Drug-resistant menin variants retain high binding affinity and interactions with MLL1

被引:3
作者
Ray, Joshua [1 ]
Clegg, Bradley [1 ,2 ]
Grembecka, Jolanta [1 ,2 ]
Cierpicki, Tomasz [1 ,2 ,3 ]
机构
[1] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Program Chem Biol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA
关键词
FUSION PROTEINS; LEUKEMIA; INHIBITION; MODELS;
D O I
10.1016/j.jbc.2024.107777
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Menin is an essential oncogenic cofactor of MLL1 fusion proteins in acute leukemias and inhibitors of the menin-MLL1 interaction are under evaluation in clinical trials. Recent studies found emerging resistance to menin inhibitor treatment in patients with leukemia as a result of somatic mutations in menin. To understand how patient mutations in menin affect the interaction with MLL1, we performed systematic characterization of the binding affinity of these menin mutants fragment of MLL1. We also determined the crystal structures of menin patient mutants and their complexes with MLL1derived peptides. We found that drug-resistant mutations in menin occur at a site adjacent to the MLL1 binding site, but they do not affect MLL1 binding to menin. On the contrary, our structural analysis shows that all these point mutations in menin generate steric clash with menin inhibitors. We also found that mutation G331D results in a very slow dissociation of MLL1 from menin and this mutant might be particularly difficult to inhibit with small molecule drugs. This work provides structural information to support the development of a new generation of small molecule inhibitors that overcome resistance caused by menin mutations.
引用
收藏
页数:10
相关论文
共 34 条
[11]   Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia [J].
Erba, Harry P. ;
Fathi, Amir T. ;
Issa, Ghayas C. ;
Altman, Jessica K. ;
Montesinos, Pau ;
Patnaik, Mrinal M. ;
Foran, James M. ;
De Botton, Stephane ;
Baer, Maria R. ;
Schiller, Gary J. ;
Walter, Roland B. ;
Kremyanskaya, Marina ;
Pettit, Kristen M. ;
Strickland, Stephen A. ;
Tomkinson, Blake ;
Tabachri, Marilyn ;
Leoni, Mollie ;
Dale, Stephen ;
Wang, Eunice S. .
BLOOD, 2022, 140
[12]   Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. [J].
Falini, B ;
Mecucci, C ;
Tiacci, E ;
Alcalay, M ;
Rosati, R ;
Pasqualucci, L ;
La Starza, R ;
Diverio, D ;
Colombo, E ;
Santucci, A ;
Bigerna, B ;
Pacini, R ;
Pucciarini, A ;
Liso, A ;
Vignetti, M ;
Fazi, P ;
Meani, N ;
Pettirossi, V ;
Saglio, G ;
Mandelli, F ;
Lo-Coco, F ;
Pelicci, P ;
Martelli, MF .
NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (03) :254-266
[13]  
Grembecka J, 2012, NAT CHEM BIOL, V8, P277, DOI [10.1038/NCHEMBIO.773, 10.1038/nchembio.773]
[14]   Molecular Basis of the Mixed Lineage Leukemia-Menin Interaction IMPLICATIONS FOR TARGETING MIXED LINEAGE LEUKEMIAS [J].
Grembecka, Jolanta ;
Belcher, Amalia M. ;
Hartley, Thomas ;
Cierpicki, Tomasz .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (52) :40690-40698
[15]   The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML [J].
Heikamp, Emily B. ;
Henrich, Jill A. ;
Perner, Florian ;
Wong, Eric M. ;
Hatton, Charles ;
Wen, Yanhe ;
Barwe, Sonali P. ;
Gopalakrishnapillai, Anilkumar ;
Xu, Haiming ;
Uckelmann, Hannah J. ;
Takao, Sumiko ;
Kazansky, Yaniv ;
Pikman, Yana ;
McGeehan, Gerard M. ;
Kolb, Edward A. ;
Kentsis, Alex ;
Armstrong, Scott A. .
BLOOD, 2022, 139 (06) :894-906
[16]  
Huynh Kathy, 2015, Curr Protoc Protein Sci, V79, DOI 10.1002/0471140864.ps2809s79
[17]   The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia [J].
Issa, Ghayas C. ;
Aldoss, Ibrahim ;
DiPersio, John ;
Cuglievan, Branko ;
Stone, Richard ;
Arellano, Martha ;
Thirman, Michael J. ;
Patel, Manish R. ;
Dickens, David S. ;
Shenoy, Shalini ;
Shukla, Neerav ;
Kantarjian, Hagop ;
Armstrong, Scott A. ;
Perner, Florian ;
Perry, Jennifer A. ;
Rosen, Galit ;
Bagley, Rebecca G. ;
Meyers, Michael L. ;
Ordentlich, Peter ;
Gu, Yu ;
Kumar, Vinit ;
Smith, Steven ;
McGeehan, Gerard M. ;
Stein, Eytan M. .
NATURE, 2023, 615 (7954) :920-+
[18]   Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia [J].
Klossowski, Szymon ;
Miao, Hongzhi ;
Kempinska, Katarzyna ;
Wu, Tao ;
Purohit, Trupta ;
Kim, EunGi ;
Linhares, Brian M. ;
Chen, Dong ;
Jih, Gloria ;
Perkey, Eric ;
Huang, Huang ;
He, Miao ;
Wen, Bo ;
Wang, Yi ;
Yu, Ke ;
Lee, Stanley Chun-Wei ;
Danet-Desnoyers, Gwenn ;
Trotman, Winifred ;
Kandarpa, Malathi ;
Cotton, Anitria ;
Abdel-Wahab, Omar ;
Lei, Hongwei ;
Dou, Yali ;
Guzman, Monica ;
Peterson, Luke ;
Gruber, Tanja ;
Choi, Sarah ;
Sun, Duxin ;
Ren, Pingda ;
Li, Lian-Sheng ;
Liu, Yi ;
Burrows, Francis ;
Maillard, Ivan ;
Cierpicki, Tomasz ;
Grembecka, Jolanta .
JOURNAL OF CLINICAL INVESTIGATION, 2020, 130 (02) :981-997
[19]   A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia [J].
Krivtsov, Andrei V. ;
Evans, Kathryn ;
Gadrey, Jayant Y. ;
Eschle, Benjamin K. ;
Hatton, Charlie ;
Uckelmann, Hannah J. ;
Ross, Kenneth N. ;
Perner, Florian ;
Olsen, Sarah N. ;
Pritchard, Tara ;
McDermott, Lisa ;
Jones, Connor D. ;
Jing, Duohui ;
Braytee, Ali ;
Chacon, Diego ;
Earley, Eric ;
McKeever, Brian M. ;
Claremon, David ;
Gifford, Andrew J. ;
Lee, Heather J. ;
Teicher, Beverly A. ;
Pimanda, John E. ;
Beck, Dominik ;
Perry, Jennifer A. ;
Smith, Malcolm A. ;
McGeehan, Gerard M. ;
Lock, Richard B. ;
Armstrong, Scott A. .
CANCER CELL, 2019, 36 (06) :660-+
[20]   Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia [J].
Kuhn, Michael W. M. ;
Song, Evelyn ;
Feng, Zhaohui ;
Sinha, Amit ;
Chen, Chun-Wei ;
Deshpande, Aniruddha J. ;
Cusan, Monica ;
Farnoud, Noushin ;
Mupo, Annalisa ;
Grove, Carolyn ;
Koche, Richard ;
Bradner, James E. ;
de Stanchina, Elisa ;
Vassiliou, George S. ;
Hoshii, Takayuki ;
Armstrong, Scott A. .
CANCER DISCOVERY, 2016, 6 (10) :1166-1181