{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T07:09:11Z","timestamp":1769843351449,"version":"3.49.0"},"reference-count":54,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T00:00:00Z","timestamp":1700179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005972","name":"German Cancer Aid","doi-asserted-by":"publisher","award":["70114873"],"award-info":[{"award-number":["70114873"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Menin\/MEN1 is a scaffold protein that participates in proliferation, regulation of gene transcription, DNA damage repair, and signal transduction. In hematological malignancies harboring the KMT2A\/MLL1 (MLLr) chromosomal rearrangements, the interaction of the oncogenic fusion protein MLLr with MEN1 has been shown to be essential. MEN1 binders inhibiting the MEN1 and KMT2A interaction have been shown to be effective against MLLr AML and B-ALL in experimental models and clinical studies. We hypothesized that in addition to the MEN1\u2013KMT2A interaction, alternative mechanisms might be instrumental in the MEN1 dependency of leukemia. We first mined and analyzed data from publicly available gene expression databases, finding that the dependency of B-ALL cell lines on MEN1 did not correlate with the presence of MLLr. Using shRNA-mediated knockdown, we found that all tested B-ALL cell lines were sensitive to MEN1 depletion, independent of the underlying driver mutations. Most multiple myeloma cell lines that did not harbor MLLr were also sensitive to the genetic depletion of MEN1. We conclude that the oncogenic role of MEN1 is not limited to the interaction with KMT2A. Our results suggest that targeted degradation of MEN1 or the development of binders that induce global changes in the MEN1 protein structure may be more efficient than the inhibition of individual MEN1 protein interactions.<\/jats:p>","DOI":"10.3390\/ijms242216472","type":"journal-article","created":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T15:30:53Z","timestamp":1700235053000},"page":"16472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1\u2013KMT2A Interaction"],"prefix":"10.3390","volume":"24","author":[{"given":"Tatjana Magdalena","family":"Wolffhardt","sequence":"first","affiliation":[{"name":"Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8525-5015","authenticated-orcid":false,"given":"Franz","family":"Ketzer","sequence":"additional","affiliation":[{"name":"Center for Molecular and Cellular Oncology, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5516-2395","authenticated-orcid":false,"given":"Stefano","family":"Telese","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Wirth","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-7253","authenticated-orcid":false,"given":"Alexey","family":"Ushmorov","sequence":"additional","affiliation":[{"name":"Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.tibs.2013.05.005","article-title":"Menin: A scaffold protein that controls gene expression and cell signaling","volume":"38","author":"Matkar","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fped.2017.00004","article-title":"MLL-Rearranged Leukemias\u2014An Update on Science and Clinical Approaches","volume":"5","author":"Winters","year":"2017","journal-title":"Front. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41392-019-0095-0","article-title":"Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials","volume":"4","author":"Cheng","year":"2019","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nrc2253","article-title":"MLL translocations, histone modifications and leukaemia stem-cell development","volume":"7","author":"Krivtsov","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.ccell.2019.11.001","article-title":"A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia","volume":"36","author":"Krivtsov","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"447","DOI":"10.4155\/fmc.13.214","article-title":"Challenges and opportunities in targeting the menin-MLL interaction","volume":"6","author":"Cierpicki","year":"2014","journal-title":"Future Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1002\/cmdc.202000972","article-title":"A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia","volume":"16","author":"Nizamuddin","year":"2021","journal-title":"ChemMedChem"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1038\/s41375-021-01309-y","article-title":"Therapeutic implications of menin inhibition in acute leukemias","volume":"35","author":"Issa","year":"2021","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1038\/s41375-021-01146-z","article-title":"Menin is necessary for long term maintenance of meningioma-1 driven leukemia","volume":"35","author":"Libbrecht","year":"2021","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.stemcr.2020.05.013","article-title":"Chromatin Complexes Maintain Self-Renewal of Myeloid Progenitors in AML: Opportunities for Therapeutic Intervention","volume":"15","author":"Uckelmann","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s11899-021-00621-9","article-title":"Novel Targeted Therapeutics in Acute Myeloid Leukemia: An Embarrassment of Riches","volume":"16","author":"Grieselhuber","year":"2021","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1097\/PPO.0000000000000571","article-title":"Menin Inhibitors in Acute Myeloid Leukemia\u2014What Does the Future Hold?","volume":"28","author":"Swaminathan","year":"2022","journal-title":"Cancer J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1182\/blood-2021-146944","article-title":"Safety and Efficacy of Menin Inhibition in Patients (Pts) with MLL-Rearranged and NPM1 Mutant Acute Leukemia: A Phase (Ph) 1, First-in-Human Study of SNDX-5613 (AUGMENT 101)","volume":"138","author":"Stein","year":"2021","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"(2021). AML Prognoses Better with Menin\u2013MLL Inhibitor?. Cancer Discov., 11, 216\u2013217.","DOI":"10.1158\/2159-8290.CD-NB2020-120"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"458","DOI":"10.18632\/oncotarget.13444","article-title":"Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin","volume":"8","author":"Svoboda","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1016\/j.celrep.2017.02.025","article-title":"Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer","volume":"18","author":"Dreijerink","year":"2017","journal-title":"Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nm.3830","article-title":"Targeting the MLL complex in castration-resistant prostate cancer","volume":"21","author":"Malik","year":"2015","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Brzezinka, K., Nevedomskaya, E., Lesche, R., Haegebarth, A., Ter Laak, A., Fern\u00e1ndez-Montalv\u00e1n, A.E., Eberspaecher, U., Werbeck, N.D., Moenning, U., and Siegel, S. (2020). Characterization of the Menin-MLL Interaction as Therapeutic Cancer Target. Cancers, 12.","DOI":"10.3390\/cancers12010201"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1038\/leu.2014.232","article-title":"Five gene probes carry most of the discriminatory power of the 70-gene risk model in multiple myeloma","volume":"28","author":"Heuck","year":"2014","journal-title":"Leukemia"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, C., Wendlandt, E.B., Darbro, B., Xu, H., Thomas, G.S., Tricot, G., Chen, F., Shaughnessy, J.D., and Zhan, F. (2021). Genetic Analysis of Multiple Myeloma Identifies Cytogenetic Alterations Implicated in Disease Complexity and Progression. Cancers, 13.","DOI":"10.3390\/cancers13030517"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1182\/blood.2021012806","article-title":"The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML","volume":"139","author":"Heikamp","year":"2022","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41408-021-00603-3","article-title":"Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)","volume":"12","author":"Fiskus","year":"2022","journal-title":"Blood Cancer J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41408-023-00826-6","article-title":"Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1","volume":"13","author":"Fiskus","year":"2023","journal-title":"Blood Cancer J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1007\/s11095-011-0608-1","article-title":"Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA","volume":"28","author":"Singh","year":"2011","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4520","DOI":"10.1038\/s41467-022-32285-1","article-title":"TP53-dependent toxicity of CRISPR\/Cas9 cuts is differential across genomic loci and can confound genetic screening","volume":"13","author":"Biayna","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00503-18","DOI":"10.1128\/JVI.00503-18","article-title":"Transduction with Lentiviral Vectors Altered the Expression Profile of Host MicroRNAs","volume":"92","author":"Huang","year":"2018","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1093\/nar\/gkz605","article-title":"Delivering Cas9\/sgRNA ribonucleoprotein (RNP) by lentiviral capsid-based bionanoparticles for efficient \u2018hit-and-run\u2019 genome editing","volume":"47","author":"Lyu","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41598-017-18551-z","article-title":"Combined shRNA over CRISPR\/cas9 as a methodology to detect off-target effects and a potential compensatory mechanism","volume":"8","author":"Peretz","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/s41591-018-0049-z","article-title":"CRISPR\u2013Cas9 genome editing induces a p53-mediated DNA damage response","volume":"24","author":"Haapaniemi","year":"2018","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41586-018-0409-3","article-title":"Genetic and transcriptional evolution alters cancer cell line drug response","volume":"560","author":"Siranosian","year":"2018","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1089\/crispr.2019.0064","article-title":"A Tandem Guide RNA-Based Strategy for Efficient CRISPR Gene Editing of Cell Populations with Low Heterogeneity of Edited Alleles","volume":"3","author":"Joberty","year":"2020","journal-title":"Crispr J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1172\/JCI129126","article-title":"Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia","volume":"130","author":"Klossowski","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1128\/MCB.23.2.493-509.2003","article-title":"The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene","volume":"23","author":"Sukhodolets","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_34","first-page":"4204","article-title":"Menin associates with FANCD2, a protein involved in repair of DNA damage","volume":"63","author":"Jin","year":"2003","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Nelakurti, D.D., Pappula, A.L., Rajasekaran, S., Miles, W.O., and Petreaca, R.C. (2020). Comprehensive Analysis of MEN1 Mutations and Their Role in Cancer. Cancers, 12.","DOI":"10.3390\/cancers12092616"},{"key":"ref_36","first-page":"6135","article-title":"Menin, a Tumor Suppressor, Represses JunD-Mediated Transcriptional Activity by Association with an mSin3A-Histone Deacetylase Complex","volume":"63","author":"Kim","year":"2003","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.neuron.2018.08.031","article-title":"Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation","volume":"100","author":"Leng","year":"2018","journal-title":"Neuron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1097\/MPA.0000000000001239","article-title":"Menin Upregulates FOXO1 Protein Stability by Repressing Skp2-Mediated Degradation in \u03b2 Cells","volume":"48","author":"Jiang","year":"2019","journal-title":"Pancreas"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gehringer, F., Weissinger, S.E., Swier, L.J., M\u00f6ller, P., Wirth, T., and Ushmorov, A. (2019). FOXO1 Confers Maintenance of the Dark Zone Proliferation and Survival Program and Can Be Pharmacologically Targeted in Burkitt Lymphoma. Cancers, 11.","DOI":"10.3390\/cancers11101427"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1182\/blood-2017-10-813576","article-title":"Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia","volume":"131","author":"Wang","year":"2018","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1158\/0008-5472.CAN-10-3221","article-title":"The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization","volume":"71","author":"Wang","year":"2011","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nm.4062","article-title":"PTEN opposes negative selection and enables oncogenic transformation of pre-B cells","volume":"22","author":"Shojaee","year":"2016","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/s41375-019-0628-0","article-title":"Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma","volume":"34","author":"Gehringer","year":"2020","journal-title":"Leukemia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nrc.2017.111","article-title":"Autoimmunity checkpoints as therapeutic targets in B cell malignancies","volume":"18","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/sj.bmt.1702817","article-title":"Aggressive neoplastic plasma cell growth with MLL gene rearrangement after high-dose therapy with autologous stem cell support for multiple myeloma","volume":"27","author":"Nishii","year":"2001","journal-title":"Bone Marrow Transpl."},{"key":"ref_46","first-page":"258","article-title":"Targeting Menin disrupts the KMT2A\/B and polycomb balance to paradoxically activate bivalent genes","volume":"25","author":"Sparbier","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e28284","DOI":"10.1002\/pbc.28284","article-title":"Evaluation of VTP-50469, a menin-MLL1 inhibitor, against Ewing sarcoma xenograft models by the pediatric preclinical testing consortium","volume":"67","author":"Kurmasheva","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1074\/jbc.270.2.815","article-title":"Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells","volume":"270","author":"Sabers","year":"1995","journal-title":"J. Biol. Chem"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1080\/13543776.2022.2045947","article-title":"Menin-MLL protein-protein interaction inhibitors: A patent review (2014\u20132021)","volume":"32","author":"Bai","year":"2022","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7541","DOI":"10.1200\/JCO.2022.40.16_suppl.7541","article-title":"Preclinical activity of irreversible Menin inhibitor, BMF-219, in chronic lymphocytic leukemia","volume":"40","author":"Somanath","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4318","DOI":"10.1182\/blood-2021-148045","article-title":"Novel Irreversible Menin Inhibitor, BMF-219, Shows Potent Single Agent Activity in Clinically Relevant DLBCL Cells","volume":"138","author":"Somanath","year":"2021","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/ijch.201800113","article-title":"A Chemical Biology View of Bioactive Small Molecules and a Binder-Based Approach to Connect Biology to Precision Medicines","volume":"59","author":"Schreiber","year":"2019","journal-title":"Isr. J. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC targeted protein degraders: The past is prologue","volume":"21","author":"Langley","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1038\/ng.3984","article-title":"Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells","volume":"49","author":"Meyers","year":"2017","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16472\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:25:07Z","timestamp":1760131507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16472"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,17]]},"references-count":54,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216472"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216472","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,17]]}}}