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<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" >  <link rel="dns-prefetch" href="//d33xdlntwy0kbs.cloudfront.net" /> <link rel="dns-prefetch" href="//www.google.com" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <link rel="dns-prefetch" href="//www.googletagmanager.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <link rel="shortcut icon" href="https://www.biorxiv.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/10.1101/2023.03.16.532874v2.full.pdf" /> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="/content/10.1101/2023.03.16.532874v2.full.txt" /> <meta name="type" content="article" /> <meta name="category" content="article" /> <meta name="HW.identifier" content="/biorxiv/early/2024/11/13/2023.03.16.532874.atom" /> <meta name="HW.pisa" content="biorxiv;2023.03.16.532874v2" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Upfront Menin-inhibitor resistance in multiply pretreated leukemias" /> <meta name="DC.Identifier" content="10.1101/2023.03.16.532874" /> <meta name="DC.Date" content="2024-11-13" /> <meta name="DC.Publisher" content="Cold Spring Harbor Laboratory" /> <meta name="DC.Rights" content="© 2024, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A -rearranged ( KMT2A -r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners ( MLLT10, MLLT4 ) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A-AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred. ### Competing Interest Statement GMM is an employee and shareholder of Syndax Pharmaceuticals Inc. KMB has previously consulted for Agios and Novartis and has received research funding from Syndax Pharmaceuticals Inc. CL received a research training grant from Institut Servier. SKT has served on scientific advisory boards for Kura Oncology and Syndax Pharmaceuticals for pediatric clinical development of Menin inhibitors and receives research funding from Kura Oncology. She also serves on the scientific advisory board for Aleta Biotherapeutics, receives research funding from Beam Therapeutics and Incyte Corporation, received travel support from Amgen, and has consulted for bluebird bio for unrelated studies. MPC has been involved as a consultant for Janssen Pharmaceuticals and on advisory committee for Cartogrpahy Biosciences." /> <meta name="DC.Contributor" content="Leila Mahdavi" /> <meta name="DC.Contributor" content="Haley Goodrow" /> <meta name="DC.Contributor" content="Fatemeh Alikarami" /> <meta name="DC.Contributor" content="Alexandra Lenard" /> <meta name="DC.Contributor" content="Simone S. Riedel" /> <meta name="DC.Contributor" content="Clara Libbrecht" /> <meta name="DC.Contributor" content="Isabel Bowser" /> <meta name="DC.Contributor" content="Sarah K. Tasian" /> <meta name="DC.Contributor" content="Catherine D. Falkenstein" /> <meta name="DC.Contributor" content="Bryan Manning" /> <meta name="DC.Contributor" content="Sarah Skuli" /> <meta name="DC.Contributor" content="Martin P. Carroll" /> <meta name="DC.Contributor" content="Gerald Wertheim" /> <meta name="DC.Contributor" content="Sheng F. Cai" /> <meta name="DC.Contributor" content="Gerard McGeehan" /> <meta name="DC.Contributor" content="Hongbo M. Xie" /> <meta name="DC.Contributor" content="Kathrin M. Bernt" /> <meta name="article:published_time" content="2024-11-13" /> <meta name="article:section" content="New Results" /> <meta name="citation_title" content="Upfront Menin-inhibitor resistance in multiply pretreated leukemias" /> <meta name="citation_abstract" lang="en" content="<p>Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A-AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.</p>" /> <meta name="citation_journal_title" content="bioRxiv" /> <meta name="citation_publisher" content="Cold Spring Harbor Laboratory" /> <meta name="citation_publication_date" content="2024/01/01" /> <meta name="citation_mjid" content="biorxiv;2023.03.16.532874v2" /> <meta name="citation_id" content="2023.03.16.532874v2" /> <meta name="citation_public_url" content="https://www.biorxiv.org/content/10.1101/2023.03.16.532874v2" /> <meta name="citation_abstract_html_url" content="https://www.biorxiv.org/content/10.1101/2023.03.16.532874v2.abstract" /> <meta name="citation_full_html_url" content="https://www.biorxiv.org/content/10.1101/2023.03.16.532874v2.full" /> <meta name="citation_pdf_url" content="https://www.biorxiv.org/content/biorxiv/early/2024/11/13/2023.03.16.532874.full.pdf" /> <meta name="citation_doi" content="10.1101/2023.03.16.532874" /> <meta name="citation_num_pages" content="17" /> <meta name="citation_article_type" content="Article" /> <meta name="citation_section" content="New Results" /> <meta name="citation_firstpage" content="2023.03.16.532874" /> <meta name="citation_author" content="Leila Mahdavi" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Haley Goodrow" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Fatemeh Alikarami" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Alexandra Lenard" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Simone S. Riedel" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Clara Libbrecht" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Isabel Bowser" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Sarah K. Tasian" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author_institution" content="Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Abramson Cancer Center" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0003-1327-1662" /> <meta name="citation_author" content="Catherine D. Falkenstein" /> <meta name="citation_author_institution" content="Division of Pediatric Oncology, Children’s Hospital of Philadelphia" /> <meta name="citation_author" content="Bryan Manning" /> <meta name="citation_author_institution" content="Department of Medicine, Perelman School of Medicine, University of Pennsylvania" /> <meta name="citation_author" content="Sarah Skuli" /> <meta name="citation_author_institution" content="Department of Medicine, Perelman School of Medicine, University of Pennsylvania" /> <meta name="citation_author" content="Martin P. 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We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners ( MLLT10, MLLT4 ) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A-AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred. ### Competing Interest Statement GMM is an employee and shareholder of Syndax Pharmaceuticals Inc. KMB has previously consulted for Agios and Novartis and has received research funding from Syndax Pharmaceuticals Inc. CL received a research training grant from Institut Servier. SKT has served on scientific advisory boards for Kura Oncology and Syndax Pharmaceuticals for pediatric clinical development of Menin inhibitors and receives research funding from Kura Oncology. She also serves on the scientific advisory board for Aleta Biotherapeutics, receives research funding from Beam Therapeutics and Incyte Corporation, received travel support from Amgen, and has consulted for bluebird bio for unrelated studies. MPC has been involved as a consultant for Janssen Pharmaceuticals and on advisory committee for Cartogrpahy Biosciences." /> <meta name="og-title" property="og:title" content="Upfront Menin-inhibitor resistance in multiply pretreated leukemias" /> <meta name="og-url" property="og:url" content="https://www.biorxiv.org/content/10.1101/2023.03.16.532874v2" /> <meta name="og-site-name" property="og:site_name" content="bioRxiv" /> <meta name="og-description" property="og:description" content="Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A -rearranged ( KMT2A -r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners ( MLLT10, MLLT4 ) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A-AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred. ### Competing Interest Statement GMM is an employee and shareholder of Syndax Pharmaceuticals Inc. KMB has previously consulted for Agios and Novartis and has received research funding from Syndax Pharmaceuticals Inc. CL received a research training grant from Institut Servier. SKT has served on scientific advisory boards for Kura Oncology and Syndax Pharmaceuticals for pediatric clinical development of Menin inhibitors and receives research funding from Kura Oncology. She also serves on the scientific advisory board for Aleta Biotherapeutics, receives research funding from Beam Therapeutics and Incyte Corporation, received travel support from Amgen, and has consulted for bluebird bio for unrelated studies. MPC has been involved as a consultant for Janssen Pharmaceuticals and on advisory committee for Cartogrpahy Biosciences." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="citation_date" content="2024-11-13" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/10.1101/2023.03.16.532874v2.ppt" /> <meta name="description" content="bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution" /> <meta name="generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://www.biorxiv.org/content/10.1101/2023.03.16.532874v2" /> <link rel="shortlink" href="https://www.biorxiv.org/node/4220526" /> <title>Upfront Menin-inhibitor resistance in multiply pretreated leukemias | bioRxiv</title> <link 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data-pisa-master="biorxiv;2023.03.16.532874" data-apath="/biorxiv/early/2024/11/13/2023.03.16.532874.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-biorxiv-article-top clearfix has-author-tooltip" > <span class="biorxiv-article-type"> New Results </span> <h1 class="highwire-cite-title" id="page-title">Upfront Menin-inhibitor resistance in multiply pretreated leukemias</h1> <div class="highwire-cite-authors" ><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">Leila</span> <span class="nlm-surname">Mahdavi</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">Haley</span> <span class="nlm-surname">Goodrow</span></span>, <span class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">Fatemeh</span> <span class="nlm-surname">Alikarami</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">Alexandra</span> <span class="nlm-surname">Lenard</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">Simone S.</span> <span class="nlm-surname">Riedel</span></span>, <span class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">Clara</span> <span class="nlm-surname">Libbrecht</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">Isabel</span> <span class="nlm-surname">Bowser</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="7"><a href="http://orcid.org/0000-0003-1327-1662" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Sarah K.</span> <span class="nlm-surname">Tasian</span></span>, <span class="highwire-citation-author" data-delta="8"><span class="nlm-given-names">Catherine D.</span> <span class="nlm-surname">Falkenstein</span></span>, <span class="highwire-citation-author" data-delta="9"><span class="nlm-given-names">Bryan</span> <span class="nlm-surname">Manning</span></span>, <span class="highwire-citation-author" data-delta="10"><span class="nlm-given-names">Sarah</span> <span class="nlm-surname">Skuli</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="11"><a href="http://orcid.org/0000-0002-5622-3735" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Martin P.</span> <span class="nlm-surname">Carroll</span></span>, <span class="highwire-citation-author" data-delta="12"><span class="nlm-given-names">Gerald</span> <span class="nlm-surname">Wertheim</span></span>, <span class="highwire-citation-author" data-delta="13"><span class="nlm-given-names">Sheng F.</span> <span class="nlm-surname">Cai</span></span>, <span class="highwire-citation-author" data-delta="14"><span class="nlm-given-names">Gerard</span> <span class="nlm-surname">McGeehan</span></span>, <span class="highwire-citation-author" data-delta="15"><span class="nlm-given-names">Hongbo M.</span> <span class="nlm-surname">Xie</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="16"><a href="http://orcid.org/0000-0002-0691-356X" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Kathrin M.</span> <span class="nlm-surname">Bernt</span></span></span></div> <div class="highwire-cite-metadata" ><span class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">doi:</span> https://doi.org/10.1101/2023.03.16.532874 </span></div> </div> <div id="hw-article-author-popups-node-4220526--2174598163" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Leila Mahdavi </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Division of Pediatric Oncology, Children’s Hospital of Philadelphia</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Leila%2BMahdavi%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Mahdavi%20L&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3ALeila%2BMahdavi%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">Haley Goodrow </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Division of Pediatric Oncology, Children’s Hospital of Philadelphia</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Haley%2BGoodrow%2B" target="_blank" class="" 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first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Fatemeh%2BAlikarami%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Alikarami%20F&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AFatemeh%2BAlikarami%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">Alexandra Lenard </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Division of Pediatric Oncology, Children’s Hospital of Philadelphia</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Alexandra%2BLenard%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Lenard%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AAlexandra%2BLenard%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">Simone S. 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Cai </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>6</span><span class='nlm-institution'>Department of Medicine, Memorial Sloan Kettering Cancer Center</span>, New York, NY, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Sheng%2BF.%2BCai%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Cai%20SF&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3ASheng%2BF.%2BCai%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-14"><div class="author-tooltip-name">Gerard McGeehan </div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Gerard%2BMcGeehan%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=McGeehan%20G&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AGerard%2BMcGeehan%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-15"><div class="author-tooltip-name">Hongbo M. Xie </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Division of Pediatric Oncology, Children’s Hospital of Philadelphia</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>2</span><span class='nlm-institution'>Department of Bioinformatics and Health Informatics (DBHI), Children’s Hospital of Philadelphia</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Hongbo%2BM.%2BXie%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Xie%20HM&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AHongbo%2BM.%2BXie%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-16"><div class="author-tooltip-name">Kathrin M. Bernt </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Division of Pediatric Oncology, Children’s Hospital of Philadelphia</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Abramson Cancer Center</span>, Philadelphia, PA, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Kathrin%2BM.%2BBernt%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Bernt%20KM&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AKathrin%2BM.%2BBernt%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link"><a href="http://orcid.org/0000-0002-0691-356X" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Kathrin M. Bernt</a></li><li class="author-corresp-email-link last"><span>For correspondence: <a href="mailto:berntk@chop.edu" class="" data-icon-position="" data-hide-link-title="0">berntk@chop.edu</a></span></li></ul></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs pane-panels-ajax-tab-tabs" > <div class="pane-content"> <div class="item-list"><ul class="tabs inline panels-ajax-tab"><li class="first"><a href="/content/10.1101/2023.03.16.532874v2" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_art" data-target-id="highwire_article_tabs" data-entity-context="node:4220526" data-trigger="" data-url-enabled="1">Abstract</a><a href="/panels_ajax_tab/biorxiv_tab_art/node:4220526/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2023.03.16.532874v2.full-text" class="panels-ajax-tab-tab" data-panel-name="article_tab_full_text" data-target-id="highwire_article_tabs" data-entity-context="node:4220526" data-trigger="full-text" data-url-enabled="1">Full Text</a><a href="/panels_ajax_tab/article_tab_full_text/node:4220526/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2023.03.16.532874v2.article-info" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_info" data-target-id="highwire_article_tabs" data-entity-context="node:4220526" data-trigger="article-info" data-url-enabled="1">Info/History</a><a href="/panels_ajax_tab/biorxiv_tab_info/node:4220526/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2023.03.16.532874v2.article-metrics" class="panels-ajax-tab-tab" data-panel-name="article_tab_metrics" data-target-id="highwire_article_tabs" data-entity-context="node:4220526" data-trigger="article-metrics" data-url-enabled="1">Metrics</a><a href="/panels_ajax_tab/article_tab_metrics/node:4220526/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2023.03.16.532874v2.supplementary-material" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_data" data-target-id="highwire_article_tabs" data-entity-context="node:4220526" data-trigger="supplementary-material" data-url-enabled="1">Supplementary material</a><a href="/panels_ajax_tab/biorxiv_tab_data/node:4220526/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li class="last"><a href="/content/10.1101/2023.03.16.532874v2.full.pdf+html" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_pdf" data-target-id="highwire_article_tabs" data-entity-context="node:4220526" data-trigger="full.pdf+html" data-url-enabled="1"><i class="icon-file-alt"></i> Preview PDF</a><a href="/panels_ajax_tab/biorxiv_tab_pdf/node:4220526/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li></ul></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs-container" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="biorxiv_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-biorxiv_tab_art"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2 class="">Abstract</h2><p id="p-2">Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of <em>KMT2A</em>-rearranged (<em>KMT2A</em>-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of <em>KMT2A-r</em> leukemias with high-risk features. Three AMLs with high-risk fusion partners (<em>MLLT10, MLLT4</em>) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated <em>KMT2A-AFF1</em> ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and <em>TP53</em> mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.</p></div><h3>Competing Interest Statement</h3><p id="p-3">GMM is an employee and shareholder of Syndax Pharmaceuticals Inc. KMB has previously consulted for Agios and Novartis and has received research funding from Syndax Pharmaceuticals Inc. CL received a research training grant from Institut Servier. SKT has served on scientific advisory boards for Kura Oncology and Syndax Pharmaceuticals for pediatric clinical development of Menin inhibitors and receives research funding from Kura Oncology. She also serves on the scientific advisory board for Aleta Biotherapeutics, receives research funding from Beam Therapeutics and Incyte Corporation, received travel support from Amgen, and has consulted for bluebird bio for unrelated studies. MPC has been involved as a consultant for Janssen Pharmaceuticals and on advisory committee for Cartogrpahy Biosciences. </p><div class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn-update fn-group-summary-of-updates" id="fn-1"><p id="p-4">Additional experiments were conducted in NSG mice.</p></li></ul></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-biorxiv-copyright" > <div class="pane-content"> <div class="field field-name-field-highwire-copyright field-type-text field-label-inline clearfix"><div class="field-label">Copyright </div><div class="field-items"><div class="field-item even">The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.<span class="license-type"> It is made available under a <a 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