Send to

Choose Destination
Haematologica. 2018 May 10. pii: haematol.2018.189399. doi: 10.3324/haematol.2018.189399. [Epub ahead of print]

GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells.

Author information

Oslo University Hospital, Montebello, Oslo, Norway.
University of Bergen, Bergen, Norway.
Oslo University Hospital, Rikshospitalet, Norway.
Oslo University Hospital, Montebello, Oslo, Norway;


Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia and there exists a need for new forms of treatment. Using ex vivo drug sensitivity screening, we found that FLT3-ITD+ patient cells are particularly sensitive to HSP90 inhibitors. While it is well known that HSP90 is important for FLT3-ITD stability, we found that HSP90 family members play a much more complex role in FLT3-ITD signaling than previously appreciated. First, we found that FLT3-ITD activates the unfolded protein response, leading to increased expression of GRP94/HSP90B1. This results in activation of a nefarious feedback loop, in which GRP94 rewires FLT3-ITD signaling by binding and retaining FLT3-ITD in the endoplasmic reticulum, leading to aberrant activation of downstream signaling pathways and further inducing the unfolded protein response. Second, HSP90 family proteins protect FLT3-ITD+ acute myeloid leukemia cells against apoptosis by alleviating proteotoxic stress, and treatment with HSP90 inhibitors results in proteotoxic overload that triggers unfolded protein response-induced apoptosis. Importantly, leukemic stem cells are strongly dependent upon HSP90 for their survival, and the HSP90 inhibitor ganetespib causes leukemic stem cell exhaustion in patient-derived mouse xenograft models. Taken together, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD+ acute myeloid leukemia cells and provides a rationale for including HSP90 inhibitors in the treatment regime for FLT3-ITD+ acute myeloid leukemia.


Acute Myeloid Leukemia; FLT3; GRP94; HSP90; Leukemic Stem Cell

Free full text

Supplemental Content

Full text links

Icon for HighWire Icon for Norwegian BIBSYS system
Loading ...
Support Center