{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T16:19:54Z","timestamp":1773677994152,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,13]]},"group-title":"Cancer Biology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["P30CA022453"],"award-info":[{"award-number":["P30CA022453"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Menin scaffolds the oncogenic histone-lysine-N-methyltransferase (KMT2A)-fusion protein (FP) complex in\n                  <jats:italic>KMT2A-<\/jats:italic>\n                  r and wild-type\n                  <jats:italic>KMT2A<\/jats:italic>\n                  complex in\n                  <jats:italic>NPM1<\/jats:italic>\n                  -m acute myeloid leukemia (AML). Menin inhibitors (MIs) are effective in\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -r AML and\n                  <jats:italic>NPM1<\/jats:italic>\n                  -m AML. However, not all patients respond to MIs as monotherapy. In this preclinical study, we demonstrate that the MI ziftomenib, in combination with the XPO1 inhibitor selinexor, synergistically inhibited the growth of multiple\n                  <jats:italic>KMT2A-<\/jats:italic>\n                  r and\n                  <jats:italic>NPM1<\/jats:italic>\n                  -m AML cell lines (CI&lt;1). The combination suppressed colony formation in primary CD34+\n                  <jats:italic>KMT2A-<\/jats:italic>\n                  r progenitor cells without affecting normal stem cells. Robust apoptosis and decreased G2\/M populations were also evident. The combination downregulated HOXA9 and MEIS1 while upregulating monocytic differentiation marker CD11b in both the AML molecular signatures. RNA sequencing and proteomic analysis in\n                  <jats:italic>KMT2A-<\/jats:italic>\n                  r revealed suppression of multiple bona fide menin-KMT2A target genes. Our mechanistic studies also identified a novel role of XPO1 in stabilizing menin\u2019s binding to chromatin and its interactions with KMT2A and KMT2A\/MLLT3. XPO1 inhibitor-mediated disruption of these interactions, particularly in combination with ziftomenib, synergistically impairs oncogenic transcriptional programs.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , combination therapy improved survival in both MV4;11 and OCI-AML3 cell line and primary patient-derived\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -\n                  <jats:italic>r<\/jats:italic>\n                  and\n                  <jats:italic>NPM1<\/jats:italic>\n                  -m AML xenograft models in NSG mice, effective even at reduced drug doses. These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and XPO1 can be a more effective translational strategy for treating\n                  <jats:italic>KMT2A-<\/jats:italic>\n                  r and\n                  <jats:italic>NPM1<\/jats:italic>\n                  -m AML than MI monotherapy to deepen responses and delay\/prevent relapses.\n                <\/jats:p>","DOI":"10.64898\/2026.03.10.710924","type":"posted-content","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:10:18Z","timestamp":1773411018000},"source":"Crossref","is-referenced-by-count":0,"title":["Combined Menin and XPO1 inhibition drive synergistic antileukemic activity in\n                  <i>KMT2A<\/i>\n                  r and\n                  <i>NPM1<\/i>\n                  -m AML"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0188-6857","authenticated-orcid":false,"given":"Md. Hafiz","family":"Uddin","sequence":"first","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandhya","family":"Dhiman","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufen","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amro","family":"Aboukameel","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikram","family":"Dhillon","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff","family":"Aguillar","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Buck","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology\/Oncology, Children\u2019s Hospital of Michigan, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhinav","family":"Deol","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie L","family":"Boerner","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Polin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Kessler","sequence":"additional","affiliation":[{"name":"Kura Oncology, San Diego, CA 92130"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"Burrows","sequence":"additional","affiliation":[{"name":"Kura Oncology, San Diego, CA 92130"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asfar S.","family":"Azmi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaroslaw P.","family":"Maciejewski","sequence":"additional","affiliation":[{"name":"Translational Hematology and Oncology Research, Cleveland Clinic Foundation\/ Taussig Cancer Institute, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jevon","family":"Cutler","sequence":"additional","affiliation":[{"name":"Oregon Health & Science University (OHSU), Portland, Oregon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh Kumar","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI"},{"name":"Translational Hematology and 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