Aaron Schimmer

Research Synopsis

Chemical Biology and Drug discovery

Our lab is interested in developing new therapeutic strategies for AML (acute myeloid leukemia) that effectively target leukemic stem cells. Using genetic and chemical approaches, including high throughput screens, we identify biological vulnerabilities in the AML cells and stem cells with a focus on mitochondrial and metabolic pathways. Through these efforts, we discover new biological pathways important for the growth and viability of AML and highlight new therapeutic approaches for this disease.

Recent Publications

• Liyanage SU, Hurren R, Voisin V, Bridon G, Wang X, Xu C, MacLean N, Siriwardena TP, Gronda M, Yehudai D, Sriskanthadevan S, Avizonis D, Shamas-Din A, Minden MD, Bader GD, Laposa R, Schimmer AD. Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML. Blood. 2017;129:2657-66.
• Seneviratne AK, Xu M, Henao JJA, Fajardo VA, Hao Z, Voisin V, Xu GW, Hurren R, Kim S, MacLean N, Wang X, Gronda M, Jeyaraju D, Jitkova Y, Ketela T, Mullokandov M, Sharon D, Thomas G, Chouinard-Watkins R, Hawley JR, Schafer C, Yau HL, Khuchua Z, Aman A, Al-Awar R, Gross A, Claypool SM, Bazinet RP, Lupien M, Chan S, De Carvalho DD, Minden MD, Bader GD, Stark KD, LeBlanc P, Schimmer AD. The Mitochondrial Transacylase, Tafazzin, Regulates AML Stemness by Modulating Intracellular Levels of Phospholipids. Cell Stem Cell. 2019;24:621-36 e16. Erratum 2019;24:1007
• Barghout SH, Patel PS, Wang X, Xu GW, Kavanagh S, Halgas O, Zarabi SF, Gronda M, Hurren R, Jeyaraju DV, MacLean N, Brennan S, Hyer ML, Berger A, Traore T, Milhollen M, Smith AC, Minden MD, Pai EF, Hakem R, Schimmer AD. Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243 in acute myeloid leukemia. Leukemia. 2019;33:37-51
• Ishizawa J*, Zarabi SF*, Davis RE†, Halgas O†, Zhao R, Jitkova Y, Heese LE, St-Germain J, Nii T, Egan G, Ruvolo VR, Barghout SH, Nishida Y, Hurren R, Ma W, Gronda M, Link T,  Wong K, Mabanglo M, Kojima K, Borthakur G, MacLean N, Man Chun Ma J, Leber AB, Minden MD, Houry W, Kantarjian H, Stogniew M, Raught B, Pai EF, Schimmer AD#, Andreeff M#. ClpP-induced mitochondrial proteolysis causes cancer selective lethality. Cancer Cell. 2019;35:721-37  *,† = equal contribution; # co-corresponding authors.
• Tan J, Grouleff JJ, Jitkova Y, Diaz DB, Griffith EC, Shao W, Bogdanchikova AF, Poda G, Schimmer AD, Lee RE, Yudin AK. De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX. J Med Chem. 2019;62:6377-90.
• Mirali S, Botham A, Voisin V, Xu C, St-Germain J, Sharon D, Hoff FW, Qiu Y, Hurren R, Gronda M, Jitkova Y, Nachmias B, MacLean N, Wang X, Arruda A, Minden MD, Horton TM, Kornblau SM, Chan SM, Bader GD, Raught B, Schimmer AD. The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability. Sci Transl Med. 2020;12.
• Khan DH, Mullokandov M, Wu Y, Voisin V, Gronda M, Hurren R, Wang X, MacLean N, Jeyaraju DV, Jitkova Y, Xu GW, Laister R, Seneviratne A, Blatman ZM, Ketela T, Bader GD, Marhon SA, De Carvalho DD, Minden MD, Gross A, Schimmer AD. Mitochondrial carrier homolog 2 is necessary for AML survival. Blood. 2020;136:81-92.
• Singh RP, Jeyaraju DV, Voisin V, Hurren R, Xu C, Hawley JR, Barghout SH, Khan DH, Gronda M, Wang X, Jitkova Y, Sharon D, Liyanagae S, MacLean N, Seneviratene AK, Mirali S, Borenstein A, Thomas GE, Soriano J, Orouji E, Minden MD, Arruda A, Chan SM, Bader GD, Lupien M, Schimmer AD. Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal. Cell Stem Cell. 2020;26:926-37 e10.
• Lee J, Khan DH, Hurren R, Xu M, Na Y, Kang H, Mirali S, Wang X, Gronda MV, Jitkova Y, MacLean N, Arruda A, Alaniz Z, Konopleva MY, Andreeff M, Minden MD, Zhang L, Schimmer AD.    Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production. Blood. 2021 Jul 22;138(3):234-245.
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Graduate Students

Jennifer Ahn
Nathan Duong
Yue Feng