TY - JOUR
T1 - Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia
AU - Minuesa, Gerard
AU - Albanese, Steven K.
AU - Xie, Wei
AU - Kazansky, Yaniv
AU - Worroll, Daniel
AU - Chow, Arthur
AU - Schurer, Alexandra
AU - Park, Sun Mi
AU - Rotsides, Christina Z.
AU - Taggart, James
AU - Rizzi, Andrea
AU - Naden, Levi N.
AU - Chou, Timothy
AU - Gourkanti, Saroj
AU - Cappel, Daniel
AU - Passarelli, Maria C.
AU - Fairchild, Lauren
AU - Adura, Carolina
AU - Glickman, J. Fraser
AU - Schulman, Jessica
AU - Famulare, Christopher
AU - Patel, Minal
AU - Eibl, Joseph K.
AU - Ross, Gregory M.
AU - Bhattacharya, Shibani
AU - Tan, Derek S.
AU - Leslie, Christina S.
AU - Beuming, Thijs
AU - Patel, Dinshaw J.
AU - Goldgur, Yehuda
AU - Chodera, John D.
AU - Kharas, Michael G.
N1 - Funding Information:
We would like to thank the current members of the M. G. Kharas and R. Levine labs, R. Levine, P. Lito, J. Vidigal, P. Rocha, C. Lengner, A. Kentsis, and K. Keshari for their critical advice and helpful suggestions. H. Djaballah, R. Garippa and the members of the former High-Throughput Screening Core and current RNAi Core (MSKCC) for their technical and project support throughout the screen and secondary validation. We would like to thank R. Sridharan, Y. Shamay, D. Heller (MSKCC), and Rui Liang (Tri-TDI) for their scientific advice and technical support. We would also like to thank A. Gruet and the Epigenetics core for his technical support with RNA-sequencing library preparation and J. Charavalli (HTSRC, The Rockefeller University) for her technical support with initial FP measurements. M.G.K. was supported by US National Institutes of Health National Institute of Diabetes, Digestive and Kidney Diseases Career Development Award, NIDDK NIH R01-DK101989–01A1, NCI 1R01CA193842–01, Louis V. Gerstner Young Investigator Award, American Society of Hematology Junior Scholar Award, Kimmel Scholar Award, V-Scholar Award, Geoffrey Beene Award and Alex’s Lemonade Stand A Award and the Starr Foundation. The research was funded by Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center. The research was funded in part through NIH/NCI Cancer Support Core Grant P30 CA08748 to M.G.K. J.D.C. acknowledges support from the Sloan Kettering Institute, a Louis V. Gerstner Young Investigator Award, NIH grant P30 CA008748, and NIH grant R01 GM121505. L.N.N. acknowledges support from Merck KGaA to support the development of open source tools for GPU-accelerated alchemical free energy calculations. M.C.P. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. C.Z.R. was supported by T32 CA062948-Gudas. The MSKCC structural biology core laboratory is supported by National Cancer Institute grant P30-CA008748. X-ray diffraction data were collected at synchrotron facilities supported by grants and contracts from the National Institutes of Health (P41GM103403, HEI-S10RR029205) and the Department of Energy (DE-AC02–06CH11357). The data collected at NYSBC was made possible by a grant from NYSTAR and ORIP/NIH facility improvement grant CO6RR015495. The console for 800US2 AVANCE III spectrometer was purchased by NIH grant S10OD016432.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067488438&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10523-3
DO - 10.1038/s41467-019-10523-3
M3 - Article
AN - SCOPUS:85067488438
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2691
ER -
