Abstract
Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
Highlights
MLL1 (KMT2A) is a large (3696 amino acids) transcriptional regulator and a histone-lysine-N-methyltransferase [1, 2]
Findings presented here demonstrate for the first time that, by either utilizing the dTAG system to degrade Menin or CRISPR-Cas9 to edit and KO Menin, depletion of Menin is associated with a reduction in expression of MEIS1, FLT3, CDK6, and BCL2, sensitizing MOLM13 cells harboring MLL1-r and FLT3-ITD to BCL2 inhibitor venetoclax and CDK6 inhibitor abemaciclib-induced apoptosis
A previous report had documented that loss of occupancy of Menin, MLL1 (N-terminus), DOT1L, and H3K79Me2 from selective chromatin targets induced concordant repression of a subset of MLL1/MLL-fusion protein (FP) target genes [17]
Summary
MLL1 (KMT2A) is a large (3696 amino acids) transcriptional regulator and a histone-lysine-N-methyltransferase [1, 2]. N-terminal 1400 amino acids of MLL1 act as a transcription factor containing Menin binding domains (MBD), and the C-terminal SET domain acts as a histone methyltransferase that mediates histone H3 lysine 4 trimethylation [1, 2]. Menin–KMT2A complex has a critical role in regulating HOX genes cluster involved in embryonic development and hematopoiesis, including the leukemogenic homeobox A9 (HOXA9) and its co-factor MEIS1 in myeloid stem progenitor cells [6,7,8]. MLL1 fusion protein (MLL-FP) binds to gene targets largely different from wild-type MLL1 and dysregulates
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