); gene expression; targeted therapies 1. Introduction Acute myeloid leukemia (AML) is a clinically and genomically heterogeneous malignancy despite having a relatively low number of genomic alterations compared to other cancers [1,2]. Mutations in bone marrow cells of the myeloid lineage or in myeloid progenitors lead to AML by hijacking properties from normal hematopoietic stem cells such as self-renewal, and via the recapitulation of the malignant progeny [3]. Treatment of AML had not changed in decades until recently, when several drugs received regulatory approval. This progress is largely due to an improved understanding of the biology and genomic landscape of this disease [4]. A mutation in the gene encoding nucleophosmin (NPM1) is one of the most commonly detected genomic alterations in AML. It is found in 20–30% of newly diagnosed AML and in 50% of those with a normal karyotype [1,5,6]. NPM1 is a chaperone protein that shuttles between the nucleus and cytoplasm with numerous functions. Multiple mechanisms through which mutations in NPM1 lead to leukemia have been described. However, despite an increased understanding of these mechanisms, there has not been to date any targeted therapy for NPM1-mutated AML. In this review, we summarize the current knowledge on the normal and aberrant functions of NPM1, highlight mechanisms of leukemogenesis and discuss rational therapeutic strategies. 2. Structure and Function of Wild-Type NPM1 2.1. NPM1 Protein Structure NPM1 is a ubiquitous and abundant protein that resides in the nucleoli under normal physiologic conditions but continuously shuttles between the nucleus and the cytoplasm. It is composed of Genes 2020, 11, 649; doi:10.3390/genes11060649 www.mdpi.com/journal/genes Genes 2020, 11, x FOR PEER REVIEW 2 of 16 2. Structure and Function of Wild-Type NPM1 2.1. NPM1 Protein Structure NPM1 is a ubiquitous and abundant protein that resides in the nucleoli under normal physiologicGenes 2020, 11conditions, 649 but continuously shuttles between the nucleus and the cytoplasm. It 2is of 16 composed of 294 amino acids with a molecular weight of 37 kDa. It is divided into three structural and294 functional amino acids domains: with a N molecular terminus, weight central of and 37 kDa.C terminus It is divided (Figure into 1). three The structuralN terminus and domain functional is highlydomains: conserved N terminus, among centralproteins and of Cthe terminus nucleoph (Figureosmin1 ).family. The N Nuclear terminus export domain signals is highly (NES) conserved which promoteamong the proteins translocation of the nucleophosminof NPM1 from the family. nucleu Nuclears to the cytoplasm export signals are found (NES) in which the N promoteterminus, the withtranslocation some contribution of NPM1 to fromthis function the nucleus by the to cent theral cytoplasm domain are[7]. foundThis translocation in the N terminus, is dependent with someon thecontribution interaction of to NES this with function the CRM1 by the export central prot domainein (Chromosomal [7]. This translocation Maintenance is 1, dependent also known on as the Exportininteraction 1 or XPO1) of NES [7,8]. with NPM1 the CRM1 binds denatured export protein protei (Chromosomalns in vitro, a hallmark Maintenance of chaperones 1, also [9]. known This as chaperoneExportin activity 1 or XPO1) is mediated [7,8]. NPM1 through binds the denaturedinteraction proteins of the N-terminusin vitro, a hallmarkwith numerous of chaperones proteins [ 9]. [10].This The chaperone hydrophobic activity N terminus is mediated also promotes through self-oligomerization, the interaction of the in which N-terminus five monomers with numerous form a pentamer,proteins [10 driving]. The hydrophobicNPM1 to the N nucleolus terminus also[11,12]. promotes The central self-oligomerization, domain contains in which two highly five monomers acidic regionsform necessary a pentamer, for driving binding NPM1 histones, to thethus nucleolus enabling [the11,12 chromatin]. The central remodeling domain functions contains of two NPM1 highly [13].acidic This regions domain necessary also has a for ribonuclease binding histones, activity thus implicated enabling in the ribosome chromatin biogenesis remodeling and functionsa nuclear of localizationNPM1 [13 signal]. This (NLS) domain [11,14]. also hasThe aC ribonuclease terminus domain activity has implicated a highly conserved in ribosome aromatic biogenesis region, and a particularlynuclear localization at the Trp-288 signal and (NLS) Trp-290 [11,14 sites]. The which C terminus form the domain nucleolar has localization a highly conserved signal (NoLS) aromatic [10,15].region, NoLS particularly is critical atfor the the Trp-288 localization and Trp-290of NPM1 sites to the which nucleoplasm, form the nucleolarwith any alteration localization at this signal site(NoLS) being [sufficient10,15]. NoLS to delocalize is critical NPM1 for the from localization the nucleolus of NPM1 [15]. to the nucleoplasm, with any alteration at this site being sufficient to delocalize NPM1 from the nucleolus [15]. Self-oligomerization Ribonuclease Chaperone function Translocation to cytoplasm Histone binding Nucleic acid binding NES Acidic regions NLS NoLS W288 W290 1 294 N-terminus Central C-terminus domain domain domain Figure 1. Nucleophosmin (NPM1) protein structure and functions. The nuclear export system (NES) Figure(blue) 1. locatedNucleophosmin in the N-terminus (NPM1) protein domain structure promotes and the functions. translocation The of nuclear NPM1 export from the system nucleus (NES) to the (blue)cytoplasm. located in The the central N-terminus domain domain contains promotes the acidic the translocation regions (green) of andNPM1 a nuclear from the localization nucleus to signalthe cytoplasm.(NLS) (orange), The central and mediatesdomain contains histone bindingthe acidic and regions the ribonuclease (green) and activity. a nuclear The localization C-terminus signal domain (NLS)has (orange), a highly conservedand mediates aromatic histone region binding and and the th nucleolare ribonuclease localization activity. signal The (NoLS)C-terminus (yellow) domain which hascontains a highly Trp-288 conserved and aromatic Trp-290. region and the nucleolar localization signal (NoLS) (yellow) which contains Trp-288 and Trp-290. The functions and localization of NPM1 are regulated by post-translational modifications [10,16]. NPM1The isfunctions phosphorylated and localization by cyclin-dependent of NPM1 are kinases regulated at diff erentby post-translational sites affecting the modifications various specific [10,16].functions NPM1 of is this phosphorylated protein. The by phosphorylation cyclin-dependent of kinases Ser-227, at Thr-234 different and sites Thr-237 affecting aff ectsthe various cell cycle specificprogression functions [10], of whereas this protein. the phosphorylation The phosphoryl of Thr-199ation of regulatesSer-227, Thr-234 the duplication and Thr-237 of cells affects by localizing cell cycleNPM1 progression to the centrosome [10], whereas [17 the,18]. phosphorylation In addition, the of phosphorylationThr-199 regulates of the Thr-199, duplication Thr-219, of cells Thr-234 by localizingand Thr-237 NPM1 inactivates to the centrosome the RNA [17,18]. binding In capabilities,addition, the thus phosphorylation affecting the roleof Thr-199, of NPM1 Thr-219, in ribosomal Thr- 234biogenesis and Thr-237 [19]. inactivates The acetylation the RNA of NPM1binding lysine capabilities, residues thus affects affecting histone the binding role of and NPM1 chromatin in ribosomaltranscription biogenesis [20]. [19]. The The acetyltransferase acetylation of p300 NPM1 modulates lysine residu the subcellulares affects histone localization binding of NPM1.and chromatinAcetylated transcription NPM1, predominantly [20]. The acetyltransferase localized in the p300 nucleoplasm, modulates associatesthe subcellular with localization transcriptionally of NPM1.active Acetylated RNA polymerase NPM1, II [predominantly21].
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