NAMPT INHIBITION SELECTIVELY TARGETS MDS MYELOBLASTS IN HIGH-RISK MDS WITH MONOSOMY 7 OR DEL(7Q)

NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS View ORCID Profile Nemo Ikonen , Tanja Ruokoranta , Salla Hyyppä , Ella Sinervuori , View ORCID Profile Juho J. Miettinen , Joseph Saad , Markus Vähä-Koskela , View ORCID Profile Caroline A. Heckman doi: https://doi.org/10.1101/2025.09.14.25335622 Nemo Ikonen 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 2 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nemo Ikonen Tanja Ruokoranta 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 3 Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Salla Hyyppä 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ella Sinervuori 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 2 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Juho J. Miettinen 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 2 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Juho J. Miettinen Joseph Saad 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 2 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Markus Vähä-Koskela 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 2 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Caroline A. Heckman 1 Institute for Molecular Medicine Finland - FIMM, Helsinki Institute of Life Science, University of Helsinki , Finland 2 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital , Finland Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Caroline A. Heckman For correspondence: caroline.heckman{at}helsinki.fi Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Chromosome 7 abnormalities -7 and -7q define a high-risk subset of myelodysplastic syndromes (MDS) with poor prognosis. The NAMPT gene, located at 7q22.3, encodes a rate limiting enzyme (nicotinamide phosphoribosyl transferase) in the NAD+ salvage pathway. Several inhibitors of NAMPT have been developed but their activity in MDS has not been previously described. In this study we investigated if MDS myeloblasts are susceptible to NAMPT inhibition. We show that primary bone marrow cells from patients with -7/-7q MDS exhibit strong and select sensitivity. Bulk viability assays and single cell, multiparametric flow cytometry confirmed enhanced NAMPT inhibitor sensitivity across leukemic cell populations, especially CD34+CD38+ blasts from -7/-7q MDS samples compared to non -7/-7q MDS and healthy donor bone marrow cells. The NAMPT inhibitor KPT-9274 combined with BCL2 inhibitor venetoclax was particularly effective at targeting MDS blasts compared to NAMPT inhibition alone. MDS samples with -7/-7q also showed significantly lower NAMPT expression compared to the non -7/-7q samples, indicative of haploinsufficient gene expression profile. In conclusion, these findings support NAMPT haploinsufficiency as a vulnerability and as biomarker for NAMPT inhibitor activity in -7/-7q MDS. Research letter Monosomy 7 and deletion of the q arm of chromosome 7 (-7/-7q) are recurrent alterations in myelodysplastic syndromes (MDS) present in approximately 10% of patients, and are associated with poor prognosis, shorter survival, and increased risk of progression to acute myeloid leukemia (AML) ( 1 , 2 ). Nicotinamide phosphoribosyl transferase (NAMPT), encoded by the NAMPT gene at chromosome 7q22.3, is the rate limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway ( 3 ). NAMPT inhibitors have shown good efficacy in preclinical studies of hematological malignancies as they effectively target cancer cell metabolism by blocking the salvage pathway which leads to NAD+ depletion and cell death ( 4 – 7 ). Previous studies have shown that AML blasts with -7/-7q are exceptionally sensitive to NAMPT inhibitors, with the sensitivity caused by NAMPT gene haploinsufficiency as a result of -7/-7q ( 8 , 9 ). The objective of this study was to investigate whether MDS blasts with -7/-7q are similarly susceptible to NAMPT inhibition, and if NAMPT haploinsufficiency could be a biomarker for NAMPT inhibitor activity in MDS. The patient sample cohort is described in Supplemental Table 1 , and the methods are described in full in the Supplemental Material and illustrated in Figure 1A . We first assessed the bulk cell viability-based drug sensitivity screening results from bone marrow (BM) cell samples collected from patients with MDS and compared it to data from BM mononuclear cells (MNCs) from healthy donors that were published previously ( 8 , 10 ). MDS and healthy donor BM-MNCs were incubated with the NAMPT inhibitor daporinad for 72 hours, and cell viability was measured using the CellTiter-Glo (CTG) and CellTox Green (CTxG) assays. Dose response curves ( Figure 1B–C ) were summarized as drug sensitivity scores (DSS) ( Figure 1D–E , Supplemental Tables 2–3 ). Overall, MDS samples were significantly more sensitive to NAMPT inhibition compared to the healthy donor samples in the CTG assay ( Supplemental Figure 1A ), indicative of an actionable therapeutic window and in line with previous studies in AML ( 4 , 5 , 8 , 11 ). The sample carrying -7/-7q was found to be the most responsive sample to NAMPT inhibition ( Figure 1D ). A similar trend was observed in the CTxG assay, with the -7/-7q MDS sample being the most sensitive, but there was no significant difference between MDS and healthy donor samples ( Figure 1E , Supplemental Figure 1B) . To assess if the -7/-7q MDS samples express less NAMPT due to NAMPT gene haploinsufficiency, we analyzed the gene expression in CD34+CD38-cells which showed that samples with -7/-7q had significantly lower NAMPT expression, indicating a haploinsufficient gene expression profile ( Figure 1F , Supplemental Table 4 ). Download figure Open in new tab Figure 1. MDS samples are sensitive to NAMPT inhibition. A) Illustration of the experimental workflow. Created with Biorender.com. B) Dose response curves for CellTiter-Glo-based and C) CellTox-Green-based bulk cell viability assays. Samples were treated with daporinad in 5 concentrations for 72 hours. D) Daporinad drug sensitivity score (DSS) values for MDS (n=6) and healthy (n=14) samples for CellTiter-Glo assay. Higher DSS indicates greater sensitivity. Data for healthy samples were summarized as one curve with standard deviations. E) Daporinad DSS values for MDS (n=7) and healthy (n=5) samples for CellTox Green assay. Data for healthy samples (n=5) were summarized as one score with standard deviation. F) NAMPT gene expression z-scores were compared between -7/-7q (n=5) and non -7/-7q MDS samples (n=25) using a the two-sample t-test. Gene expression profiles were analyzed from sorted CD34+CD38-cells. To investigate NAMPT inhibitor activity in different cell subpopulations, we performed flow cytometry-based drug sensitivity analysis. MDS BM-MNCs were incubated with the NAMPT inhibitors daporinad and KPT-9274 for 72 hours ( Supplemental Table 5 ) and subsequently stained with an antibody panel ( Supplemental Table 6 ). We observed that NAMPT inhibitors effectively target the different myeloblast populations in MDS samples and that CD34+, CD117+, CD34+CD117+, CD34+CD38- and CD34+CD38+ blasts from -7/-7q MDS were significantly more sensitive to NAMPT inhibition by daporinad compared to non -7/-7q MDS blasts ( Figure 2A , Supplemental Figure 2, Supplemental Table 7 ). Similar trends were observed for KPT-9274, however, the results were not significant ( Figure 2B ). Additionally, CD34+CD38+ blasts were more sensitive to daporinad and KPT-9274 than CD3+ T lymphocyte cells representing a healthy cell population control and CD14+ monocytic cell population in -7/-7q samples ( Supplemental Figure 3A-B ). These results indicate that the cell populations with a leukemic phenotype, particularly CD34+CD38+, are sensitive to NAMPT inhibition. Download figure Open in new tab Figure 2. Flow cytometry-based drug sensitivity screening shows that MDS samples with -7/-7q are highly sensitive to NAMPT inhibition. Drug sensitivity scores for the different cell populations for A) daporinad and B) KPT-9274. MDS samples with (n=8) and without (n=12) -7/-7q were incubated with the inhibitors for 72 hours and dose response curves were summarized as DSS values. Higher DSS indicates greater sensitivity. Samples with -7/-7q were compared to those without -7/-7q using a two-sample t-test. C) Comparison of cell viability between single agents and the combination of 1000 nM of KPT-9274 and 10 nM of venetoclax in CD34+CD38-cells in -7/-7q (n=5) and non -7/-7q (n=5) MDS samples. Samples were treated with the inhibitors for 72 hours, after which the cells were stained with detection antibodies to separate different cell types. Comparisons were done using a two-sample t-test and P values were adjusted using the Benjamini-Hochberg method. Next, we assessed KPT-9274 efficacy with three different clinically relevant drug combinations: venetoclax, azacitidine and cytarabine. We observed that the combination of KPT-9274 and venetoclax was significantly more cytotoxic towards CD34+CD38-cells in samples with -7/-7q compared to KPT-9274 alone ( Figure 2C ), and the combination was significantly more cytotoxic in -7/-7q compared to non -7/-7q samples ( Figure 2C ). The addition of azacitidine or cytarabine did not significantly decrease the cell viability ( Supplemental Table 8, Supplemental Figure 3C–D ). The data from this study demonstrate that NAMPT inhibitors are highly active in -7/-7q MDS ex vivo and establish NAMPT haploinsufficiency as a vulnerability and biomarker for NAMPT inhibitor activity. The findings suggest that patients with MDS, especially those with -7/-7q, could benefit from NAMPT inhibitors, and support expanded investigations, including clinical evaluation, of NAMPT inhibitors in high-risk MDS. Data Availability The data generated or analyzed during this study are included in this manuscript and its supplementary files. RNA counts data have been deposited to Zenodo: link and DOI will be provided following manuscript acceptance. All other relevant data to the current study are available from the corresponding author (Caroline Heckman, caroline.heckman{at}helsinki.fi ) on reasonable request. Declarations Ethics approval and consent to participate Bone marrow (BM) or peripheral blood (PB) samples were collected from patients with MDS after informed consent using protocols approved by the Institutional Review Board at the Helsinki University Hospital (permit numbers 239/13/03/00/2010 and 303/13/03/01/2011, Helsinki University Hospital Ethics Committee) in compliance with the Declaration of Helsinki. Consent for publication Not applicable Availability of data and materials The data generated or analyzed during this study are included in this manuscript and its supplementary files. RNA counts data have been deposited to Zenodo: link and DOI will be provided following manuscript acceptance. All other relevant data to the current study are available from the corresponding author (Caroline Heckman, caroline.heckman{at}helsinki.fi ) on reasonable request. Competing interest C.A.H. has received research funding for unrelated work from Oncopeptides, IMI2 projects HARMONY and HARMONY PLUS, WNTResearch, Orion, Kronos Bio, Novartis, Celgene, and Zentalis Pharmaceuticals; has been awarded honoraria from Amgen and consultancy fees from Autolus. M.V.-K has received research funding from Immunocore UK for unrelated work. Other authors declare no conflicts of interest. Funding This work was supported by the University of Helsinki, Cancer Foundation Finland, the Academy of Finland (grants 334781, 1357686, 1320185) (C.A.H.), the Sigrid Jusélius Foundation, Veritautien tutkimussäätiö (N.I.), Ida Montin Foundation (N.I.), the Finnish Cultural Foundation (N.I.), Orion Research Foundation (N.I.), Finnish Hematology Association (N.I.) and Instrumentarium Science Foundation (N.I.). Authors’ contributions N.I., T.R., S.H., E.S., J.M. and J.S. planned and conducted experiments. N.I. analyzed and interpreted the data. N.I., and C.A.H wrote the manuscript. M.V.-K. and C.A.H. provided leadership and funding. All authors read and approved the manuscript. Acknowledgements The authors thank the patients and clinics who made this study possible. The authors also thank the Finnish Hematology Registry and Clinical Biobank (FHRB) for providing the samples and clinical information. Instruments, drug plate preparation and part of the flow cytometry analysis were carried out by the FIMM High Throughput Biomedicine Unit, and library preparation and RNA sequencing were performed by Biomedicum Functional Genomics Unit and FIMM Genomics NGS Sequencing unit, which all are hosted by the University of Helsinki and supported by HiLIFE and Biocenter Finland. Cell sorting and analysis were performed at the HiLife Flow Cytometry Unit, University of Helsinki. N.I. is a Ph.D. candidate at the University of Helsinki. This work is submitted in partial fulfillment of the requirement for the Ph.D. The authors would like to express gratitude to Minna Suvela and Alun Parsons for their role in processing the samples for the study and to Natalia Mokrzecka for her help with the flow cytometry. Footnotes Updated manuscript text and abstract References 1. ↵ Haase D , Germing U , Schanz J , Pfeilstöcker M , Nösslinger T , Hildebrandt B , et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients . Blood . 2007 Dec 15; 110 ( 13 ): 4385 – 95 . doi: 10.1182/blood-2007-03-082404 OpenUrl Abstract / FREE Full Text 2. ↵ Schanz J , Tüchler H , Solé F , Mallo M , Luño E , Cervera J , et al. New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge . 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Blood Adv . 2024 Mar 27; 8 ( 7 ): 1621 – 33 . doi: 10.1182/bloodadvances.2023010435 OpenUrl CrossRef PubMed 9. ↵ Senagolage MD , Blaylock HZ , Khan S , Skuli SJ , Carroll MP , McNerney ME . NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation . Blood Neoplasia . 2025 Aug 20; 2 ( 3 ): 100119 . doi: 10.1016/j.bneo.2025.100119 OpenUrl CrossRef PubMed 10. ↵ Malani D , Kumar A , Brück O , Kontro M , Yadav B , Hellesøy M , et al. Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia . Cancer Discov . 2022 Feb ; 12 ( 2 ): 388 – 401 . doi: 10.1158/2159-8290.CD-21-0410 PubMed PMID: 34789538 ; PubMed Central PMCID: PMC9762335 . OpenUrl Abstract / FREE Full Text 11. ↵ Jones CL , Stevens BM , Pollyea DA , Culp-Hill R , Reisz JA , Nemkov T , et al. Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells . Cell Stem Cell . 2020 Nov 5; 27 ( 5 ): 748 - 764.e4 . doi: 10.1016/j.stem.2020.07.021 PubMed PMID: 32822582 ; PubMed Central PMCID: PMC7655603 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted March 24, 2026. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following NAMPT haploinsufficiency is a therapeutic vulnerability to NAMPT inhibition in -7/-7q MDS Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. 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