2. Academic Validation
  3. Combining menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia

Combining menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia

  • Blood Adv. 2026 Jul 14;10(13):4757-4771. doi: 10.1182/bloodadvances.2025016208.
Nastassja Scheidegger 1 2 3,  Constanze Schneider 1 2,  Gabriela Alexe 1 2,  Yi-Cheng Wang 4,  Todd A Alonzo 4 5,  Allen Basanthakumar 1 2,  Wallace A Bourgeois 1,  Julia Dudkiewicz-Garbicz 1,  Delan Khalid 1 2,  Lucy A Merickel 1 2,  Jennifer A Perry 1,  Rhonda E Ries 6,  Silvi Salhotra 1 2,  Audrey Taillon 1 2,  Alan Gamis 7,  Richard Aplenc 8,  Marian H Harris 9,  Mark Wunderlich 10,  Scott A Armstrong 1,  Jessica A Pollard 1,  Soheil Meshinchi 6,  Yana Pikman 1 2,  Kimberly Stegmaier 1 2
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA.
  • 3 Department of Pediatric Oncology, Children's University Hospital of Zurich, Zurich, Switzerland.
  • 4 Children's Oncology Group, Monrovia, CA.
  • 5 Keck School of Medicine, University of Southern California, Los Angeles, CA.
  • 6 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA.
  • 7 Division of Hematology/Oncology, Children's Mercy Kansas City, Kansas City, MO.
  • 8 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 9 Department of Pathology, Boston Children's Hospital, Boston, MA.
  • 10 Division of Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
PMID: 42085603 DOI: 10.1182/bloodadvances.2025016208
Abstract

KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. Ras pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified Ras pathway mutations in 43% of acute myeloid leukemia (AML) cases. The presence of Ras pathway mutations in KMT2A-r AML was associated with a lower complete remission rate, poor event-free survival and overall survival (OS), and early relapses. Given the inferior outcome observed for children with dual mutations, we next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated Ras/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Treatment of AML cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability and promoted cell cycle arrest, Apoptosis, and downregulation of Myc targets in the combination compared with each drug alone. In vivo, the combination treatment of AML pediatric PDX models harboring KMT2A-r and Ras mutations reduced leukemia burden compared with single-drug treatments but without improving OS compared with menin inhibition alone. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and Ras pathway-mutant leukemia but one that will require further optimization. These trials were registered at www.clinicaltrials.gov as NCT00070174, NCT00372593, NCT01371981, and NCT00002798.

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