Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Blood Cancer J. 2022 Jan 11;12(1):5. doi: 10.1038/s41408-021-00603-3.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminopyridines / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Rearrangement / drug effects
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mutation / drug effects
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Nucleophosmin / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Sulfonamides / pharmacology


  • Aminopyridines
  • Antineoplastic Agents
  • Benzimidazoles
  • Bridged Bicyclo Compounds, Heterocyclic
  • KMT2A protein, human
  • MEN1 protein, human
  • NPM1 protein, human
  • Proto-Oncogene Proteins
  • Sulfonamides
  • Nucleophosmin
  • Myeloid-Lymphoid Leukemia Protein
  • abemaciclib
  • Histone-Lysine N-Methyltransferase
  • venetoclax