Summary Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.
Bibliographical noteFunding Information:
We thank Constellation Pharmaceuticals for providing CPI203; W. Pear, P. Premsrirut, J. Aster, J. Silva, M. Kelliher, and A. Klinakis for sharing materials; the NYU Genome Technology Center (supported in part by an NIH/NCI P30 CA016087-30 grant); L. Deriano and J. Chaumeil for mFISH analysis; the NYU Flow Cytometry facility for cell sorting; and the NYU Histology Core and Transgenic Mouse Core (NYU Cancer Institute Center grant 5P30CA16087-31). I.A. was supported by the NIH (1RO1CA133379, 1RO1CA105129, 1RO1CA149655, 5RO1CA173636, and 1RO1GM088847). I.A. was also supported by the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society (TRP#6340-11 and LLS#6373-13), the Chemotherapy Foundation, the V Foundation for Cancer Research, and the St. Baldrick’s Foundation. B.K. was supported by the NYU CMB Training Program. L.R. is supported by a Ruth L. Kirschstein F31 Award and a Marie Curie Actions Fellowship. J.M. is supported by NWO Rubicon and the Dutch Cancer Society. B.A.-O. is supported by the José Carreras Leukemia Foundation (FIJC-12/EDTHOMAS). I.A. is a Howard Hughes Medical Institute Early Career Scientist. I.A. and B.K. designed experiments and wrote the manuscript. B.K. performed most of the experiments. L.R. generated Eef1a1-targeted ESCs. L.X., A.P.-G., and A.F. assisted with in vivo and primary human T-ALL drug studies. P.S. assisted with inhibitor production and provided advice for use. C.V., J.S., and J.M. performed BRD4 knockdown experiments. B.A.-O. performed ubiquitylation assays. P.N., T.T., and S.S.S. performed and analyzed RNA-seq and ChIP-seq experiments. P.S. is an employee of Constellation Pharmaceuticals.