Rotation project 6

Dr. med. Friedrich Stölzel
Assistenzarzt / Wissenschaftlicher Mitarbeiter
Medizinische Klinik und Poliklinik I
Universitätsklinikum Carl Gustav Carus
der Technischen Universität Dresden
Fetscherstraße 74
01307 Dresden 

PD Dr. Thomas Illmer
Medizinische Klinik und Poliklinik I
Universitätsklinikum Carl Gustav Carus
der Technischen Universität Dresden
SFB project section B7  

The signalling-, differentiation-, and migratory properties of hematopoietic stem cells (HSC) are of interest for various fields of research. Since some of these characteristics of HSCs strongly depend on a robust CXCL12/CXCR4 signalling, previous work in the B7 project of the SFB 655 focused on the posttranscriptional modulation of CXCL12 expression in mesenchymal stem cells (MSC) by various micro RNAs (miRNAs) and thereby affecting the migration potential of HSCs.

Additionally, in previous research performed in our group, we were able to characterize miR-10a overexpression as a hallmark of NPM1 mutated human acute myeloid leukemia (AML). Further analysis showed that posttranscriptional regulation of the p53-antagonist Mdm4 is influenced by miR-10a. This finding may help to explain growth characteristics as well as stress response mechanisms of this particular AML type. Based on these observations we propose that posttranscriptional regulation of the hematopoietic niche by miRNAs might influence differentiation, proliferation, homing and mobilization of HSCs. Therefore, we will characterize the miRNA signalling profiles in MSCs in steady state as well as in the differentiation process. In particular we will investigate how interference with miRNAs identified as differentiation-specific may influence also homing capacity for benign and malignant hematopoietic stem cells.

Furthermore, a meanwhile established transfection assay of a whole genome miRNA library in the MSC cell line SCP-1 will be employed to study alterations of the homing capacity of those cells. Here we will harvest supernatant of transfected SCP-1 cells for use in proliferation assay and migration assay of normal CD34 cells as well as OCI/AML1 cells. This aims to contribute to a better understanding of the hematopoietic niche as well as altered mechanisms between MSCs and HSCs. 

1. Stolzel, F., et al., Mobilization of PML/RARalpha negative peripheral blood stem cells with a combination of G-CSF and CXCR4 blockade in relapsed acute promyelocytic leukemia pretreated with arsenic trioxide. Haematologica, 2010. 95(1): p. 171-2. 
2. Stolzel, F., et al., Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol, 2010. 89(7):p. 653-62.
3.  Ovcharenko, D. and Stolzel, F., et al., miR-10a overexpression is associated with NPM1 mutations and Mdm4 downregulation in intermediate-risk acute myeloid leukemia. Manuscript under revision