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The role of evolutionary conserved signaling pathways and cell fate determinants (polarity regulators) in hematopoietic and leukemic stem cell biology
Finanzierung:
Deutsche Forschungsgemeinschaft (DFG) ;
A key characteristic of hematopoietic stem cells (HSC) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSC and potentially also in leukemic stem cells (LSC). Cell fate determinants, such as RNA-binding proteins or polarity regulators have been recently described as effectors in stem cell biology. RNAinterference led to enhanced (Prox1) or decreased (Pard6a, Prkcz, Msi2) repopulation potential in vivo.

Loss of cell polarity influences epithelial cancers and supports tumorigenesis by altering cell-cell-matrix interactions. Additionally, regulation of cell polarity is essential for asymmetric cell division (ACD). ACD is involved in differentiation of the progeny and maintenance of stemness . Asymmetric cell division is an important part of cell polarity that may have an important impact in both, hematopoiesis and leukemogenesis. ACD regulates the induction and maintenance of polarity during cell division, resulting in the generation of two daughter cells with different genetic properties. As a consequence, the asymmetrically localized proteins often include determinants of cell fate. In regular hematopoiesis, ACD is involved in maintenance of the HSC pool. When a stem cell divides, one daughter cell follows a genetic program inducing proliferation and differentiation, while the second daughter cell stays under a program, inducing quiescence and the capacity for longevity. ACD leads to asymmetric segregation of self-renewal to one daughter cell in HSC. In leukemia development, disturbance of ACD (e.g. by loss of proteins involved in cell polarity) therefore may lead to coinheritance of both, self-renewal and proliferative capacity and thus creating a leukemic transformation. Supporting the hypothesis that leukemia can arise from HSC but also from more differentiated progenitor cells, ACD could enhance proliferative capacity of a pre-leukemic HSC population or conversely enhance self-renewal capacity of more differentiated pre-leukemic GMP. Thus, loss of ACD may alter the balance between expansion of differentiated progenitors and maintenance of HSC, thereby acting as an oncogenic event in leukemogenesis.
We investigate different pathways and cell fate determinants involved in self-renewal capacity in vivo using gene-specific knockout mouse models.

Schlagworte

leukemia, signaling pathway, stem cell
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