Epigenetic targeting of dormant leukemic stem cells


Project Summary

Leukemic Stem Cells (LSCs) reside in a long-term quiescent state, reversal of LSC quiescence drives acute myeloid leukemia (AML) relapse. We identified distinct DNA methylation changes upon healthy hematopoietic stem cells (HSCs) commitment. Our data suggest a novel role for Gprc5c as a marker of LSC dormancy. Thus, we hypothesise that dormant LSCs are epigenetically distinct and that targeting the epigenetic landscape of Gprc5c+-LSCs might delay relapse. We propose to define the epigenetic features of dormant Gprc5c+-LSCs in AML and compare them to healthy dormant HSCs. This may allow us to determine novel therapeutic avenues in AML.

Selected project-relevant publications

  • Renders S., Svendsen A.F., Panten J., Rama N., Maryanovich M., Sommerkamp P., Ladel L., Redavid A.R., Gibert B., Lazare S., Ducarouge B., Schönberger K., Narr A., Tourbez M., Dethmers-Ausema B., Zwart E., Hotz-Wagenblatt A., Zhang D., Korn C., Zeisberger P., Przybylla A., Sohn M., Mendez-Ferrer S., Heikenwälder M., Brune M., Klimmeck D., Bystrykh L., Frenette P.S., Mehlen P., De Haan G., Cabezas-Wallscheid N. and Trumpp A. (2021) Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1. Nat Commun 12, 608.
  • Zhang Y.W., Mess J. and Cabezas-Wallscheid N. (2021) Characterizing the In Vivo Role of Candidate Leukemia Stem Cell Genes. Methods Mol Biol 2185, 307-316.
  • Sommerkamp P., Altamura S., Renders S., Narr A., Ladel L., Zeisberger P., Eiben P.L., Fawaz M., Rieger M.A., Cabezas-Wallscheid N. and Trumpp A. (2020) Differential Alternative Polyadenylation Landscapes Mediate Hematopoietic Stem Cell Activation and Regulate Glutamine Metabolism. Cell Stem Cell 26, 722-738.e727.
  • Sommerkamp P., Renders S., Ladel L., Hotz-Wagenblatt A., Schonberger K., Zeisberger P., Przybylla A., Sohn M., Zhou Y., Klibanski A., Cabezas-Wallscheid N. and Trumpp A. (2019) The long non-coding RNA Meg3 is dispensable for hematopoietic stem cells. Sci Rep 9, 2110.
  • Zhang Y.W. and Cabezas-Wallscheid N. (2019) Assessment of Young and Aged Hematopoietic Stem Cell Activity by Competitive Serial Transplantation Assays. Methods Mol Biol 2017, 193-203.
  • Cabezas-Wallscheid N., Buettner F., Sommerkamp P., Klimmeck D., Ladel L., Thalheimer F.B., Pastor-Flores D., Roma L.P., Renders S., Zeisberger P., Przybylla A., Schonberger K., Scognamiglio R., Altamura S., Florian C.M., Fawaz M., Vonficht D., Tesio M., Collier P., Pavlinic D., Geiger H., Schroeder T., Benes V., Dick T.P., Rieger M.A., Stegle O. and Trumpp A. (2017) Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy. Cell 169, 807-823.e819.
  • Scognamiglio R., Cabezas-Wallscheid N., Thier M.C., Altamura S., Reyes A., Prendergast A.M., Baumgartner D., Carnevalli L.S., Atzberger A., Haas S., Von Paleske L., Boroviak T., Worsdorfer P., Essers M.A., Kloz U., Eisenman R.N., Edenhofer F., Bertone P., Huber W., Van Der Hoeven F., Smith A. and Trumpp A. (2016) Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause. Cell 164, 668-680.
  • Lipka D.B., Wang Q., Cabezas-Wallscheid N., Klimmeck D., Weichenhan D., Herrmann C., Lier A., Brocks D., Von Paleske L., Renders S., Wunsche P., Zeisberger P., Gu L., Haas S., Essers M.A., Brors B., Eils R., Trumpp A., Milsom M.D. and Plass C. (2014) Identification of DNA methylation changes at cis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing. Cell Cycle 13, 3476-3487.
  • Klimmeck D., Cabezas-Wallscheid N., Reyes A., Von Paleske L., Renders S., Hansson J., Krijgsveld J., Huber W. and Trumpp A. (2014) Transcriptome-wide profiling and posttranscriptional analysis of hematopoietic stem/progenitor cell differentiation toward myeloid commitment. Stem Cell Reports 3, 858-875.
  • Cabezas-Wallscheid N., Klimmeck D., Hansson J., Lipka D.B., Reyes A., Wang Q., Weichenhan D., Lier A., Von Paleske L., Renders S., Wunsche P., Zeisberger P., Brocks D., Gu L., Herrmann C., Haas S., Essers M.a.G., Brors B., Eils R., Huber W., Milsom M.D., Plass C., Krijgsveld J. and Trumpp A. (2014) Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 15, 507-522.
  • Cabezas-Wallscheid N., Eichwald V., De Graaf J., Lower M., Lehr H.A., Kreft A., Eshkind L., Hildebrandt A., Abassi Y., Heck R., Dehof A.K., Ohngemach S., Sprengel R., Wortge S., Schmitt S., Lotz J., Meyer C., Kindler T., Zhang D.E., Kaina B., Castle J.C., Trumpp A., Sahin U. and Bockamp E. (2013) Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model. EMBO Mol Med 5, 1804-1820.