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Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Author

Listed:
  • Gerard Minuesa

    (Memorial Sloan-Kettering Cancer Center)

  • Steven K. Albanese

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Wei Xie

    (Memorial Sloan Kettering Cancer Center)

  • Yaniv Kazansky

    (Rockefeller University and Sloan Kettering Institute)

  • Daniel Worroll

    (Weill Cornell Graduate School of Medical Sciences)

  • Arthur Chow

    (Memorial Sloan-Kettering Cancer Center)

  • Alexandra Schurer

    (Memorial Sloan-Kettering Cancer Center)

  • Sun-Mi Park

    (Memorial Sloan-Kettering Cancer Center)

  • Christina Z. Rotsides

    (Memorial Sloan Kettering Cancer Center)

  • James Taggart

    (Memorial Sloan-Kettering Cancer Center)

  • Andrea Rizzi

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Levi N. Naden

    (Memorial Sloan Kettering Cancer Center)

  • Timothy Chou

    (Memorial Sloan-Kettering Cancer Center)

  • Saroj Gourkanti

    (Memorial Sloan-Kettering Cancer Center)

  • Daniel Cappel

    (Schrödinger GmbH)

  • Maria C. Passarelli

    (Memorial Sloan Kettering Cancer Center
    Rockefeller University and Sloan Kettering Institute)

  • Lauren Fairchild

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Carolina Adura

    (The Rockefeller University)

  • J. Fraser Glickman

    (The Rockefeller University)

  • Jessica Schulman

    (Memorial Sloan Kettering Cancer Center)

  • Christopher Famulare

    (Memorial Sloan Kettering Cancer Center)

  • Minal Patel

    (Memorial Sloan Kettering Cancer Center)

  • Joseph K. Eibl

    (Northern Ontario School of Medicine)

  • Gregory M. Ross

    (Northern Ontario School of Medicine)

  • Shibani Bhattacharya

    (New York Structural Biology Center, NMR Group)

  • Derek S. Tan

    (Memorial Sloan Kettering Cancer Center)

  • Christina S. Leslie

    (Memorial Sloan Kettering Cancer Center)

  • Thijs Beuming

    (Schrödinger, Inc.)

  • Dinshaw J. Patel

    (Memorial Sloan Kettering Cancer Center)

  • Yehuda Goldgur

    (Memorial Sloan Kettering Cancer Center)

  • John D. Chodera

    (Memorial Sloan Kettering Cancer Center)

  • Michael G. Kharas

    (Memorial Sloan-Kettering Cancer Center)

Abstract

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08–2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI’s oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

Suggested Citation

  • Gerard Minuesa & Steven K. Albanese & Wei Xie & Yaniv Kazansky & Daniel Worroll & Arthur Chow & Alexandra Schurer & Sun-Mi Park & Christina Z. Rotsides & James Taggart & Andrea Rizzi & Levi N. Naden &, 2019. "Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10523-3
    DOI: 10.1038/s41467-019-10523-3
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    Cited by:

    1. Tatiana Erazo & Chiara M. Evans & Daniel Zakheim & Eren L. Chu & Alice Yunsi Refermat & Zahra Asgari & Xuejing Yang & Mariana Silva Ferreira & Sanjoy Mehta & Marco Vincenzo Russo & Andrea Knezevic & X, 2022. "TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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