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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\u003Cp id=\u0022p-1\u0022\u003EThis study identifies a potential mechanism of action for lenalidomide in del(5q) myelodysplastic syndrome and identifies a single nonconserved amino acid in mice and humans that determines lenalidomide susceptibility. The results may facilitate the development of improved preclinical models and reinforces the importance of haploinsufficient genes in the pathogenesis and treatment of disease.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Edel(5q)\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emouse model\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ehuman cell lines\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eproteomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eubiquitination\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Edegradation\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group drug\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Elenalidomide\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003ELenalidomide is a highly effective treatment for multiple myeloma (MM) and myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del[5q]). In MM, the activity of lenalidomide is thought to be the result of activation of the cereblon (CRBN)-CRL4 E3 ubiquitin ligase to ubiquitinate the transcription factors IKZF1 and IKZF3 [Kr\u00f6nke J et al. \u003Cem\u003EScience.\u003C\/em\u003E 2014]. Emma C. Fink an MD\/PhD student at Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA, reported the results of a study [Fink EC et al. ASH 2014 (abstr 4)] indicating that in MDS with del(5q), lenalidomide induces the ubiquitination of casein kinase 1A1 (CSNK1A1) by CRBN-CRL4 and its subsequent degradation by the proteasome. Haploinsufficiency for CSNK1A1 sensitizes del(5q) to lenalidomide treatment and results in p53-dependent killing.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe investigators used global proteomics profiling in the myeloid cell line KG-1 to identify CSNK1A1 as a novel and direct target of lenalidomide. CSNK1A1 is haploinsufficient in del(5q) MDS and is a negative regulator of p53 and \u03b2-catenin [Schneider RK et al. \u003Cem\u003ECancer Cell.\u003C\/em\u003E 2014]. Lenalidomide treatment increased ubiquitination and decreased protein levels of CSNK1A1.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EAdditional analyses showed that lenalidomide treatment resulted in a dose-dependent decrease in CSNK1A1 protein levels in multiple human cell lines without altering CSNK1A1 mRNA levels. In addition, the investigators found that CSNK1A1 associates with CRBN-CRL4 only in the presence of lenalidomide, suggesting that lenalidomide induces the recruitment of CSNK1A1 to CRBN-CRL4. When mixed in vitro, CSNK1A1 is ubiquitinated by CRBN-CRL4. Ubiquitinated CSNK1A1 is then subsequently degraded by the proteasome leading to low protein levels.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe investigators then analyzed the effects of CSNK1A1 haploinsufficiency on lenalidomide sensitivity in a genetically defined Csnk1a1 conditional knockout mouse model. They found that mouse cells do not respond to lenalidomide. Expression of human CRBN rendered the cells sensitive to lenalidomide, suggesting that sequence differences between mouse and human CRBN, the direct binding partner of lenalidomide, explained this species-specific response. A single amino acid change in mouse CRBN (isoleucine to valine at position 391; I391V) was identified that restored lenalidomide response in mouse CRBN.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EAfter identifying a method to make mouse cells sensitive to lenalidomide, the investigators returned to the Csnk1a1 conditional knockout mouse model. Bone marrow cells from control mice or mice heterozygous for Csnk1a1 were transduced with the mouse CRBN I391V allele then treated with lenalidomide. Unlike controls, which did not respond to lenalidomide, Csnk1a1\u003Csup\u003E\u003Cem\u003E+\/\u2013\u003C\/em\u003E\u003C\/sup\u003E cells depleted almost 50% over 5 days of lenalidomide treatment. These results demonstrate that hematopoietic Csnk1a1\u003Csup\u003E\u003Cem\u003E+\/\u2013\u003C\/em\u003E\u003C\/sup\u003E cells are more sensitive to lenalidomide than wild type cells with 2 copies of the gene (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Csnk1a1+\/\u0026#x2013; Cells Are More Sensitive to LenalidomideCsnk1a1, casein kinase 1A1; Len, lenalidomide.Reproduced with permission from EC Fink, MD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2095496422\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Csnk1a1\u0026amp;lt;sup\u0026amp;gt;+\/\u0026#x2013;\u0026amp;lt;\/sup\u0026amp;gt; Cells Are More Sensitive to LenalidomideCsnk1a1, casein kinase 1A1; Len, lenalidomide.Reproduced with permission from EC Fink, MD.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11647\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003ECsnk1a1\u003Csup\u003E+\/\u2013\u003C\/sup\u003E Cells Are More Sensitive to Lenalidomide\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ECsnk1a1, casein kinase 1A1; Len, lenalidomide.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EReproduced with permission from EC Fink, MD.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-10\u0022\u003ELenalidomide treatment led to the induction of the p53 target p21 in Csnk1a1\u003Csup\u003E+\/\u2013\u003C\/sup\u003E cells, suggesting that the activation of the p53 pathway is involved in lenalidomide\u2019s downstream mechanism. Deletion of a single allele of p53 completely rescued the lenalidomide sensitivity of Csnk1a1\u003Csup\u003E+\/\u2013\u003C\/sup\u003E cells, implying a p53 killing mechanism. Further, CSNK1A1 overexpression reduces lenalidomide sensitivity in del(5q) patient samples (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Effect of Overexpression of CSNK1A1 on Lenalidomide Sensitivity of del(5q)CSNK1A1, casein kinase 1A1; del(5q), deletion of chromosome 5q; DMSO, dimethyl sulfoxide; len, lenalidomide; MDS, myelodysplastic syndrome.Reproduced with permission from EC Fink, MD.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2095496422\u0022 data-figure-caption=\u0022Effect of Overexpression of CSNK1A1 on Lenalidomide Sensitivity of del(5q)CSNK1A1, casein kinase 1A1; del(5q), deletion of chromosome 5q; DMSO, dimethyl sulfoxide; len, lenalidomide; MDS, myelodysplastic syndrome.Reproduced with permission from EC Fink, MD.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/55\/7\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11648\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EEffect of Overexpression of CSNK1A1 on Lenalidomide Sensitivity of del(5q)\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003ECSNK1A1, casein kinase 1A1; del(5q), deletion of chromosome 5q; DMSO, dimethyl sulfoxide; len, lenalidomide; MDS, myelodysplastic syndrome.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EReproduced with permission from EC Fink, MD.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-14\u0022\u003ETo conclude, Dr Fink noted that another study [Macbeth et al. ASH 2014 (abstr 3606)] showed similar results regarding lenalidomide inducing ubiquitination of CSNK1A1 by the CRBN-CRL4 and its subsequent degradation.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/55\/7.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzo9aq\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo9aq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}