PXD006581

PXD006581 is an original dataset announced via ProteomeXchange.

Title	Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment
Description	The myeloma bone marrow microenvironment drives proliferation of malignant plasma cells and promotes resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells.Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not rescue ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells drive a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.
HostingRepository	PRIDE
AnnounceDate	2018-10-24
AnnouncementXML	Submission_2018-10-24_12:44:42.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christine Lam
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2017-05-24 05:13:20	ID requested
⏵ 1	2018-10-24 12:44:43	announced

Lam C, Ferguson ID, Mariano MC, Lin YT, Murnane M, Liu H, Smith GA, Wong SW, Taunton J, Liu JO, Mitsiades CS, Hann BC, Aftab BT, Wiita AP, Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment. Haematologica, 103(7):1218-1228(2018) [pubmed]

curator keyword: Biomedical

submitter keyword: human, myeloma, tofacitinib, bone marrow microenvironment, LC-MSMS, LFQ

Arun Paul Wiita
contact affiliation	Department of Laboratory Medicine, Wiita Lab, University of California San Francisco
contact email	Arun.Wiita@ucsf.edu
lab head
Christine Lam
contact affiliation	UCSF
contact email	christine.yt.lam@ucsf.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD006581
     1. Label: PRIDE project
     2. Name: Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment