Professor of Internal Medicine and
Adjunct Professor of Oncological Sciences
Chief, Division of Hematology and Hematologic Malignancies
Senior Director for Transdisciplinary Research, Huntsman Cancer Institute
M.D. University of Wuerzburg Medical School, Germany
Ph.D. Imperial College, London
Michael Deininger's Lab Page
Michael Deininger's PubMed Literature Search
Molecular Biology Program
Leukemia Biology, Treatment and Treatment Resistance, Myeloproliferative Neoplasms, Chronic Myeloid Leukemia, Acute Myeloid Leukemia, Tumor Metabolism
Biology and targeted therapy of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML)
Compared to CML, the molecular biology of other types of MPN, such as chronic myelomonocytic leukemia (CMML) is more complex and much less well characterized. Many of the treatments are still non-specific rather than based on molecular understanding. In AML, standard of care therapy has remained almost identical for more than 30 years, and translating the extensive molecular knowledge into novel therapies has only started. We are applying genome-wide scanning technologies to study genetics and signal transduction in primary MPN patient samples, many of whom are treated on clinical trials. Simultaneously we are applying function first genetic approaches such as shRNA and CRSIPR-Cas9 library screens to identify vulnerabilities. Our overarching objective is to discover new and better therapeutic targets, identify biomarkers to predict response to treatment and using this knowledge to develop new therapeutic algorithms. Our approach has led to the identification of a metabolic regulator protein as a new target in AML and potentially other types of leukemia.
Tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)
Starting with imatinib, our lab has been intimately involved in the development of small molecule inhibitors of the BCR-ABL tyrosine kinase that have transformed the treatment of chronic myeloid leukemia (CML). Imatinib, while much more effective than conventional therapies, is liable to acquired drug resistance. We and others have identified point mutations in BCR-ABL as an important pathway of escape. Based on this knowledge, structure-based incremental improvements have led to second and third generation TKIs with increased potency and reduced vulnerability to BCR-ABL mutations, yet resistance still occurs. We are interested in understanding these novel resistance mechanisms, and exploit this knowledge to develop strategies to prevent resistance. On the other end of the clinical spectrum, the next quantum leap in CML therapy will be to eliminate residual disease, so that responses are sustained without continued treatment. We have discovered that extrinsic signals from the bone marrow microenvironment protect CML stem cells upon TKI inhibition of BCR-ABL. Characterizing these signals may identify novel therapeutic opportunities to eliminate residual CML cells, transforming excellent responses into true cure. Our work has led to the identification of the MS4A3 signaling protein as a novel tumor suppressor in CML, and current work is focused in understanding MS4A3 regulation and function.
Selected Recent Publications
- Heaton WL, Senina AV, Pomicter AD, Salama ME, Clair PM, Yan D, Bell RN, Gililland JM, Prchal JT, O'Hare T, Deininger MW. Autocrine Tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion.Leukemia. 2018.
- Patel AB, Lange T, Pomicter AD, Conley CJ, Harrington CA, Reynolds KR, Kelley TW, O'Hare T, Deininger MW. Similar expression profiles in CD34+ cells from chronic phase chronic myeloid leukemia patients with and without deep molecular responses to nilotinib.Oncotarget. 2018; 9(25):17889-17894.
- Than H, Qiao Y, Huang X, Yan D, Khorashad JS, Pomicter AD, Kovacsovics TJ, Marth GT, O'Hare T, Deininger MW. Ongoing clonal evolution in chronic myelomonocytic leukemia on hypomethylating agents: a computational perspective.Leukemia. 2018.
- Zabriskie MS, Antelope O, Verma AR, Draper LR, Eide CA, Pomicter AD, Tran TH, Druker BJ, Tyner JW, Miles RR, Graham JM, Hwang JY, Varley KE, Toydemir RM, Deininger MW, Raetz EA, O'Hare T. A novel AGGF1-PDGFRb fusion in pediatric T-cell acute lymphoblastic leukemia.Haematologica. 2018; 103(2):e87-e91.
- Qiang W, Antelope O, Zabriskie MS, Pomicter AD, Vellore NA, Szankasi P, Rea D, Cayuela JM, Kelley TW, Deininger MW, O'Hare T. Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib.Leukemia. 2017; 31(12):2844-2847.
- Deininger MWN, Tyner JW, Solary E. Turning the tide in myelodysplastic/myeloproliferative neoplasms.Nature Reviews. Cancer. 2017;
- Wallace JA, Kagele DA, Eiring AM, Kim CN, Hu R, Runtsch MC, Alexander M, Huffaker TB, Lee SH, Patel AB, Mosbruger TL, Voth WP, Rao DS, Miles RR, Round JL, Deininger MW, O'Connell RM. miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.Blood. 2017; 129(23):3074-3086.
- Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia.The New England Journal of Medicine. 2017; 376(10):917-927.
- Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Jones M, Kornacki D, Sun K, Kantarjian H. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial.Journal of Hematology & Oncology. 2017; 10(1):55.
- Khorashad JS, Tantravahi SK, Yan D, Mason CC, Qiao Y, Eiring AM, Gligorich K, Hein T, Pomicter AD, Reid AG, Kelley TW, Marth GT, O'Hare T, Deininger MW. Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy.Leukemia. 2016; 30(11):2275-2279.
- Mughal TI, Radich JP, Deininger MW, Apperley JF, Hughes TP, Harrison CJ, Gambacorti-Passerini C, Saglio G, Cortes J, Daley GQ. Chronic myeloid leukemia: reminiscences and dreams.Haematologica. 2016; 101(5):541-58.
- Khoury HJ, Goldberg SL, Mauro MJ, Stone RM, Deininger MW, Bradley-Garelik MB, Mohamed H, Guilhot F. Cross-Intolerance With Dasatinib Among Imatinib-Intolerant Patients With Chronic Phase Chronic Myeloid Leukemia.Clinical Lymphoma, Myeloma & Leukemia. 2016; 16(6):341-349.e1.
- Wagle M, Eiring AM, Wongchenko M, Lu S, Guan Y, Wang Y, Lackner M, Amler L, Hampton G, Deininger MW, O'Hare T, Yan Y. A role for FOXO1 in BCR-ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Leukemia. 2016; 30(7):1493-501.
- Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial.The Lancet. Oncology. 2016; 17(5):612-21.
- Ali AM, GÛmez-Biagi RF, Rosa DA, Lai PS, Heaton WL, Park JS, Eiring AM, Vellore NA, de Araujo ED, Ball DP, Shouksmith AE, Patel AB, Deininger MW, O'Hare T, Gunning PT. Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)-Resistant CML Lines While Circumventing Pharmacokinetic Liabilities.ChemMedChem. 2016; 11(8):850-61.
- Patel AB, Vellore NA, Deininger MW. New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape.Clinical Cancer Research. 2016; 22(5):1037-47. NIHMSID: NIHMS744037PMID: 26933174.
- Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim DW, Nicolini FE, Talpaz M, Baccarani M, M¸ller MC, Li J, Parker WT, Lustgarten S, Clackson T, Haluska FG, Guilhot F, Kantarjian HM, Soverini S, Hochhaus A, Hughes TP, Rivera VM, Branford S. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.Blood. 2016; 127(6):703-12.
- Tantravahi SK, Szankasi P, Khorashad JS, Dao KH, Kovacsovics T, Kelley TW, Deininger MW. A phase II study of the efficacy, safety, and determinants of response to 5-azacitidine (Vidaza) in patients with chronic myelomonocytic leukemia.Leukemia & Lymphoma. 2016; 57(10):2441-4.
- Mason CC, Khorashad JS, Tantravahi SK, Kelley TW, Zabriskie MS, Yan D, Pomicter AD, Reynolds KR, Eiring AM, Kronenberg Z, Sherman RL, Tyner JW, Dalley BK, Dao KH, Yandell M, Druker BJ, Gotlib J, O'Hare T, Deininger MW. Age-related mutations and chronic myelomonocytic leukemia.Leukemia. 2016; 30(4):906-13.
- Deininger MW. Molecular monitoring in CML and the prospects for treatment-free remissions.Hematology. American Society of Hematology. Education Program. 2015; 2015:257-63.
- Moslehi JJ, Deininger M. Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia.Journal of Clinical Oncology. 2015; 33(35):4210-8.
- Davare MA, Vellore NA, Wagner JP, Eide CA, Goodman JR, Drilon A, Deininger MW, O'Hare T, Druker BJ. Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors.Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(39):E5381-90.
- Mughal TI, Barbui T, Abdel-Wahab O, Kralovics R, Jamieson C, Kvasnicka HM, Mullaly A, Rampal R, Mesa R, Kiladjian JJ, Deininger M, Prchal J, Hehlmann R, Saglio G, Van Etten RA. Novel insights into the biology and treatment of chronic myeloproliferative neoplasms.Leukemia & Lymphoma. 2015; 56(7):1938-48.
- Deininger M, Radich J, Burn TC, Huber R, Paranagama D, Verstovsek S. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Blood. 2015; 126(13):1551-4.