2. Academic Validation
  3. IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia

IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia

  • Nat Cancer. 2022 May;3(5):595-613. doi: 10.1038/s43018-022-00366-1.
Brandon J Aubrey  # 1 2,  Jevon A Cutler  # 1,  Wallace Bourgeois  # 1 3,  Katherine A Donovan 4 5,  Shengqing Gu 6 7,  Charlie Hatton 1,  Sarah Perlee 1,  Florian Perner 1 8,  Homa Rahnamoun 1,  Alexandra C P Theall 1,  Jill A Henrich 1,  Qian Zhu 1 3,  Radosław P Nowak 4 5,  Young Joon Kim 1,  Salma Parvin 9,  Anjali Cremer 1 10 11,  Sarah Naomi Olsen 1,  Nicholas A Eleuteri 4,  Yana Pikman 1 3,  Gerard M McGeehan 12,  Kimberly Stegmaier 1 3 13,  Anthony Letai 9,  Eric S Fischer 4 5,  X Shirley Liu 6 7,  Scott A Armstrong 14 15
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 3 Division of Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Internal Medicine C, Universitaetsmedizin Greifswald, Greifswald, Germany.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Department of Hematology-Oncology, University Hospital Frankfurt, Frankfurt/Main, Germany.
  • 11 German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
  • 12 Syndax Pharmaceuticals, Waltham, MA, USA.
  • 13 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 14 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. scott_armstrong@dfci.harvard.edu.
  • 15 Division of Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA. scott_armstrong@dfci.harvard.edu.
  • # Contributed equally.
PMID: 35534777 DOI: 10.1038/s43018-022-00366-1
Abstract

Acute myeloid leukemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens, we identified IKAROS (encoded by IKZF1) as an essential transcription factor in KMT2A (MLL1)-rearranged (MLL-r) AML that maintains leukemogenic gene expression while also repressing pathways for tumor suppression, immune regulation and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with mixed lineage leukemia (MLL)1-MENIN and the regulator MEIS1 and an extensive hematopoietic transcriptional complex involving homeobox (HOX)A10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukemogenic transcriptional networks, resulting in synergistic killing of leukemia cells and providing a paradigm for improved drug targeting of transcription and an opportunity for rapid clinical translation.

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