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Epigenomics, Epitranscriptomics
and novel therapy approaches in AML

Our Vision - What we do


 

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. Lead investigators of our group are Stefanie Göllner, Carsten Müller-Tidow, Marina Scheller-Wendorff and Fengbiao Zhou.

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 (Figure 1).

 

 

Figure 1:

Leukemic stem cells and bulk leukemia cells within one patient contain the same genetic mutations. Epigenetic and epitranscriptomic mechanisms affect stemness features and therapy response. Epi-therapy could shift the balance and increase therapeutic efficacy.

We have identified a novel epigenetic therapy resistance mechanism in Acute Myeloid Leukemia (Figure 2). 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.

 

 

Figure 2:

Loss of EZH2 is a frequent mechanism of therapy resistance in relapsed and refractory AML. CDK1 phosphorylated T487 of EZH2 via a HSP90 dependent mechanism. As a consequence, EZH2 is destabilized and degraded in the proteasome.

Loss of EZH2 leads to increased stemness and therapy resistance of leukemia cells by loss of repressive H3K27me3 marks in stemness genes (e.g. HOX genes). Proteasome inhibition leads to EZH2 protein re-expression and increased therapeutic efficacy. (Göllner et al., Nature Med 2017)

A clinical trial based on this novel therapeutic opportunity is about to start early in 2018.

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 https://clinicaltrials.gov/show/NCT02502968 .

With clinical trial data we developed a patient specific score to predict older AML patient´s  response to induction chemotherapy (Krug et al., 2010)  http://www.aml-score.org/.

Recently, we identified a novel familial AML syndrome caused by germline DDX41 mutations (Figure 3) (Polprasat, Schulze et al., 2015).

 

Figure 3:

Hereditary DDX41 mutations are associated with MDS and AML in older patients.

We discovered in collaboration with J. Maciejewski´s group that germline DDX41 mutations are associated with familial hematological neoplasms (Polprasat, Schulze et al., Cancer Cell 2015). Multiple families have now been described and DDX41 mutations were included into the WHO 2016 myeloid disease classification. These mutations appear to alter stemness properties in hematopoietic progenitor cells and thus predispose for malignant diseases that are typically diagnosed 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.

These mutations predispose to AML, MDS and other hematological malignancies. We are currently investigating the pathogenetic mechanisms of mutations in the RNA helicase DDX41.

Non-coding RNAs are important mediators of disease aggressiveness. We discovered MALAT-1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) as a long non-coding RNA that is closely associated with lung cancer metastasis (Ji, Diederichs et al., 2003). Recently, we discovered that snoRNA functions are essential for leukemic stem cell self renewal in AML1-ETO induced leukemia (Figure 4)(Zhou et al., 2017). Currently, we are analyzing the specific functions of non-coding RNAs in leukemia and lung cancer.

Figure 4:

Stemness of AML1-ETO induced leukemias depend on AES (Amino Enhancer of Split). AES mediates its functions via snoRNAs which are stabilized upon AES induction. Increased snoRNAs with snoRNP formation lead to enhanced leukemic stem cell self renewal. (Zhou et al., Nature Cell Biol 2017). Currently, we are working on further mechanisms how snoRNAs contribute to leukemogenesis.

Vacancies


We are always looking for outstanding postdocs, physician scientists and graduate students.

If you are interested in our team, projects and research, please contact our science coordinator Annette Becker by emailing annette.becker@med.uni-heidelberg.de or by phone +49 (0)6221 56 8552. Thank you very much!

Who we are


Head of group


Carsten Müller-Tidow, MD

Professor of Medicine
Director
Department of Medicine V
Hematology, Oncology and Rheumatology

 


Phone: +49 6221 - 56 8000/8001
Fax: +49 6221 - 56 5813
Email:Opens window for sending emailcarsten.mueller-tidow@med.uni-heidelberg.de

 

Group Members


Dr. Stefanie Göllner

Senior Scientist, Lead Investigator


Tel.: 06221 - 5634086
E-Mail: stefanie.goellner@med.uni-heidelberg.de

 

Dr. Yi Liu

Postdoctoral Fellow


Tel.: 06221 - 5637478
E-Mail: yi.liu@med.uni-heidelberg.de 

 

 

Dr. Christian Rohde

Senior Scientist


Tel.: 06221 - 5637487
E-Mail: christian.rohde@med.uni-heidelberg.de

 

Dr. Marina Scheller-Wendorff

Senior Scientist, Lead Investigator


Tel.: 06221 - 5634139
E-Mail: marina.scheller-wendorff@med.uni-heidelberg.de

 

Dr. Fengbiao Zhou

Postdoctoral Fellow, Lead Investigator


Tel.: 06221 - 56 37487
E-Mail: fengbiao.zhou@med.uni-heidelberg.de

 

 

Dr. med. Maximilian Felix Blank

Clinician Researcher, MD


E-Mail:

MaximilianFelix.Blank@med.uni-heidelberg.de

 

Dr. med. Nina Rosa Neuendorff

Clinical Researcher, MD

E-Mail: NinaRosa.Neuendorff@med.uni-heidelberg.de

 

Chunghong Cui

PhD student

 

Tel.: 06221 - 56 37604
E-Mail: chunghong.cui@med.uni-heidelberg.de

 

James Arne Müller

PHD student

E-Mail: JamesArne.Mueller@med.uni-heidelberg.de

Birgit Besenbeck

Senior Technician, lab manager

 

Tel.: 06221 - 56 34086
E-Mail: birgit.besenbeck@med.uni-heidelberg.de

 

Michelle Lotze

Technician (BTA)

 

Tel.: 06221 - 56 37487
E-Mail: michelle.lotze@med.uni-heidelberg.de

 

 

 

Annette Becker M.A.

Science coordinator

 

Tel.: 06221 - 56 8552
E-Mail: annette.becker@med.uni-heidelberg.de

 

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.
  • Polprasert C*, Schulze I*, Sekeres MA, Makishima H, Przychodzen B, Hosono N, Singh J, Padgett RA, Gu X, Phillips JG, Clemente M, Parker Y, Lindner D, Dienes B, Jankowsky E, Saunthararajah Y, Du Y, Oakley K, Nguyen N, Mukherjee S, Pabst C, Godley LA, Churpek JE, Pollyea DA, Krug U, Berdel WE, Klein HU, Dugas M, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Yoshida K, Ogawa S, Müller-Tidow C*, Maciejewski JP*: Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell. 2015;27(5):658-70. 
  • Bäumer S, Bäumer N, Appel N, Terheyden L, Fremerey J, Schelhaas S, Wardelmann E, Buchholz F, Berdel WE, Müller-Tidow C: Antibody-mediated delivery of anti-KRAS-siRNA in vivo overcomes therapy resistance in colon cancer. Clin Cancer Res. 2015;21(6):1383-94.
  • Hascher A*, Haase AK*, Hebestreit K, Rohde C, Klein HU, Rius M, Jungen D, Witten A, Stoll M, Schulze I, Ogawa S, Wiewrodt R, Tickenbrock L, Berdel WE, Dugas M, Thoennissen NH*, Müller-Tidow C*: DNA methyltransferase inhibition reverses epigenetically embedded phenotypes in lung cancer preferentially affecting polycomb target genes. Clin Cancer Res. 2014;20(4):814-26. 
  • Schoofs T*, Rohde C*, Hebestreit K, Klein HU, Göllner S, Schulze I, Lerdrup M, Dietrich N, Agrawal-Singh S, Witten A, Stoll M, Lengfelder E, Hofmann WK, Schlenke P, Buchner T, Hansen K, Berdel WE, Rosenbauer F, Dugas M, Müller-Tidow C: DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding. Blood. 2013;121(1):178-87.
  • Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, Klein HU, Popescu AC, Burnett A, Mills K, Casero RA, Jr., Marton L, Woster P, Minden MD, Dugas M, Wang JC, Dick JE, Müller-Tidow C, Petrie K, Zelent A: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18(4):605-11.
  • Krug U, Rollig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M, Thiede C, Kramer M, Braess J, Spiekermann K, Haferlach T, Haferlach C, Koschmieder S, Rohde C, Serve H, Wormann B, Hiddemann W, Ehninger G, Berdel WE, Büchner T*, Müller-Tidow C*, German Acute Myeloid Leukaemia Cooperative G, Study Alliance Leukemia I: Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 2010;376(9757):2000-8.
  • Ji P*, Diederichs S*, Wang W, Boing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, Thomas M, Berdel WE, Serve H, Müller-Tidow C. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 2003;22(39):8031-8041.
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