Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support

Azadniv, Mitra; Myers, Jason R.; McMurray, Helene R.; Guo, Naxin; Rock, Phil; Coppage, Myra; Ashton, John M.; Becker, Michael W.; Calvi, Laura M.; Liesveld, Jane L.

doi:10.1038/s41375-019-0568-8

Cited by 65 publications

(65 citation statements)

References 61 publications

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“…MSCs from AML patients have a higher propensity to differentiate into adipocytes, and the interactions between AML blasts and adipocytes in the bone marrow niche impact cellular metabolism (118). AML blasts induce lipolysis in bone marrow adipocytes, shifting toward fatty acid oxidation and an environment favorable for leukemic survival (119).…”

Section: Bone Marrow Nichementioning

confidence: 99%

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

Epperly

Velasquez

2020

Front. Oncol.

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Chimeric antigen receptor (CAR) T cells targeting CD19 have been successful treating patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) and B cell lymphomas. However, relapse after CAR T cell therapy is still a challenge. In addition, preclinical and early clinical studies targeting acute myeloid leukemia (AML) have not been as successful. This can be attributed in part to the presence of an AML microenvironment that has a dampening effect on the antitumor activity of CAR T cells. The AML microenvironment includes cellular interactions, soluble environmental factors, and structural components. Suppressive immune cells including myeloid derived suppressor cells and regulatory T cells are known to inhibit T cell function. Environmental factors contributing to T cell exhaustion, including immune checkpoints, anti-inflammatory cytokines, chemokines, and metabolic alterations, impact T cell activity, persistence, and localization. Lastly, structural factors of the bone marrow niche, secondary lymphoid organs, and extramedullary sites provide opportunities for CAR T cell evasion by AML blasts, contributing to treatment resistance and relapse. In this review we discuss the effect of the AML microenvironment on CAR T cell function. We highlight opportunities to enhance CAR T cell efficacy for AML through manipulating, targeting, and evading the anti-inflammatory leukemic microenvironment.

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Section: Bone Marrow Nichementioning

confidence: 99%

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

Epperly

Velasquez

2020

Front. Oncol.

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“…Details are shown in Table 3 [1,2,6,8,[25][26][27][28][29]. MSCs are major constituents of the BM microenvironment and the HSC niche and apparently they are the masters of survival and clonality [30][31][32]. The main functions of MSCs include: formation of hematopoietic microenvironment, modulation of the activity of the immune system, and regulating cell trafficking [33].…”

Section: Functions Properties and Therapeutic Indications Of Mscsmentioning

confidence: 99%

The Rising Role of Mesenchymal Stem Cells in the Treatment of Various Infectious Complications

Al-Anazi¹,

Al-Anazi²,

Al-Jasser³

2020

Update on Mesenchymal and Induced Pluripotent Stem Cells

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Mesenchymal stem cells are heterogenous adult multipotent stromal cells that can be isolated from various sources including: bone marrow, peripheral blood, umbilical cord blood, dental pulp, and adipose tissue. They have certain immunomodulatory, immunosuppressive, and antimicrobial properties that enable them to have several therapeutic and clinical applications including: treatment of autoimmune disorders, role in hematopoietic stem cell transplantation and regenerative medicine, as well as treatment of various infections and their associated complications such as septic shock and acute respiratory distress syndrome. Although more success has been achieved in preclinical trials on the use of mesenchymal stem cells in animal models than in human clinical trials, particularly in septic shock and Chagas disease, more progress has been made in both disorders after the recent use of specific sources and certain doses of mesenchymal stem cells. Nevertheless, the utilization of this type of stem cells has shown remarkable progress in the treatment of few infections such as tuberculosis. The clinical application of mesenchymal stem cells in the treatment of several diseases still faces real challenges that need to be resolved. The following book chapter will be an updated review on the role of mesenchymal stem cells in various infections and their complications.

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“…Studies using leukemic mice models have reported that LCs transplanted into a mouse model can "hijack" the normal BM niche into a leukemic niche which impairs normal hematopoiesis, favors leukemic stem cell survival and expansion 15,33 . It has been shown that AML-MSCs show special characteristics including over expression of a series of chemokines and cytokines 11 − 13, 31, 32 , increased adipogenic and osteoblastic potential, and improved the ability to support leukemia progenitor cells survival 29,34 . However, there are also opposite reports.…”

Section: Lc-treated Mscs Support Survival and Promote Migration Of Ammentioning

confidence: 99%

Co-culture with leukemia cells decreases proliferation and increases chemoprotective capacity of normal mesenchymal stromal cells

Hou¹,

Yang²,

Zhang³

et al. 2020

Preprint

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Background Bone marrow mesenchymal stromal cells (BM-MSCs) are essential structural and functional components of the BM microenvironment and play an important role in acute myeloid leukemia (AML) pathogenesis. BM-MSCs isolated from AML patients (AML-MSCs) show distinct signatures from normal BM-MSCs. However, the exact abnormalities of AML-MSCs and the origin of these abnormalities are still unknown.Methods In this study, we evaluated the proliferative activity of AML-MSCs, and the influence of leukemia cells (LCs) on BM-MSCs. These two cell types were co-cultured using an in vitro co-culture system, and the biological functions of AML-MSCs, healthy donor derived MSCs (HD-MSCs), and LC-treated HD-MSCs (LCtrHD-MSCs) were compared by flow cytometry, and CCK-8 and chemotaxis assays. Student t-test (between two groups) and one-way ANOVA (more than 2 groups) were used to compare differences. Pearson correlation coefficients were used to assess correlations between two factors.Results AML-MSCs display a significant proliferative deficiency, which correlates with primary leukemic blast cell counts but not with patients’ age. Inhibition of BM-MSC proliferation could be induced by leukemia cells through direct contact. Co-cultured leukemia cells also increase expression of several inflammatory cytokines, and chemokines in BM-MSCs. Furthermore, LCtrHD-MSCs reduced apoptosis, and increased migration and chemoresistance in co-cultured AML cells, comparable with AML-MSCs.Conclusions Our results showed that leukemia cells can induce healthy donor derived BM-MSCs to exhibit AML-MSC-like characteristics and indicated that AML-MSC abnormalities may be partly induced by leukemia cells.

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Bone marrow mesenchymal stromal cells from acute myelogenous leukemia patients demonstrate adipogenic differentiation propensity with implications for leukemia cell support

Cited by 65 publications

References 61 publications

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

The Rising Role of Mesenchymal Stem Cells in the Treatment of Various Infectious Complications

Co-culture with leukemia cells decreases proliferation and increases chemoprotective capacity of normal mesenchymal stromal cells

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