4.5 Article

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

Journal

NATURE CANCER
Volume 3, Issue 5, Pages 595-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s43018-022-00366-1

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Funding

  1. National Institutes of Health (NIH) [CA176745, CA206963, CA204639, CA066996]
  2. St. Jude Children's Research Hospital Research Consortium grant, Curing Kids Cancer
  3. Leukemia and Lymphoma Society, USA
  4. Ruth L. Kirschstein Postdoctoral Individual National Research Service award (NIH) [F32CA250240-02]
  5. NIH T32 training grant [5T32HL007574-38-40]
  6. Wong Family Award in Translational Oncology
  7. Sara Elizabeth O'Brien Trust Fellowship
  8. Breast Cancer Research Foundation [BCRF-20-100]
  9. NIH [CA066996, CA214608, CA231637, DRR-50-18]
  10. Damon Runyon Cancer Research Foundation [26-18]
  11. German Research Foundation [PE 3217/1-1]
  12. German Cancer Aid (Deutsche Krebshilfe)
  13. St. Baldrick's Foundation

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The combination targeting of IKAROS and MENIN is an effective therapeutic strategy for AML, disrupting leukemogenic transcriptional networks and resulting in synergistic killing of leukemia cells.
Armstrong and colleagues discover that combined targeting of IKAROS and MENIN is a therapeutic strategy for acute myeloid leukemia through disruption of essential leukemogenic transcriptional programs. 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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