Hematopoietic and Leukemic Stem Cells (Head: Prof. Andreas Trumpp)

Somatic stem cells are the cellular components responsible for the life-long maintenance and repair of highly regenerative tissues such as the skin, the gastro-intestinal mucosa or the blood forming system. In addition stem cells are critical components of repair in response to tissue injury and infection. Moreover, genetic alterations of stem cells and their progeny can lead to the generation of “leukemic stem cells” (LSC) or solid “cancer stem cells” (CSCs) that drive tumorigenesis and metastasis in hierarchically organized cancer entities. Due to their remarkable resistance to chemotherapy and radiation, CSCs are thought to be responsible for tumor re-occurrence and the initiation and maintenance of metastases. (Baccelli et al 2012 JCB Review).


Hematopoietic Stem Cells (HSC)

One of the goals of our program is to elucidate the molecular and cellular basis of hematopoietic stem cell (HSC) self-renewal and differentiation as well as their interaction with their stem cell niches. We have recently shown, that the most potent HSCs are in a state of deep dormancy during steady-state homeostasis (Figure 1). In striking contrast, dormant HSCs become rapidly activated to produce new stem cells and progenitors in response to stress signals. These can be released by bacterial (LPS) or viral infections (Interferons) or by chemotherapy mediated cell loss. We also use mouse genetics to study the role of oncogenes and tumor suppressor genes such as c-Myc, N-Myc and PTEN. Moreover, we have shown that Granzyme B deficiency promotes HSC reconstitution and protection from inflammatory stress and chemotherapy.

Regulators of HSC dormancy

Figure 1. Regulators of HSC dormancy.
Individual dormant HSCs reside in the BM niche, anchored to the stroma via a network of adhesion molecules. Various soluble ligands interact with their receptors expressed by HSCs. During homeostasis these signals contribute to maintaining HSCs in a dormant, metabolically inactive state. To self-renew or in response to stress/injury, HSCs exit dormancy (and maybe even the niche) and proliferate. Left side of arrows: expression of genes, or soluble molecules that drive HSC proliferation. Right side: Negative regulators of dormancy. All these genes repress cycling in HSCs (in the absence of any one, HSCs go into cycle) and contribute to maintaining quiescence (Wilson and Trumpp (2009). Curr. Op. Genet. Develop.)


Stem Cells in Myeloid Dysplasia (MDS)

In collaboration with Prof. Wolf-Karsten Hofmann and Dr. Daniel Nowak (University hospital Mannheim) we have established novel patient derived animal models for MDS, in particular for the lower risk types. Most relevant, we show that the mutant MDS stem cells (lin-CD34+CD38-) re-program their microenviromental niches and establish a cross talk, which establishes an “MDS-hematopoietic-niche unit”. The functional relevance of this unit for the development and progression of MDS in patients is demonstrated by its capacity to propagate MDS in immune-compromised mice. Finally, since patients are still alive at the time the models are established, this generates a platform for personalized oncology allowing assessment and possibly targeting of MDS pathology at the level of individual patients (Medyouf et al., (2014). Cell Stem Cell, accepted).

 

Future Outlook

Using genome-wide transcriptomics, proteomics and methylome analysis (in collaboration with the groups of Jeroen Krigsveld, Wolfgang Huber (both EMBL) and Christoph Plass (DKFZ)), we have recently established the molecular landscape (proteins, mRNAs, lncRNAs, methylation status of active or repressed genes) of HSCs and their immediate progeny to understand the molecular basis of self-renewal and multipotency as well as the complex dynamic interactions between stem cells and their niche. Finally, we are studying the molecular features of acute myeloid leukemia stem cells by combining transcriptomic analysis with functional in vivo assays.

Most significant recent publications:
Carnevalli et al., (2014). Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking Granzyme B. J Exp Med., in press
Tesio, Gabriela M. et al., (2013). Pten loss in the bone marrow leads to G-CSF mediated HSC mobilization. J Exp Med. 2013. Oct 21;210(11):2337-49
Trumpp A. et al. (2010). Awakening dormant haematopoietic stem cells. Nature Rev Immunol, 10:201-209 (Review)
Essers MAG et al., (2009). IFNa activates dormant HSCs in vivo. Nature, 458:904-908
Laurenti et al., (2008). Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell, 3(6):611-24.
Wilson A et al. (2008). Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell, 135:1118-29