Professor of Internal Medicine and
Adjunct Professor of Oncological Sciences
Chief, Division of Hematology and Hematologic Malignancies
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 and Treatment, Leukemia Drug Resistance, Myeloproliferative Neoplasms, Chronic Myeloid Leukemia, Autologous Stem Cell Transplantation
CANCER could be defined as the clinical consequence of genetic accidents that perturb differentiation, proliferation and programmed death as the fundamental mechanisms of tissue homeostasis. Conventional therapy relies on physical means (surgery) to remove diseased tissue or non-specific cytotoxic agents that exploit differential toxicity between normal and malignant cells. The dramatic progress of molecular biology and genetics has led to a much more profound understanding of cancer biology and has started to transform our approach to diagnosing, classifying and treating malignant disease. The overarching goal of our lab is to contribute to this transformation process, with a focus on leukemia. Our work takes place at the interface between clinical and basic science and is interested in mechanisms as much as the practical application of new mechanistic knowledge.
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.
Biology and targeted therapy of myeloproliferative neoplasms (MPN) and acute myeloid
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 although the somatic mutation spectrum has been revealed for most part, this knowledge has not yet been translated into novel therapies. 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 discovering new and better therapeutic targets, identify biomarkers to predict response to treatment and using this knowledge to develop new therapeutic algorithms.
Selected Recent Publications
- Khorashad JS, Tantravahi SK, Yan D, Mason CC, Qiao Y, Eiring A, Gligorich K, Hein T, Pomicter AD, Reid A, Kelley TW, Marth G, O’Hare T, Deininger MW. Rapid Conversion of Chronic Myeloid Leukemia to Chronic Myelomonocytic Leukemia in a Patient on Imatinib Therapy. Leukemia, 2016, accepted.
- 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. Clin Lymphoma Myeloma Leuk, 2016, 16(6):341-49.
- Wagle M, Eiring AM, Wongchenko M, Lu S, Guan 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, Deinigner MW, EPIC investigators. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol, 2016, 17(5):612-21.
- Ali AM, Gomez-Biagi RF, Rosa DA, Lai PS, Heaton WL, 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. Chem Med Chem 2016, 11(8):850-61.
- Patel AB, Vellore NA, Deininger MW. New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape. Clin Cancer Res 2016, 22(5):1037-47.
- Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim D, Nicolini FE, Talpaz M, Baccarani M, Muller 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. Leuk Lymphoma. 2016 Feb 8. Epub ahead of print.
- 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 K-H, 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 Am Soc Hematol Educ Program 2015, (1):257-63.
- Moslehi JJ, Deininger MW. Tyrosine Kinase Inhibitor Associated Cardiovascular Toxicity In Chronic Myeloid Leukemia. J Clin Oncol 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. Proc Natl Acad Sci U S A 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. Leuk Lymphoma 2015, 56(7):1938-48.
- Deininger MW, Radich J, Burn T, Huber R, Paranagama D, Verstovsek S. The Effect of Long-Term Ruxolitinib Treatement on JAK2p.V617F Allele Burden in Patients with Myelofibrosis. Blood 2015, 126(13):1551-4.