A comparative study of various FLT3-ITDs in relation to function and signaling
(English)Manuscript (preprint) (Other academic)
Internal tandem duplications (ITD) in the FMS like tyrosine kinase (FLT3) receptor are one of the most common classes of mutations in acute myeloid leukemia (AML), which presence indicates a poor prognosis. Lengths of FLT3-ITD mutations found in patients can vary from 3 up to hundreds of nucleotides and may be located either in the juxtamembrane domain or the tyrosine kinase-1 domain (TKD1). There are contradicting opinions whether the length of the ITD has an impact on the clinical situation and whether tyrosines duplicated are of any significance for oncogenic signaling. Considering the substantial differences in lengths as well as the variability of start and end points of ITDs, we have performed a study of various FLT3-ITD mutations isolated from AML-patients. The ITD region from leukemic blasts of nine AML patients were sequenced and cloned by PCR into the human wildtype FLT3 cDNA, inserted to a retroviral GFP-containing vector. The hematopoietic progenitor cell line FDC-P1 was used to elucidate the impact of the different ITDs on growth, survival, signal transduction, and resistance to the FLT3-targeting inhibitor PKC412. Interestingly, the shortest and the longest ITDs were two of the three mutations that lead to the poorest survival of cells upon cytokine-deprivation, indicating that ITD size may not influence the transforming potential of cells. Furthermore one ITD that starts and ends relatively 3´ positioned, and comprises the 5´-part of the TKD1 showed both a survival advantage in starvation experiments and a significantly higher proliferation potential in comparison to several other mutations. Two other ITDs spanning this region, but with more 5´localized starting points, displayed less sensitivity to PKC412 treatment. However, this was not associated to STAT5 activity and MCL-1 upregulation as suggested by previous report. Taken together, this study suggests that different FLT3-ITD mutations may induce distinct signaling and response towards FLT3 targeting drugs, dependent of FLT3-ITD composition and not length.
FLT3-ITD, proliferation, apoptosis, tyrosine kinase inhibitor, resistance
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-88200OAI: oai:DiVA.org:liu-88200DiVA: diva2:602072