Timothy J. Ley, M.D.

Lewis T. and Rosalind B. Apple Chair in Oncology
Internal Medicine
Associate Director, Cancer Genomics
The Genome Center

Molecular Genetics and Genomics Program
Immunology Program

Research Abstract:

For many years, the lab has used mouse models of acute myeloid leukemia (AML) to establish key principles of AML pathogenesis. The lab established that the initiating event for Acute Promyelocytic Leukemia is the PML-RARA fusion gene created by the t(15;17) that is found in nearly all patients with this disease. The roles of cooperating mutations and the cellular milieu for APL pathogenesis have also been established. In collaboration with the McDonnell Genome Institute at Washington University, the investigators of the Genomics of AML PPG (TJ Ley, PI) sequenced the first human cancer genome (a patient with AML) and the first mouse cancer genome (from the mouse model of APL), and have discovered several new recurrent mutations that are important for AML pathogenesis and outcomes, including recurring mutations in DNMT3A and IDH1/2, among many others. These data are now being correlated to RNA expression, DNA methylation, protein abundance and modification, and clinical datasets. Mouse models of epigenetic modifier mutations in AML are now being created and analyzed. These efforts will hopefully lead to new tests to better establish prognosis, and new approaches for the therapy of patients with this disease.

Selected Publications:

Ley, TJ, Mardis, E, Ding L, Fulton B, McLellan M, Chen K, Dooling D, McGrath S, Hickerbotham M, Cook L, Abbott R, Larson D, Koboldt D, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier L, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne J, Minx P, Gordon D, Zhao Y, Ries R, Payton J, Westervelt P, Tomasson M, Watson M, Baty J, Ivanovich J, Heath S, Shannon W, Nagarajan R, Walter M, Link DC, Graubert T, DiPersio J, Wilson R. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008, 456(7218):66-72.

Mardis, E.R., Ding, L., Dooling, D.J., Larson, D.E., McLellan, M.D., Chen, K., Koboldt, D.C., Fulton, R.S., Delehauntry, K.D., McGrath, S.D., Fulton, L.A., Locke, D.P., Magrini, V.J., Abbott, R.M., Vickery, T.L., Reed, J.S., Robinson, J.S., Wylie, T., Smith, S.M., Carmichael, L., Eldred, J.E., Harris, C.C., Walker, J., Peck, J.B., Du, F., Dukes, A.F., Sanderson, G.E., Brummett, A.M., Clark, E., McMichael, J.F., Meyer, R.J., Schindler, J.K., Pohl, C.S., Wallis, J.W., Shi, X., Lin, L., Schmidt, H., Tang, Y., Haipek, C., Wiechert, M.E., Ivy, J.V., Kalicki, J., Elliott, G., Ries, R.E., Payton, J.E., Westervelt, P., Tomasson, M.H., Watson, M., Baty, J., Heath, S., Shannon, W.D., Nagarajan, R., Link, D.C., Walter, M.J., Graubert, T.A., DiPersio, J.F., Wilson, R.K., and Ley, T.J. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009. 361: 1058-66.

Ley, T.J., Ding, L., Walter, M.J., McLellan, M.D., Lamprecht, T., Larson, D.E., Kandoth, C., Payton, J.E., Baty, J., Welch, J., Harris, C.C., Lichti, C.F., Townsend, R.R., Fulton, R.S., Dooling, D.J., Koboldt, D.C., Schmidt, H., Zhang, Q., Osborne, J.R., Lin, L., O’Laughlin, M., McMichael, J.F., Delehaunty, K.D., McGrath, S.D., Fulton, L.A., Magrini, V.J., Vickery, T.L., Hundal, J., Cook, L.L., Conyers, J.J., Swift, G.W., Reed, J.P., Alldredge, P.A., Wylie, T., Walker, J., Kalicki, J., Watson, M.A., Heath, S., Shannon, W.D., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M.H., Link, D.C., Graubert, T.A., DiPersio, J.F., Mardis, E.R., Wilson, R.K. DNMT3A mutations in acute myeloid leukemia. New Engl J Med 2010, 363(25):2424-33.

Wartman, L.D., Larson, D.E., Xiang, Z., Ding, L., Chen, K., Lin, L., Cahan, P., Klco, J.M., Welch, J.S., Li, C., Payton, J.E., Uy, G.L., Varghese, N., Ries, R.E., Hoock, M., McLellan, M.D., Schmidt, H., Fulton, R.S., Abbott, R.M., Cook, L., McGrath, S.D., Fan, X., Dukes, A.F., Lamprecht, T.L., Graubert, T.A., Tomasson, M.H., Mardis, E.R., Wilson, R.K., Ley, T.J. Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. J Clin Invest 2011, 121(4):1445-1455.

Ding, L.*, Ley, T.J.*, Larson, D.E., Miller, C.A., Koboldt, D.C., Welch, J.C., Ritchey, J.K., Young, M.A., Lamprecht, T., McLellan, M.D., McMichael, J.F., Wallis, J.W., Lu, C., Shen, D., Harris, C.C., Dooling, D.J., Fulton, R.S., Fulton, L.L., Chen, K., Schmidt, H., Kalicki-Veizer, J., Magrini, V.J., Cook, L., McGrath, S.D., Vickery, T.L., Wendl, M.C., Heath, S., Watson, M.A., Link, D.C., Tomasson, M.H., Shannon, W.D., Payton, J.E., Kulkarni, S., Westervelt, P., Walter, M.J., Graubert, T.A., Mardis, E.R., Wilson, R.K., DiPersio, J.F. Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing. Nature 2012, 481(7382):506-10. *Authors contributed equally to this work.

Welch, J.S.*, Ley, T.J.*, Link, D.C.*, Miller, C.A., Larson, D.E., Koboldt, D.C., Wartman, L.D., Lamprecht, T.L., Liu, F., Xia, J., Kandoth, C., Fulton, R.S., McLellan, M.D., Dooling, D.J., Wallis, J.W., Chen, K., Harris, C.C., Schmidt, H.K., Kalicki-Veizer, J.M., Lu, C., Zhang, Q., Lin, L., O`Laughlin, M.D., McMichael, J.F., Delehaunty, K.D., Fulton, L.A., Magrini, V.J., McGrath, S.D., Demeter, R.T., Vickery, T.L., Hundal, J., Cook, L.L., Swift, G.W., Reed, J.P., Alldredge, P.A., Wylie, T.N., Walker, J.R., Watson, M.A., Heath, S.E., Shannon, W.D., Varghese, N., Nagarajan, R., Payton, J.E., Baty, J.D., Kulkarni, S., Klco, J.M., Tomasson, M.H., Westervelt, P., Walter, M.J., Graubert, T.A., DiPersio, J.F., Ding, L., Mardis, E.R., Wilson, R.K. The Origin and Evolution of Mutations in Acute Myeloid Leukemia. Cell, 2012, 150 (2): 264-78. *Authors contributed equally to this work.

The Cancer Genome Atlas Research Network*. Genomic and Epigenomic landscapes of adult de novo acute myeloid leukemia. New Eng J Med 2013, 368(22):2059-74. *Corresponding author: T.J. Ley

Klco, J.M., Spencer, D.H., Miller, C.A., Griffith, M., Lamprecht, T.L., O’Laughlin, M., Fronick, C., Magrini, V., Demeter, R.T., Fulton, R.S., Eades, W.C., Link, D.C., Graubert, T.A., Walter, M.J., Mardis, E.R., DiPersio, J.F., Wilson, R.K., Ley, T.J. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell 2014, 25(2):379-92.

Russler-Germain, D.A., Spencer, D.H., Young, M.A., Lamprecht, T.L., Miller, C.A., Fulton, R., Meyer, M.R., Erdmann-Gilmore, P., Townsend, R.R., Wilson, R.K., Ley, T.J. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 2014, 25(4):442-52.

Klco, J.M., Miller, C.A., Griffith, M., Petti, A., Spencer, D.H., Ketkar-Kulkarni, S., Wartman, L.D., Christopher, M., Lamprecht, T.L., Helton, N.M., Duncavage, E.J., Payton, J.E., Baty, J., Heath, S.E., Griffith, O.L., Shen, D., Hundal, J., Chang, G.S., Fulton, R., O’Laughlin, M., Fronick, C., Magrini, V., Demeter, R.T., Larson, D.E., Kulkarni, S., Ozenberger, B.A., Welch, J.S., Walter, M.J., Graubert, T.A. Westervelt, P., Radich, J.P., Link, D.C, Mardis, E.R., DiPersio, J.F., Wilson, R.K., Ley, T.J. Association between mutation clearance after induction therapy and outcomes in patients with Acute Myeloid Leukemia. JAMA 2015, in press.

Last Updated: 8/17/2015 10:48:16 AM

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