DNA methylation control of myeloid leukemia stem cell genes

There is increasing evidence that apart from the rapidly proliferating, aggressive cancer cells, there are cancer stem cells (CSCs) that are able to escape conventional cancer therapy and cause disease relapses. They have a lot in common with normal stem cells, their self-renewal, long-term survival and differentiation potential. It is not known, how these CSCs develop. To answer this question is a main objective of our research.
DNMT1 is a DNA-methyltransferase that is responsible for the maintenance of methylation marks on the DNA. It is likely that the inheritable methylation marks have influence on the cellular fate by regulation of cell-type specific gene expression. In our previous work we could show that hematopoietic stem cells (HSCs) as well as leukemic stem cells (LSCs) have impaired self-renewal when they are transformed by a hypomorphic DNMT1 allele combined with a null allele, pointing to reduced ‘stemness’. Furthermore the hypomethylation led to a lower expression of stem cell genes and lymphoid genes in HSCs as well as to an increased synthesis of myeloerythroid gene products.

In our work we want to identify gene programs that are responsible for the development and maintenance of stem cell properties in LSC by analyzing gene expression profiles and methylation marks in hypomethylated LSCs. Uncovering these epigenetically controlled mechanisms could lead to the identification of targets for anti-cancer therapy with demethylating chemicals.
We are also exploring computational methods to improve the predictions of miRNA regulatory actions of the epigenetic modifications occurring along haematopoietic differentiation using network analysis. Initially we are integrating ChIP-seq data of transcription factors with miRNA target predictions to select biologically relevant miRNA targets for genes differentially expressed during differentiation and reprogramming.

Ghani S, Riemke P, Schönheit J, Lenze D, Stumm J, Hoogenkamp M, Lagendijk A, Heinz S, Bonifer C, Bakkers J, Abdelilah-Seyfried S, Hummel M, Rosenbauer F. (2011). Macrophage development from hematopoietic stem cells requires PU.1 coordinated microRNA expression. Blood 118:2275-2284. PMID:21730352

Leddin M, Perrod C, Hoogenkamp M, Ghani S, Assi S, Heinz S, Wilson NK, Follows G, Schönheit J, Vockentanz L, Mosamam A, Chen W, Tenen DG, Westhead DR, Göttgens B, Bonifer C, Rosenbauer F. (2011). Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells. Blood 117:2827-2838. PMID:21239694

Vockentanz L, Bröske AM, and Rosenbauer F. (2010). Uncovering a unique role for DNA methylation in hematopoietic and leukemic stem cells. Cell Cycle 9:640-641. PMID:20107327

Bröske AM, Vockentanz L, Kharazi S, Huska M, Mancini E, Scheller M, Enns A, Prinz M, Jaenisch R, Nerlov C, Leutz A, Andrade-Navarro MA, Jacobsen SEW, Rosenbauer F. (2009). DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nature Genetics 41: 1207-1215. PMID:19801979

Mah, N., Y. Wang, R. Mrowka, F. Rosenbauer, J. Adjaye, M.A. Andrade-Navarro. (2010). Die Entwicklungsuhr zurückdrehen. Systembiologie.de. 2, 15-19. pdf

Frank Rosenbauer

Institut for Molecular Tumorbiology - IMTB
University of Münster
Robert-Koch-Str 43
D-48149 Münster, Germany
Phone +49-251-83-55312
Fax +49-251-83-55303

Miguel Andrade-Navarro

Max-Delbrück-Centrum for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Str 10
D-13125 Berlin, Germany
Phone +49-30-94064250
Fax +49-30-94064240

Irina Savelyeva

Institut for Molecular Tumorbiology - IMTB
University of Münster
Robert-Koch-Str 43
D-48149 Münster, Germany
Phone +49-251-83-51601
Fax +49-251-83-55303

Links:

Homepage