A tubulin binding molecule drives differentiation of acute myeloid leukemia cells

• Published in: iScience Vol. 25; no. 8; p. 104787
• Main Authors: Jackson, Thomas R., Vuorinen, Aini, Josa-Culleré, Laia, Madden, Katrina S., Conole, Daniel, Cogswell, Thomas J., Wilkinson, Isabel V.L., Kettyle, Laura M., Zhang, Douzi, O’Mahony, Alison, Gracias, Deanne, McCall, Lorna, Westwood, Robert, Terstappen, Georg C., Davies, Stephen G., Tate, Edward W., Wynne, Graham M., Vyas, Paresh, Russell, Angela J., Milne, Thomas A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.08.2022; Elsevier
• Subjects: Biological sciences; Cancer; Chemistry; Molecular biology; Molecular medicine; Chemistry; Biological sciences; Molecular biology; Molecular medicine; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.104787

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. [Display omitted] •Cancer treatments usually focus on killing rapidly growing cells•We focused on differentiating cancer cells independent of the driver mutation•We identified tubulin as the drug target•This work illustrates how phenotypic screening can identify unique drug targets Chemistry; Biological sciences; Molecular biology; Molecular medicine; Cancer