Format:
Online-Ressource
Content:
Zusammenfassung: Activating mutations of Fms-like tyrosine kinase 3 (FLT3) are among the most frequent alterations in acute myeloid leukemia (AML). Two distinct types of mutations have been described: internal duplication of the juxtamembraneous domain (ITD) and point mutations of the tyrosine kinase domain (TKD). Although both mutations lead to constitutive FLT3 signaling, only FLT3-ITD strongly activates STAT5. In a murine transplantation model, FLT3-ITD induces a myeloproliferative neoplasm (MPN), while FLT3-TKD leads to a lymphoid disease with significantly longer latency. In the present study it should be examined, to which extent STAT5 has a role for the induction and phenotype of the MPN in the murine model. Furthermore, it should be addressed whether cell-type specific STAT5 signaling in myeloid, but not lymphoid progenitors is responsible for the FLT3-ITD-mediated myeloid expansion in mice and humans.In an initial in vitro experiment, STAT5 was found to be critical for the colony formation of FLT3-ITD+, but not FLT3-TKD+ fetal liver cells. These results were further confirmed in a conditional murine knockout model of Stat5, where the development of a myeloproliferative disease by FLT3-ITD is also dependent on STAT5. In case of the FLT3-TKD-induced disease, Stat5-deficiency has no impact on disease latency and the lymphoid phenotype. The phenotype of FLT3-TKD+ and FLT3-ITD+ Stat5del/del mice is remarkably similar, suggesting that the downstream signaling pathways activated by both types of mutations are also similar with the exception of STAT5.Interestingly, STAT5 activation is stronger in sorted myeloid progenitors compared to lymphoid progenitors expressing FLT3-ITD. These cells also show increased expression of the STAT5 target genes Oncostatin M (OSM), c-Myc and Bcl-2, confirming the cell-type specific signaling of FLT3-ITD in hematopoietic progenitor cells. Moreover, myeloid progenitors - unlike lymphoid progenitors - express significant amounts of c-Src, thereby mediating the activation of STAT5 exclusively in the myeloid compartment. Notably, only bone marrow cells derived from Stat5+/Flt3-ITD+ mice reveal marked upregulation of OSM. Strikingly, Osm expression is sufficient to induce a myeloid disease together with FLT3-D838Y, indicating that the expression of this STAT5 target gene substitutes for the lack of STAT5 activation by FLT3-D838Y.The findings described here provide a rationale for the validation of STAT5 inhibition in FLT3-ITD+, but not FLT3-D835Y+ AML. Additionally, the present study has proven the relevance of OSM for the induction of a myeloid phenotype in mice, justifying further investigations to validate OSM and OSMR as clinical relevant targets in AML and MPN patients with an active STAT5
Note:
Dissertation Albert-Ludwigs-Universität Freiburg 2016
Language:
English
URN:
urn:nbn:de:bsz:25-freidok-108738
