The Clinical Menin Inhibitor Ziftomenib and the Nuclear Export Inhibitor Selinexor Synergistically Inhibit the Growth of MLL-r AML

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.4168-4168
• Main Authors: Uddin, Md. Hafiz, Aboukameel, Amro, Siddiqui, Sharif hasan, Khan, Husain, Bannoura, Sahar, Deol, Abhinav, Yang, Jay, Dyson, Gregory, Azmi, Asfar, Polin, Lisa, Maciejewski, Jaroslaw P., Balasubramanian, Suresh Kumar
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-190638

Menin is a scaffold protein that interacts with oncogenic histone-lysine-N-methyltransferase MLL1 (KMT2A)-fusion protein (FP) complex in MLL-rearranged ( MLL-r) AML. Menin inhibitors that evict menin from this interaction have been shown to be active against MLL-r and NPM1MT leukemia by modulating the expression of the leukemogenic homeobox A9 ( HOXA9) gene and its co-factor, MEIS1. Recent evidence showed that menin inhibitors can activate a tumor-suppressive network via a non-canonical transcriptional program through UTX. On the other hand, selective inhibitor of nuclear export (SINE) against XPO1/CRM1 has been shown to have robust anti-leukemia activity via enrichment of tumor suppressor proteins in the nucleus. In the present study, we hypothesized that menin and nuclear export inhibition would synergistically suppress AML cell proliferation and possibly sensitize menin inhibitor-resistant cells. We have used the clinical-stage menin inhibitor ziftomenib and SINE compound selinexor to simultaneously target menin-KMT2A protein-protein interactions and nuclear export. To assess growth inhibition, an ATP-based cell proliferation assay was used. Combination synergy was determined using CalcuSyn Version 2.0 synergy software. Stem-like progenitor cells were isolated using the StemSpan CD34+ expansion kit (StemCell Tech). Colony formation efficiency was determined using a Methocult assay (StemCell Tech). Gene and protein expression was detected using quantitative real-time PCR and western blotting. Flow cytometric analysis was performed to detect cell death and cell cycle status. We have performed the whole transcriptomic analysis via the RNA sequencing approach. The clinical candidate drug ziftomenib, in combination with selinexor, synergistically inhibited the growth of MLL-r AML cell lines (MV4;11 and MOLM13) (CI