Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication

摘要: The type III receptor tyrosine kinase fms-like 3 (FLT3) is expressed on both normal hematopoietic stem cells and acute myeloid leukemia (AML) regulates their proliferation. Internal tandem duplication (ITD) mutation of FLT3 present in a third AML cases, results constitutive activation aberrant signaling FLT3, associated with adverse treatment outcomes. While wild-type (WT) predominantly 150 kDa complex glycosylated cell surface protein, FLT3-ITD partially retained the endoplasmic reticulum as 130 underglycosylated species chaperones calnexin heat shock protein (HSP) 90, mediates STAT5 signaling, which upregulates oncogenic serine/threonine Pim-1. contains Pim-1 substrate consensus serine phosphorylation site, we hypothesized that it might be substrate. was indeed found to directly interact serine-phosphorylate FLT3. inhibition decreased expression half-life partial abrogation by proteasome inhibition, association binding HSP90, increased half-life, glycosylation. These findings were consistent stabilizing HSP90 inhibiting its glycosylation form species. knockdown effects similar. also at 591 STAT5, itself, FLT3-ITD-STAT5 pathway. Finally, synergized inducing apoptosis cells. This is, our knowledge, first demonstration role positive feedback loop promoting malignant