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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99293 | GEO | 2017/05/26

SECONDARY ACCESSION(S): PRJNA388051

REPOSITORIES: GEO

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

Project 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.

2018-10-24 | PXD006581 | Pride

Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

Project description:The type I JAK inhibitor ruxolitinib is approved for therapy of MPN patients but evokes resistance with longer exposure. Several novel type I JAK inhibitors were studied and we show that they uniformly induce resistance via a shared mechanism of JAK family heterodimer formation.Here we studied the expression profiles of SET2 cell lines persistent to several different type I JAK inhibitors in comparison to naive SET2 cells or in comparison to SET2 cells with acute exposure to ruxolitinib. Analysis of RNA isolated from several type I JAK inhibitor SET2 cell lines in comparison to naïve SET2 cells

2015-07-11 | E-GEOD-69827 | biostudies-arrayexpress

Bulk RNAseq of control and 5TGM1 myeloma-bearing bone marrow T, NK, and non-hematopoietic stromal cells from C57Bl/6 mice

Project description:We hypothesized that the immune microenvironment of the bone marrow influences the progression of myeloma outgrowth in the 5TGM1 transfer model of multiple myeloma. Therefore we sorted bone marrow T, NK, and non-hematopoietic stromal cells from control and tumor-bearing C57Bl/6 mice.

2023-02-24 | E-MTAB-12615 | biostudies-arrayexpress

Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

2015-07-11 | GSE69827 | GEO

Bone Marrow Stromal Cells Induce Chromatin Remodeling in Multiple Myeloma Cells Leading to Transcriptional Changes [Multiome (10X Genomics) - scRNA-Seq & scATAC-Seq]

Project description:The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.

2024-04-04 | GSE263178 | GEO

Gene expression analysis of bone marrow stromal cells from multiple myeloma patients and controls

Project description:Multiple myeloma is hematologic malignancies result from clonal proliferation of plasma cells. Recently, increasing evidence supports the hypothesis that microenvironment cells play important roles in the proliferation, survival, and drug resistance of clonal plasma cells. The aim of this study is to culture stromal cells from bone marrow aspirates of patients with multiple myeloma, and to investigate expression profiles of bone marrow stromal cells and their relationships with the clinical characteristics of patients. RNA was extracted cultured bone marrow stromal cells from 15 patients with plasma cell neoplasms, and bone marrow stromal cells from 13 control patients with 9 B-cell lymphoma patients with no evidence of BM involvement and 4 patients with mild-to-moderate cytopenia without evidence of hematologic malignancies

2016-08-20 | E-GEOD-85837 | biostudies-arrayexpress

Stretch-Enhancers Delineate Disease-Associated Regulatory Nodes in T Cells

Project description:T Cell stretch-enhancers are vulnerable to Jak inhibitor tofacitinib Treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with stretech-enhancer (SE) structures.

2015-02-18 | E-GEOD-60482 | biostudies-arrayexpress

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

Project description:We evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Solving the structure of FDA-approved type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 JH1 tyrosine kinase domain enabled the rational design and optimization of Cereblon (CRBN)-directed JAK PROTACs utilizing multiple derivatives of JAK inhibitors, linkers and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation by proteomic approaches, and activity tested in CRLF2-rearranged cell line and xenograft models of ALL.

| EGAS00001005180 | EGA

Gene expression analysis of bone marrow stromal cells from multiple myeloma patients and controls

2016-08-20 | GSE85837 | GEO

RNA-seq of murine mesenchymal stem cells during differentiation to osteoblasts, treated with tofacitinib or baricitinib against vehicle control

Project description:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, characterized by synovial hyperplasia and progressive joint destruction. For treating inflammatory diseases, such as RA, the Janus kinase (JAK)-mediated signaling pathway has emerged as a therapeutic target. Therefore, JAK inhibitors, such as tofacitinib and baricitinib, are approved for the treatment of RA. While the immunomodulatory characteristics of JAK inhibition (JAKi) are well defined, the current knowledge of how JAKi affects bone homeostasis is limited. Addressing this question becomes increasingly relevant, as current therapeutic options can slow down RA progression, but joint damage and especially perarticular bone erosion remain. Therefore, the impact of JAKi on bone homeostasis requires further elucidation. For in vitro analysis, the impact of JAK inhibitors tofacitinib and baricitinib on bone-forming osteoblasts was analyzed with respect to their mineralization capability. JAKi, by both tofacitinib and baricitinib, increased mineralization function in mesenchymal stem cells (MSCs)-derived osteoblasts. Having observed increased mineralization capability in mesenchymal stem cells (MSCs)-derived osteoblasts, RNA-seq was performed to shed light on potential signaling pathways and mediators causing this effect. For that, MSCs were plated at 6,000 cells per well in a 24-well-plate in alpha-MEM, supplemented with 10% heat-inactivated FCS and 1% P/S. After one day medium was changed to alpha-MEM, 10% heat-inactivated FCS, 1% P/S and 568 mikromolar L-Ascorbic acid 2-phosphate 351 sesquimagnesium salt hydrate, containing either tofacitinib (500 nM), baricitinib (300 nM) or DMSO as vehicle control. After osteogenic induction, RNA was isolated via phenol-chloroform extraction. At least 3 mikrogram high quality RNA were used for RNA-seq analysis with the Illumina TrueSeq Stranded mRNA Kit and sequenced on an Illumina HiSeq 2500 platform.

2020-02-12 | E-MTAB-8536 | biostudies-arrayexpress

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