PXD009423

PXD009423 is an original dataset announced via ProteomeXchange.

Title	GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells
Description	Internal tandem duplications in the tyrosine kinase receptor FLT3 (FLT3-ITD) are among the most common lesions in acute myeloid leukemia (AML) 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 (UPR), leading to increased expression of GRP94/HSP90B1. GRP94 rewires FLT3-ITD signaling by binding and retaining FLT3-ITD in the ER, where it aberrantly activates downstream signaling pathways. Second, HSP90 family proteins protect FLT3-ITD+ AML cells against apoptosis by alleviating proteotoxic stress, and treatment with HSP90 inhibitors results in proteotoxic overload that triggers UPR-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 mouse PDX models. Taken together, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD+ AML cells and provides a rationale for including HSP90 inhibitors in the treatment regime for FLT3-ITD+ AML.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:11:48.689.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tuula Nyman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-04-06 02:13:09	ID requested
1	2020-09-03 00:52:12	announced
⏵ 2	2024-10-22 05:11:54	announced	2024-10-22: Updated project metadata.

10.3324/haematol.2019.220533;

Zhang B, Ayuda-Dur, á, n P, Piechaczyk L, Fl, ø, isand Y, Safont MM, Karlsen IT, Fandalyuk Z, Tadele D, van Mierlo P, Rowe AD, Robertson JM, Gjertsen BT, McCormack E, Enserink JM, GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells. Haematologica, 104(5):e229(2019) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: Leukemic stem cells, HSP90,FLT3, ER Stress, Acute Myeloid Leukemia

Jorrit Enserink
contact affiliation	Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0379 Oslo, Norway
contact email	jorrit.enserink@rr-research.no
lab head
Tuula Nyman
contact affiliation	University of Oslo
contact email	tuula.nyman@medisin.uio.no
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/09/PXD009423

PRIDE project URI

• PRIDE
  1. PXD009423
     1. Label: PRIDE project
     2. Name: GRP94 rewires and buffers the FLT3-ITD signaling network and promotes survival of acute myeloid leukemic stem cells