Transcriptomics,Genomics

Dataset Information

171

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment


ABSTRACT: The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and 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 enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate 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. Overall design: Single-end 50 bp RNA-seq of MM.1S myeloma cell line either grown alone in monoculture, MM.1S isolated after 24 hr co-culture with immortalized HS5 bone marrow stromal cells, or HS5 bone marrow stromal cells grown alone

INSTRUMENT(S): Illumina HiSeq 2500 (Homo sapiens)

SUBMITTER: Arun P. Wiita 

PROVIDER: GSE99293 | GEO | 2017-05-26

SECONDARY ACCESSION(S): PRJNA388051

REPOSITORIES: GEO

Similar Datasets

2018-10-24 | PXD006581 | Pride
2008-04-07 | E-GEOD-10595 | ArrayExpress
2020-02-12 | E-MTAB-8536 | ArrayExpress
2015-07-11 | E-GEOD-69827 | ArrayExpress
2008-02-22 | GSE10595 | GEO
2011-02-04 | E-TABM-937 | ArrayExpress
2013-12-10 | E-GEOD-53199 | ArrayExpress
2016-08-20 | E-GEOD-85837 | ArrayExpress
2008-04-06 | E-GEOD-9390 | ArrayExpress
2008-03-01 | GSE9390 | GEO