Summary

The aim of our group is to identify pathogenetic mechanisms in acute leukemias and other cancers to ultimately develop and test novel therapy approaches in early phase clinical trials. Clinical specimens from these trials are then analyzed to further understand mechanisms of disease and therapy resistance. For the clinical trials we work closely with the different groups in the Department and the NCT.

-       One important hypothesis of our work states that epigenetic changes affect stemness of cancer cells and cause therapy resistance. Hence, epigenetic therapies may be an efficient approach to overcome therapy resistance. We have identified a novel epigenetic therapy resistance mechanism in Acute Myeloid Leukemia. Importantly, therapy resistance can be tackled by proteasome inhibition (or HSP90 inhibition). A multicenter clinical trial is planned to evaluate this concept in relapsed and refractory AML patients.

-       Chromatin and histone modifications as therapeutic targets are a field of active investigation. In an international collaborative effort we took part in the identification of LSD1 as a suitable target for differentiation therapy in AML (Schenk et al., 2012). Currently, we are performing a phase I/II clinical trial to test this approach in patients with refractory AML (NCT02261779). Biomarker analyses to identify why patients respond or do not respond are underway.

-       Alterations of DNA methylation occur frequently in most cancers. We are studying how changes in DNA methylation affect disease pathogenesis and therapy resistance in several cancer types. In genetic mouse models we are modeling leukemogenesis under conditions with increased or decreased DNA methyltransferase activity (Schulze et al., Blood 2016). In clinical trials we evaluate how DNA hypomethylating drugs such as Azacytidine can affect therapy response (Müller-Tidow et al., Leukemia 2016). 

-       Mechanisms of stemness and aggressive disease in leukemia and beyond. In a clinical trial we are evaluating whether a novel CXCR4 inhibitor, BL-8040, that targets leukemic stem cells can improve therapy outcome for patients in first clinical remission. Find more information here.

-       With clinical trial data we developed a patient specific score to predict older AML patient´s  response to induction chemotherapy (Krug et al., 2010). Find more information here. 

-       Recently, we identified a novel familial AML syndrome caused by germline DDX41 mutations (Polprasat, Schulze et al., 2015). Hereditary DDX41 mutations are associated with MDS and AML in older patients. We are currently analyzing the relevant mechanisms and we are screening patients with familial AML and MDS for mutations in DDX41 and other genes.

-       We discovered that snoRNA functions are essential for leukemic stem cell self renewal in AML1-ETO induced leukemia (Zhou et al., 2017). Currently, we are analyzing the specific functions of non-coding RNAs in leukemia and lung cancer. We are working on further mechanisms how snoRNAs contribute to leukemogenesis.

Find more information on the group here.

Selected Publications

Zhou F, Liu Y, Rohde C, Pauli C, Gerloff D, Köhn M, Misiak D, Bäumer N, Cui C, Göllner S, Oellerich T, Serve H, Garcia-Cuellar M-P, Slany R, Maciejewski JP, Przychodzen B, Seliger B, Klein H-U, Bartenhagen C, Berdel WE, Dugas M, Taketo MM, Farouq D, Schwartz S, Regev A, Hébert J, Sauvageau G, Pabst C, Hüttelmaier S, Müller-Tidow C: AML1-ETO requires enhanced snoRNP formation to induce self-renewal and leukemia. Nature Cell Biology 2017;19(7):844-855

Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C, Pabst C, Sauer T, Lerdrup M, Tavor S, Stolzel F, Herold S, Ehninger G, Kohler G, Pan KT, Urlaub H, Serve H, Dugas M, Spiekermann K, Vick B, Jeremias I, Berdel WE, Hansen K, Zelent A, Wickenhauser C, Müller LP, Thiede C, Müller-Tidow C: Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nature Medicine 2017;23(1):69-78.

Schulze I, Rohde C, Scheller-Wendorff M, Bäumer N, Krause A, Herbst F, Riemke P, Hebestreit K, Tschanter P, Lin Q, Linhart H, Godley LA, Glimm H, Dugas M, Wagner W, Berdel WE, Rosenbauer F, Müller-Tidow C: Increased DNA methylation of Dnmt3b targets impairs leukemogenesis. Blood. 2016;127(12):1575-86.

Müller-Tidow C*, Tschanter P*, Rollig C, Thiede C, Koschmieder A, Stelljes M, Koschmieder S, Dugas M, Gerss J, Butterfass-Bahloul T, Wagner R, Eveslage M, Thiem U, Krause SW, Kaiser U, Kunzmann V, Steffen B, Noppeney R, Herr W, Baldus CD, Schmitz N, Gotze K, Reichle A, Kaufmann M, Neubauer A, Schafer-Eckart K, Hanel M, Peceny R, Frickhofen N, Kiehl M, Giagounidis A, Gorner M, Repp R, Link H, Kiani A, Naumann R, Brummendorf TH, Serve H, Ehninger G, Berdel WE, Krug U, Study Alliance Leukemia G: Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Leukemia. 2016;30(3):555-61.