Die Bedeutung von EZH2-abhängigen Stammzellprogrammen für Therapieansprechen und Resistenz bei der Akuten Myeloischen Leukämie
Zusammenfassung der Projektergebnisse
In summary, data from our newly developed single cell Clone Tracer approach using matched diagnostic and post-induction AML samples demonstrate increased LSC/stemness signatures in EZH2low leukemic cells with increased expression of surface markers associated with self-renewal capacity, therapy response and poor prognosis. Surface markers of EZH2low leukemic cells identified in this study will be investigated and validated in a larger AML cohort with matched diagnosis/treatment samples by use of FACS-based approaches to establish markers for detection of EZH2low therapyresistant leukemic cells present at diagnosis. Currently, the TEAM trial (Targeting Epigenetic Therapy Resistance in AML With Bortezomib, PI: C Müller-Tidow) is ongoing to analyze whether proteasome inhibition with bortezomib is able to restore chemo-sensitivity via EZH2 stabilisation. Here, EZH2 mRNA and protein expression levels of patients before and upon start of therapy will be analyzed by qRT-PCR, FACS and MassSpec. Using the newly identified surface markers for EZH2low leukemic cells, we will have the option to analyze expression of „EZH2-specific“ surface markers in longitudinal samples under a „EZH2-restoring“ therapy and correlate findings with clinical data. Single cell analyses of the primary patient samples before and after bortezomib treatment by the newly established Clone Tracer approach will be performed to further analyze EZH2 effects onto therapy response. Funding of this project already contributed to several publications.
Projektbezogene Publikationen (Auswahl)
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NOP10 predicts lung cancer prognosis and its associated small nucleolar RNAs drive proliferation and migration. Oncogene, 40(5), 909-921.
Cui, Chunhong; Liu, Yi; Gerloff, Dennis; Rohde, Christian; Pauli, Cornelius; Köhn, Marcel; Misiak, Danny; Oellerich, Thomas; Schwartz, Schraga; Schmidt, Lars-Henning; Wiewrodt, Rainer; Marra, Alessandro; Hillejan, Ludger; Bartel, Frank; Wickenhauser, Claudia; Hüttelmaier, Stefan; Göllner, Stefanie; Zhou, Fengbiao; Edemir, Bayram & Müller-Tidow, Carsten
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Site-specific methylation of 18S ribosomal RNA by SNORD42A is required for acute myeloid leukemia cell proliferation. Blood, 135(23), 2059-2070.
Pauli, Cornelius; Liu, Yi; Rohde, Christian; Cui, Chunhong; Fijalkowska, Daria; Gerloff, Dennis; Walter, Carolin; Krijgsveld, Jeroen; Dugas, Martin; Edemir, Bayram; Pabst, Caroline; Müller, Lutz P.; Zhou, Fengbiao & Müller-Tidow, Carsten
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Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response. Nature Cancer, 2(5), 527-544.
Scheller, Marina; Ludwig, Anne Kathrin; Göllner, Stefanie; Rohde, Christian; Krämer, Stephen; Stäble, Sina; Janssen, Maike; Müller, James-Arne; He, Lixiazi; Bäumer, Nicole; Arnold, Christian; Gerß, Joachim; Schönung, Maximilian; Thiede, Christian; Niederwieser, Christian; Niederwieser, Dietger; Serve, Hubert; Berdel, Wolfgang E.; Thiem, Ulrich ... & Müller-Tidow, Carsten
