FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2891652691> ?p ?o ?g. }

• W2891652691 endingPage "357" @default.
• W2891652691 startingPage "355" @default.
• W2891652691 abstract "In this issue of Cancer Cell, Brunetti and colleagues elucidate the role of mutant NPM1c and its cytoplasmic mislocalization in acute myeloid leukemia. They demonstrate how mutant-specific degradation or relocalization leads to a loss of the stem cell signature characteristic of these leukemias and induces their differentiation. In this issue of Cancer Cell, Brunetti and colleagues elucidate the role of mutant NPM1c and its cytoplasmic mislocalization in acute myeloid leukemia. They demonstrate how mutant-specific degradation or relocalization leads to a loss of the stem cell signature characteristic of these leukemias and induces their differentiation. Acute myeloid leukemia (AML), the tenth leading cause of cancer deaths in the United States, is often a devastating disease, especially in older adults and those with an adverse biologic subtype (Döhner et al., 2015Döhner H. Weisdorf D.J. Bloomfield C.D. Acute myeloid leukemia.N. Engl. J. Med. 2015; 373: 1136-1152Crossref PubMed Scopus (1995) Google Scholar). AML is heterogeneous both in regard to host factors such as age, but particularly with respect to intrinsic disease biology (Papaemmanuil et al., 2016Papaemmanuil E. Gerstung M. Bullinger L. Gaidzik V.I. Paschka P. Roberts N.D. Potter N.E. Heuser M. Thol F. Bolli N. et al.Genomic classification and prognosis in acute myeloid leukemia.N. Engl. J. Med. 2016; 374: 2209-2221Crossref PubMed Scopus (2291) Google Scholar). The intrinsic genetic heterogeneity of AML, which has been well described, includes a sizeable minority whose blasts have NPM1 mutations (Papaemmanuil et al., 2016Papaemmanuil E. Gerstung M. Bullinger L. Gaidzik V.I. Paschka P. Roberts N.D. Potter N.E. Heuser M. Thol F. Bolli N. et al.Genomic classification and prognosis in acute myeloid leukemia.N. Engl. J. Med. 2016; 374: 2209-2221Crossref PubMed Scopus (2291) Google Scholar). AML patients whose blasts have an NPM1 mutation but do not have a FLT3 internal tandem duplication (ITD) represent a common molecular category and have a relatively good prognosis. However, despite its designation as a “favorable” subtype, approximately 40% of patients will succumb to their disease. Moreover, AML with NPM1 mutations that are associated with other genetic subtypes, such as high allelic burden FLT3 ITD mutations, are considered adverse (Döhner et al., 2015Döhner H. Weisdorf D.J. Bloomfield C.D. Acute myeloid leukemia.N. Engl. J. Med. 2015; 373: 1136-1152Crossref PubMed Scopus (1995) Google Scholar), mandating a potentially dangerous allogeneic stem cell transplant after an initial response. The work of Brunetti et al., 2018Brunetti L. Gundry M.C. Sorcini D. Guzman A.G. Huang Y.-H. Ramabadran R. Gionfriddo I. Mezzasoma F. Milano F. Nabet B. et al.Mutant NPM1 maintains the leukemic state through HOX expression.Cancer Cell. 2018; 34 (this issue): 499-512Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar helps us understand the pathophysiology and potential translational aspects of such mutations. Mutations in NPM1, the most frequently mutated gene in cytogenetically normal AML, are typically small insertions in the terminal exon resulting in the loss of the nuclear localization signal and the concurrent generation of a C-terminal nuclear export signal (NES); mutant NPM1 is therefore exported to the cytoplasm (NPM1-cytoplasmic or NPM1c), whereas wild-type NPM1 is localized in the nucleus (Sportoletti et al., 2015Sportoletti P. Varasano E. Rossi R. Mupo A. Tiacci E. Vassiliou G. Martelli M.P. Falini B. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications.Leukemia. 2015; 29: 269-278Crossref PubMed Scopus (33) Google Scholar). However, proof that this mislocalization is absolutely required for maintenance of the leukemic state has been lacking. Second, it has been known that NPM1 mutant AML cells highly express members of a stem cell gene signature including HOXA and HOXB genes and MEIS1 (Alcalay et al., 2005Alcalay M. Tiacci E. Bergomas R. Bigerna B. Venturini E. Minardi S.P. Meani N. Diverio D. Bernard L. Tizzoni L. et al.Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.Blood. 2005; 106: 899-902Crossref PubMed Scopus (258) Google Scholar). However, whether this association between NPM1c, its presence in the cytoplasm, and overexpression of HOX genes is merely an epiphenomenon or specifically related to the mutation has been debated. To directly address these questions, the authors took advantage of mutant-specific CRISPR-Cas9-mediated editing of the mutant NPM1 allele, which resulted in a loss of the NES and thereby nuclear re-localization of NPM1c. The loss of cytoplasmic NPM1c caused a proliferative defect and resulted in differentiation of AML cells confirming the requirement of its aberrant localization for the maintenance of AML. Second, the authors wished to confirm that the HOX/MEIS1 gene signature was a consequence of cytoplasmic localization of NPM1c as well. Indeed HOX/MEIS1 gene expression was rapidly lost upon CRISPR-mediated relocalization of NPM1c. In parallel with these transcriptional changes, the authors observed a decrease in chromatin modifications, such as H3K4me3, which are associated with active gene expression. Furthermore, enhancers near the HOXA-MEIS1 loci were activated in the mutated state and inactivated upon disruption of the C-terminal NES. To evaluate the immediate effects of loss of NPM1c protein, the authors employed an inducible FKPB-based degron system allowing the rapid degradation of FKBP-tagged mutant protein. Degradation of the cytoplasmic NPM1c did result in a rapid downregulation of HOX/MEIS1 gene expression and loss of leukemogenicity. The similarities between NPM1c re-localization and degradation suggest that the cytoplasmic export of NPM1c and not merely the loss of NPM1c in the nucleus is functionally important in these AML cells. Finally, by using a lentiviral construct to drive HOXA9 and MEIS1 expression, the authors showed that even with nuclear relocalization of mutant NPM1, overexpression of HOXA9 and MEIS1 repressed differentiation, underscoring their importance as central transcriptional regulators downstream of NPM1c. In addition to the commonality and less-than-ideal prognosis, an important reason that NPM1 mutation represents a therapeutic target is that this mutation is considered to be a leukemia-initiating event. Evidence for the primacy of the NPM1 mutation is its typical persistence at relapse (Ivey et al., 2016Ivey A. Hills R.K. Simpson M.A. Jovanovic J.V. Gilkes A. Grech A. Patel Y. Bhudia N. Farah H. Mason J. et al.UK National Cancer Research Institute AML Working GroupAssessment of minimal residual disease in standard-risk AML.N. Engl. J. Med. 2016; 374: 422-433Crossref PubMed Scopus (521) Google Scholar). This contrasts with the less profound but still potentially beneficial consequences of inhibiting a progression mutation such as FLT3 ITD, which encodes an overactive kinase. Indeed, small molecules that target FLT3 ITD, or IDH1/2, which cause neomorphic production of the leukemogenic reactive product 2-hydroxyglutarate, have led to important advances in the treatment of this difficult disease. Could NPM1 mutations also be targetable? As suggested by Brunetti et al., 2018Brunetti L. Gundry M.C. Sorcini D. Guzman A.G. Huang Y.-H. Ramabadran R. Gionfriddo I. Mezzasoma F. Milano F. Nabet B. et al.Mutant NPM1 maintains the leukemic state through HOX expression.Cancer Cell. 2018; 34 (this issue): 499-512Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, being able to reverse the mislocalization could be profoundly anti-leukemogenic. However, reversing mislocalization pharmacologically is more challenging than inhibiting an overactive signaling molecule. Brunetti and colleagues reasoned that NPM1c cytoplasmic localization could represent a therapeutic opportunity if the mutant species could either be destroyed, leaving the normal allelic product of the typically heterozygous state to function normally, or redirected back into the nucleus where leukemogenicity might be suppressed. The key developmental therapeutic message from the Brunetti paper was utilization of the nuclear export protein (XPO1) inhibitor KPT-330 to retain mutant NPM1 within the nucleus. Indeed, relocalization of NPM1c could be elicited by treatment with this inhibitor; XPO1 inhibition resulted in NPM1c nuclear relocalization, differentiation, HOX gene repression, and suppressed leukemia cell growth (Figure 1). While exposing the cells to KPT-330 did result in relocalization of the target NPM1 mutant species, it likely also caused the redistribution of other proteins participating in the maintenance of the leukemic phenotype. Overactive XPO1 is thought to be leukemogenic due to expulsion of growth suppressors from the nucleus such as p53, Rb, p21, and others (Kau et al., 2004Kau T.R. Way J.C. Silver P.A. Nuclear transport and cancer: from mechanism to intervention.Nat. Rev. Cancer. 2004; 4: 106-117Crossref PubMed Scopus (364) Google Scholar). KPT-330 is in development as an anti-leukemic agent that could yield therapeutic efficacy by maintaining such tumor suppressors in the nucleus (Etchin et al., 2016Etchin J. Montero J. Berezovskaya A. Le B.T. Kentsis A. Christie A.L. Conway A.S. Chen W.C. Reed C. Mansour M.R. et al.Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.Leukemia. 2016; 30: 190-199Crossref PubMed Scopus (62) Google Scholar). Thus, the pharmacologic aspect of the Brunetti study does not precisely prove that the mechanism of this drug is via NPM1 relocalization. Moreover, in clinical trials, KPT-330 was mainly active in lymphoma and myeloma. In AML, results were more modest (Garzon et al., 2017Garzon R. Savona M. Baz R. Andreeff M. Gabrail N. Gutierrez M. Savoie L. Mau-Sorensen P.M. Wagner-Johnston N. Yee K. et al.A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia.Blood. 2017; 129: 3165-3174Crossref PubMed Scopus (87) Google Scholar); the drug caused side effects, particularly profound anorexia thought to be due to CNS effects. Other less CNS-penetrating analogs are being developed and may allow better tolerance and perhaps better therapeutic index in AML. The limited numbers of AML patients having been treated with XPO1 inhibition preclude discernment at this time as to any increased KPT-330 activity in the mutant NPM1 subtype. In summary, the work by Brunetti et al., 2018Brunetti L. Gundry M.C. Sorcini D. Guzman A.G. Huang Y.-H. Ramabadran R. Gionfriddo I. Mezzasoma F. Milano F. Nabet B. et al.Mutant NPM1 maintains the leukemic state through HOX expression.Cancer Cell. 2018; 34 (this issue): 499-512Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar has given new insight into the importance of NPM1c localization for maintenance of AML. These studies demonstrate that cytoplasmic NPM1c is essential for maintaining active chromatin marks that may help maintain HOX/MEIS1 gene expression, thereby inhibiting differentiation of AML cells. However, it remains unclear what the link is between NPM1c nuclear export and chromatin modifiers to induce a specific group of stem cell genes. The study by Brunetti et al., 2018Brunetti L. Gundry M.C. Sorcini D. Guzman A.G. Huang Y.-H. Ramabadran R. Gionfriddo I. Mezzasoma F. Milano F. Nabet B. et al.Mutant NPM1 maintains the leukemic state through HOX expression.Cancer Cell. 2018; 34 (this issue): 499-512Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar also suggests strategies, including use of nuclear export inhibitors, to reverse the altered state, but specificity of the nuclear export inhibitor molecules both in terms of therapeutic index and activity in specific genetic subtypes of AML, especially NPM1 mutant disease, remains to be elucidated. Future studies could also focus on how we can target mutant NPM1c more specifically. Other approaches could target processes downstream of NPM1c with small molecules that interfere with chromatin complexes required to maintain the expression of stem cell-associated genes that appear to be essential for NPM1c+ leukemias (Kühn et al., 2016Kühn M.W. Song E. Feng Z. Sinha A. Chen C.W. Deshpande A.J. Cusan M. Farnoud N. Mupo A. Grove C. et al.Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia.Cancer Discov. 2016; 6: 1166-1181Crossref PubMed Scopus (120) Google Scholar). Continued characterization of leukemogenic mechanisms used by oncogenes that drive AML should deliver new therapeutic approaches for this devastating disease. Mutant NPM1 Maintains the Leukemic State through HOX ExpressionBrunetti et al.Cancer CellSeptember 10, 2018In BriefBrunetti et al. show that specific loss of NPM1c from the cytoplasm leads to downregulation of HOX genes and differentiation in NPM1 mutant AML. Blocking NPM1c nuclear export by XPO1 inhibition reduces cytoplasmic NPM1c, promotes AML differentiation, and prolongs the survival of a mouse model of NPM1c+ AML. Full-Text PDF Open Archive" @default.
• W2891652691 created "2018-09-27" @default.
• W2891652691 creator A5012956545 @default.
• W2891652691 creator A5029398334 @default.
• W2891652691 creator A5071023119 @default.
• W2891652691 date "2018-09-01" @default.
• W2891652691 modified "2023-09-29" @default.
• W2891652691 title "Location, Location, Location: Mutant NPM1c Cytoplasmic Localization Is Required to Maintain Stem Cell Genes in AML" @default.
• W2891652691 cites W1952112347 @default.
• W2891652691 cites W2028885314 @default.
• W2891652691 cites W2095251486 @default.
• W2891652691 cites W2098058376 @default.
• W2891652691 cites W2276580523 @default.
• W2891652691 cites W2419140434 @default.
• W2891652691 cites W2602169105 @default.
• W2891652691 cites W2890477656 @default.
• W2891652691 doi "https://doi.org/10.1016/j.ccell.2018.08.013" @default.
• W2891652691 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30205041" @default.
• W2891652691 hasPublicationYear "2018" @default.
• W2891652691 type Work @default.
• W2891652691 sameAs 2891652691 @default.
• W2891652691 citedByCount "5" @default.
• W2891652691 countsByYear W28916526912018 @default.
• W2891652691 countsByYear W28916526912020 @default.
• W2891652691 countsByYear W28916526912021 @default.
• W2891652691 crossrefType "journal-article" @default.
• W2891652691 hasAuthorship W2891652691A5012956545 @default.
• W2891652691 hasAuthorship W2891652691A5029398334 @default.
• W2891652691 hasAuthorship W2891652691A5071023119 @default.
• W2891652691 hasBestOaLocation W28916526911 @default.
• W2891652691 hasConcept C104317684 @default.
• W2891652691 hasConcept C143065580 @default.
• W2891652691 hasConcept C190062978 @default.
• W2891652691 hasConcept C28328180 @default.
• W2891652691 hasConcept C54355233 @default.
• W2891652691 hasConcept C86803240 @default.
• W2891652691 hasConcept C95444343 @default.
• W2891652691 hasConceptScore W2891652691C104317684 @default.
• W2891652691 hasConceptScore W2891652691C143065580 @default.
• W2891652691 hasConceptScore W2891652691C190062978 @default.
• W2891652691 hasConceptScore W2891652691C28328180 @default.
• W2891652691 hasConceptScore W2891652691C54355233 @default.
• W2891652691 hasConceptScore W2891652691C86803240 @default.
• W2891652691 hasConceptScore W2891652691C95444343 @default.
• W2891652691 hasIssue "3" @default.
• W2891652691 hasLocation W28916526911 @default.
• W2891652691 hasLocation W28916526912 @default.
• W2891652691 hasOpenAccess W2891652691 @default.
• W2891652691 hasPrimaryLocation W28916526911 @default.
• W2891652691 hasRelatedWork W1983725845 @default.
• W2891652691 hasRelatedWork W2009416280 @default.
• W2891652691 hasRelatedWork W2101920100 @default.
• W2891652691 hasRelatedWork W2111311526 @default.
• W2891652691 hasRelatedWork W2111958127 @default.
• W2891652691 hasRelatedWork W2117110650 @default.
• W2891652691 hasRelatedWork W2130233455 @default.
• W2891652691 hasRelatedWork W2140441397 @default.
• W2891652691 hasRelatedWork W2150914257 @default.
• W2891652691 hasRelatedWork W2156674132 @default.
• W2891652691 hasVolume "34" @default.
• W2891652691 isParatext "false" @default.
• W2891652691 isRetracted "false" @default.
• W2891652691 magId "2891652691" @default.
• W2891652691 workType "article" @default.