Skip to content

Main Navigation

Michael Deininger

Professor of Internal Medicine and
Adjunct Professor of Oncological Sciences

Deininger 2020

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

Research

References

michael.deininger@hci.utah.edu

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

Research

 

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.

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.

References

Selected Recent Publications

  1. Patel AB, Pomicter AD, Yan D, Eiring AM, Antelope O, Schumacher JA, Kelley TW, Tantravahi SK, Kovacsovics TJ, Shami PJ, O'Hare T, Deininger MW. Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms. Leukemia2020 May 14;. 
  2. Dao KT, Gotlib J, Deininger MMN, Oh ST, Cortes JE, Collins RH Jr, Winton EF, Parker DR, Lee H, Reister A, Schultz, Savage S, Stevens, Brockett C, Subbiah N, Press RD, Raess PW, Cascio M, Dunlap J, Chen Y, Degnin C, Maxson JE, Tognon CE, Macey T, Druker BJ, Tyner JW. Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia. J Clin Oncol. 2020 Apr 1;38(10):1006-1018.
  3. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, Clark RE, Cortes JE, Deininger MW, Guilhot F, Hjorth-Hansen H, Hughes TP, Janssen JJWM, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Mayer J, Nicolini F, Niederwieser D, Pane F, Radich JP, Rea D, Richter J, Rosti G, Rousselot P, Saglio G, Saußele S, Soverini S, Steegmann JL, Turkina A, Zaritskey A, Hehlmann R. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020 Apr;34(4):966-984.
  4. Than H, Pomicter AD, Yan D, Beaver LP, Eiring AM, Heaton WL, Senina A, Clair PM, Shacham S, Mason CC, Hare TO, Deininger MW. Coordinated inhibition of nuclear export and Bcr-Abl1 selectively targets chronic myeloid leukemia stem cells. Leukemia. 2020 Jan 24;.
  5. Patel AB, Franzini A, Leroy E, Kim SJ, Pomicter AD, Genet L, Xiao M, Yan D, Ahmann JM, Agarwal AM, Clair P, Addada J, Lambert J, Salmon M, Gleich GJ, Cross NCP, Constantinescu SN, O'Hare T, Prchal JT, Deininger MW. JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera. Blood. 2019 Dec 26;134(26):2388-2398.
  6. Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, Breccia M, Goh YT, Talpaz M, Hochhaus A, le Coutre P, Ottmann O, Heinrich MC, Steegmann JL, Deininger MWN, Janssen JJWM, Mahon FX, Minami Y, Yeung D, Ross DM, Tallman MS, Park JH, Druker BJ, Hynds D, Duan Y, Meille C, Hourcade-Potelleret F, Vanasse KG, Lang F, Kim DW. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019 Dec 12;381(24):2315-2326.
  7. Schneeweiss-Gleixner M, Byrgazov K, Stefanzl G, Berger D, Eisenwort G, Lucini CB, Herndlhofer S, Preuner S, Obrova K, Pusic P, Witzeneder N, Greiner G, Hoermann G, Sperr WR, Lion T, Deininger M, Valent P, Gleixner KV. CDK4/CDK6 inhibition as a novel strategy to suppress the growth and survival of BCR-ABL1T315I+ clones in TKI-resistant CML. EBioMedicine. 2019 Dec;50:111-121.
  8. Yan D, Pomicter AD, O'Hare T, Deininger MW. ddeeper Than Deep: Can ddPCR Predict Successful Imatinib Cessation?. Clin Cancer Res. 2019 Nov 15;25(22):6561-6563.
  9. Franzini A, Pomicter AD, Yan D, Khorashad JS, Tantravahi SK, Than H, Ahmann JM, O'Hare T, Deininger MW. The transcriptome of CMML monocytes is highly inflammatory and reflects leukemia-specific and age-related alterations. Blood Adv. 2019 Oct 22;3(20):2949-2961.
  10. Eide CA, Zabriskie MS, Savage Stevens SL, Antelope O, Vellore NA, Than H, Schultz AR, Clair P, Bowler AD, Pomicter AD, Yan D, Senina AV, Qiang W, Kelley TW, Szankasi P, Heinrich MC, Tyner JW, Rea D, Cayuela JM, Kim DW, Tognon CE, O'Hare T, Druker BJ, Deininger MW. Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants. Cancer Cell2019 Oct 14;36(4):431-443.e5.
  11. Valent P, Orazi A, Savona MR, Patnaik MM, Onida F, van de Loosdrecht AA, Haase D, Haferlach T, Elena C, Pleyer L, Kern W, Pemovska T, Vladimer GI, Schanz J, Keller A, Lübbert M, Lion T, Sotlar K, Reiter A, De Witte T, Pfeilstöcker M, Geissler K, Padron E, Deininger M, Orfao A, Horny HP, Greenberg PL, Arber DA, Malcovati L, Bennett JM. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica. 2019 Oct;104(10):1935-1949.
  12. Zhang H, Wilmot B, Bottomly D, Dao KT, Stevens E, Eide CA, Khanna V, Rofelty A, Savage S, Reister Schultz A, Long N, White L, Carlos A, Henson R, Lin C, Searles R, Collins RH, DeAngelo DJ, Deininger MW, Dunn T, Hein T, Luskin MR, Medeiros BC, Oh ST, Pollyea DA, Steensma DP, Stone RM, Druker BJ, McWeeney SK, Maxson JE, Gotlib JR, Tyner JW. Genomic landscape of neutrophilic leukemias of ambiguous diagnosis. Blood. 2019 Sep 12;134(11):867-879.
  13. Antelope O, Vellore NA, Pomicter AD, Patel AB, Van Scoyk A, Clair PM, Deininger MW, O'Hare T. BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits preclinical activity in Philadelphia chromosome-positive leukemia. Exp Hematol2019 Sep;77:36-40.e2. 
  14. Mughal TI, Pemmaraju N, Radich JP, Deininger MW, Kucine N, Kiladjian JJ, Bose P, Gotlib J, Valent P, Chen CC, Barbui T, Rampal R, Verstovsek S, Koschmieder S, Saglio G, Van Etten RA. Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms. Hematol Oncol2019 Aug;37(3):240-252.
  15. Gilreath JA, Tchertanov L, Deininger MW. Novel approaches to treating advanced systemic mastocytosis. Clin Pharmacol. 2019;11:77-92.
  16. Patel AB, Miles RR, Deininger MW. Lysozyme nephropathy in chronic myelomonocytic leukemia. Clin Case Rep2019 Jun;7(6):1263-1264. 
  17. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Crescenzo R, Mamolo C, Reisman A, Hochhaus A, Brümmendorf TH. Patient-reported outcomes in the phase 3 BFORE trial of bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia. J Cancer Res Clin Oncol. 2019 Jun;145(6):1589-1599.
  18. Gerds AT, Tauchi T, Ritchie E, Deininger M, Jamieson C, Mesa R, Heaney M, Komatsu N, Minami H, Su Y, Shaik N, Zhang X, DiRienzo C, Zeremski M, Chan G, Talpaz M. Corrigendum to "Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib" [Leukemia Res. 79 (2019) 38-44]. Leuk Res. 2019 Jun;81:105.
  19. Patel AB, Pettijohn EM, Abedin SM, Raps E, Deininger MW. Leukemoid reaction in chronic myelomonocytic leukemia patients undergoing surgery: perioperative management recommendations. Blood Adv2019 Apr 9;3(7):952-955.
  20. Yan D, Pomicter AD, Tantravahi S, Mason CC, Senina AV, Ahmann JM, Wang Q, Than H, Patel AB, Heaton WL, Eiring AM, Clair PM, Gantz KC, Redwine HM, Swierczek SI, Halverson BJ, Baloglu E, Shacham S, Khorashad JS, Kelley TW, Salama ME, Miles RR, Boucher KM, Prchal JT, O'Hare T, Deininger MW. Nuclear-Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis. Clin Cancer Res. 2019 Apr 1;25(7):2323-2335.
  21. Gerds AT, Tauchi T, Ritchie E, Deininger M, Jamieson C, Mesa R, Heaney M, Komatsu N, Minami H, Su Y, Shaik N, Zhang X, DiRienzo C, Zeremski M, Chan G, Talpaz M. Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. Leuk Res2019 Apr;79:38-44.
  22. Shouksmith AE, Shah F, Grimard ML, Gawel JM, Raouf YS, Geletu M, Berger-Becvar A, de Araujo ED, Luchman HA, Heaton WL, Bakhshinyan D, Adile AA, Venugopal C, O'Hare T, Deininger MW, Singh SK, Konieczny SF, Weiss S, Fishel ML, Gunning PT. Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer. J Med Chem. 2019 Mar 14;62(5):2651-2665.
  23. Wang J, Li L, Yang J, Clair PM, Glenn MJ, Stephens DM, Radford DC, Kosak KM, Deininger MW, Shami PJ, Kopeček J. Drug-free macromolecular therapeutics induce apoptosis in cells isolated from patients with B cell malignancies with enhanced apoptosis induction by pretreatment with gemcitabine. Nanomedicine. 2019 Feb;16:217-225. 
  24. Niyongere S, Lucas N, Zhou JM, Sansil S, Pomicter AD, Balasis ME, Robinson J, Kroeger J, Zhang Q, Zhao YL, Ball M, Komrokji R, List A, Deininger MW, Fridley BL, Santini V, Solary E, Padron E. Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML. Leukemia. 2019 Jan;33(1):205-216.
  25. Gotlib J, Gerds AT, Bose P, Castells MC, Deininger MW, Gojo I, Gundabolu K, Hobbs G, Jamieson C, McMahon B, Mohan SR, Oehler V, Oh S, Padron E, Pancari P, Papadantonakis N, Pardanani A, Podoltsev N, Rampal R, Ranheim E, Rein L, Snyder DS, Stein BL, Talpaz M, Thota S, Wadleigh M, Walsh K, Bergman MA, Sundar H. Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018 Dec;16(12):1500-1537.
  26. 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; 32(11):2399-2411.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. Deininger MWN, Tyner JW, Solary E. Turning the tide in myelodysplastic/myeloproliferative neoplasms.Nature Reviews. Cancer. 2017;
    17(7):425-440.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. Deininger MW. Molecular monitoring in CML and the prospects for treatment-free remissions.Hematology. American Society of Hematology. Education Program. 2015; 2015:257-63.
  46. Moslehi JJ, Deininger M. Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia.Journal of Clinical Oncology. 2015; 33(35):4210-8.
  47. 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.
  48. 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.
  49. 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. 

to page top

Last Updated: 10/1/20