iScience (Aug 2022)
A tubulin binding molecule drives differentiation of acute myeloid leukemia cells
- Thomas R. Jackson,
- Aini Vuorinen,
- Laia Josa-Culleré,
- Katrina S. Madden,
- Daniel Conole,
- Thomas J. Cogswell,
- Isabel V.L. Wilkinson,
- Laura M. Kettyle,
- Douzi Zhang,
- Alison O’Mahony,
- Deanne Gracias,
- Lorna McCall,
- Robert Westwood,
- Georg C. Terstappen,
- Stephen G. Davies,
- Edward W. Tate,
- Graham M. Wynne,
- Paresh Vyas,
- Angela J. Russell,
- Thomas A. Milne
Affiliations
- Thomas R. Jackson
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Aini Vuorinen
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Laia Josa-Culleré
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
- Katrina S. Madden
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
- Daniel Conole
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, 82 Wood Lane, London W12 0BZ, UK
- Thomas J. Cogswell
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
- Isabel V.L. Wilkinson
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
- Laura M. Kettyle
- Axis Bioservices, 189 Castleroe Rd, Coleraine, Co. Londonderry BT51 3RP, Northern Ireland
- Douzi Zhang
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Alison O’Mahony
- Eurofins Discovery Phenotypic Services, St. Charles, MO 63304 and Burlingame, CA 94010, USA; Discovery Platform at Recursion, 41 S Rio Grande Street, Salt Lake City, UT 84101, USA
- Deanne Gracias
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Lorna McCall
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Robert Westwood
- Oxstem Ltd, Midland House West Way, Botley, Oxford OX2 0PH, UK
- Georg C. Terstappen
- Oxstem Ltd, Midland House West Way, Botley, Oxford OX2 0PH, UK
- Stephen G. Davies
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
- Edward W. Tate
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, 82 Wood Lane, London W12 0BZ, UK
- Graham M. Wynne
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK; Oxstem Ltd, Midland House West Way, Botley, Oxford OX2 0PH, UK
- Paresh Vyas
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Corresponding author
- Angela J. Russell
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK; Corresponding author
- Thomas A. Milne
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 8
p. 104787
Abstract
Summary: Despite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells.
