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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

1
Oslo University Hospital, Montebello, Oslo, Norway.
2
University of Bergen, Bergen, Norway.
3
Oslo University Hospital, Rikshospitalet, Norway.
4
Oslo University Hospital, Montebello, Oslo, Norway; jorrit.enserink@rr-research.no.

Abstract

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.

KEYWORDS:

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

PMID:
29748445
DOI:
10.3324/haematol.2018.189399
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