Similar Datasets
Project description:Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here we identify and validate that TNF receptor associated factor protein family TRAF2 KD/KO in MM cells mediates IMiDs resistance via activation of non-canonical NF-kB and MEK-ERK signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-a induces proteasomal degradation of TRAF2, non-canonical NF-kB, and downstream ERK signaling in MM cells, whereas IL-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiDs sensitivity of TRAF2 KO cells both in vitro and in vivo using an inducible TRAF2 KD MM xenograft model. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiDs resistance in the BM microenvironment and improve patient outcome in MM.
2021-06-15 | GSE171340 | GEO
Project description:Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here we identify and validate that TNF receptor associated factor protein family TRAF2 KD/KO in MM cells mediates IMiDs resistance via activation of non-canonical NF-kB and MEK-ERK signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-a induces proteasomal degradation of TRAF2, non-canonical NF-kB, and downstream ERK signaling in MM cells, whereas IL-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiDs sensitivity of TRAF2 KO cells both in vitro and in vivo using an inducible TRAF2 KD MM xenograft model. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiDs resistance in the BM microenvironment and improve patient outcome in MM.
2021-06-15 | GSE171339 | GEO
Project description:ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment
| PRJNA719150 | ENA
Project description:ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment (CRISPR Screen)
| PRJNA719239 | ENA
Project description:ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment (RNA-Seq)
| PRJNA719234 | ENA
Project description:Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis.
| S-EPMC7578922 | biostudies-literature
Project description:Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and noncanonical Wnt pathways play a critical role in the maintenance of normal hematopoietic stem cells (HSC) and LSCs. In this review, we summarize recent findings on the role of Wnt signaling in leukemia and its microenvironment and provide information on the currently available strategies for targeting Wnt signaling.
| S-EPMC7503842 | biostudies-literature
Project description:The survival of leukemic cells is significantly influenced by the bone marrow microenvironment, where stromal cells play a crucial role. While there has been substantial progress in understanding the mechanisms and pathways involved in this crosstalk, limited data exist regarding the impact of leukemic cells on bone marrow stromal cells and their potential role in drug resistance. In this study, we identify that leukemic cells prime bone marrow stromal cells towards osteoblast lineage and promote drug resistance. This biased differentiation of stroma is accompanied by dysregulation of the canonical Wnt signaling pathway. Inhibition of Wnt signaling in stroma reversed the drug resistance in leukemic cells, which was further validated in leukemic mice models. This study evaluates the critical role of leukemic cells in establishing a drug-resistant niche by influencing the bone marrow stromal cells. Additionally, it highlights the potential of targeting Wnt signaling in the stroma by repurposing an anthelmintic drug to overcome the microenvironment-mediated drug resistance.
| S-EPMC11006665 | biostudies-literature
Project description:The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.
| S-EPMC2654350 | biostudies-other
Project description:BackgroundChemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and bone marrow stromal cells (BMSCs) protect leukemia cells from chemotherapy eventually leading to recurrence. This study was designed to investigate the role of p21-activated kinase 1 (PAK1) in AML progression and chemosensitivity, highlighting the mechanism of stroma-mediated chemoresistance.MethodsThe GEPIA and TCGA datasets were used to analyze the relationship between PAK1 mRNA expression and various clinical parameters of AML patients. Cell proliferation and apoptosis were examined to evaluate the role of PAK1 on chemosensitivity in AML by silencing PAK1 with shRNA or small molecular inhibitor. Human BMSC (HS-5) was utilized to mimic the leukemia bone marrow microenvironment (BMM) in vitro, and co-culture model was established to investigate the role of PAK1 in BMSC-mediated drug resistance.Resultsp21-activated kinase 1 high expression was shown to be associated with shorter overall survival in AML patients. The silence of PAK1 could repress cell proliferation, promote apoptosis, and enhance the sensitivity of AML cells to chemotherapeutic agents. More importantly, BMSCs induced PAK1 up-regulation in AML cells, subsequently activating the ERK1/2 signaling pathway. The effect of BMSC-mediated apoptotic-resistance could be partly reversed by knock down of PAK1.Conclusionp21-activated kinase 1 is a potential prognostic predictor for AML patients. PAK1 may play a pivotal role in mediating BMM-induced drug resistance, representing a novel therapeutic target in AML.
| S-EPMC8297649 | biostudies-literature