DNA-methyltransferase 1 (DNMT1) activity in regulation of hematopoietic stem and progenitor cells
Final Report Abstract
Understanding the molecular mechanisms underlying cell fate choices of somatic stem cells is a major goal of today's research as this is essential for potential exploitation of such stem cells in therapeutic regenerative applications like tissue repair. Moreover, this knowledge is of great significance when it comes to counteracting the consequences of abnormal stem cell properties which can lead to diseases such as cancer. In this funding period, we investigated the role of the major DNA methyltransferase (DNMT), the maintenance methyltransferase DNMT1, in adult hematopoietic stem cells (HSC). We could show that DNA methylation is essential to suppress premature expression of genes inducing myeloiderythroid differentiation, which is a prerequisite to maintain self-renewal and multipotency as the defining hallmark properties of a stem cell. Consequently, DNA methylation can be viewed as a guardian mechanism to protect stem cells from exhaustion upon premature differentiation. In a model of acute myeloid leukemia (AML) induced by the well characterized oncogenic fusion protein MLL-AF9, we could further show that reduced DNMT1 expression severely irnpairs acquisition of leukemic self-renewal qualities demonstrating a requirement of certain DNMT1 levels for leukemic transformation. Collectively, we could demonstrate that the fate of cancer stem cells, similarly to that of normal stem cells, is governed by the DNA methylation dosage. However, it remains elusive which epigenetic programs are responsible for controlling stem cell decision in leukemia. Unraveling these mechanisms will give insights into molecular connections valuable for therapeutic strategies involving demethylating drugs.
Publications
- DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. 2009; Nature Genetics 41: 1207-1215
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
- Uncovering a unique role for DNA methylation in hematopoietic and leukemic stem cells. 2010; Cell Cycle 9:640-641
Vockentanz L, Bröske AM, and Rosenbauer F
