Regulatory effect of chemokines in bone marrow niche

Ahmadzadeh, Ahmad; Kast, Richard E.; Ketabchi, Neda; Shahrabi, Saeid; Shahjahani, Mohammad; Jaseb, Kaveh; Saki, Najmaldin

doi:10.1007/s00441-015-2129-4

Cited by 15 publications

(13 citation statements)

References 99 publications

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“…4h ). Interestingly, the genes critical for the function of the BM niche on hematopoiesis, such as Vcam1, Cxcl1 33 , and Cxcl2 34 , were downregulated in Asxl1 −/− BMSCs (Fig. 4i ; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Zhang

Chen

et al. 2018

Cell Discov

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Somatic or de novo mutations of Additional sex combs-like 1 (ASXL1) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of Asxl1 leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of Asxl1 deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1, which impaired the maintaining cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias. Furthermore, Asxl1 deletion in the mouse BMSCs altered hematopoietic stem and progenitor cell (HSC/HPC) pool and a preferential myeloid lineage increment. Immunoprecipitation and ChIP-seq analyses demonstrated a novel interaction of ASXL1 with the core subunits of RNA polymerase II (RNAPII) complex. Convergent analyses of RNA-seq and ChIP-seq data revealed that loss of Asxl1 deregulated RNAPII transcriptional function and altered the expression of genes critical for HSC/HPC maintenance, such as Vcam1. Altogether, our study provides a mechanistic insight into the function of ASXL1 in the niche to maintain normal hematopoiesis; and ASXL1 alteration in, at least, a subset of the niche cells induces myeloid differentiation bias, thus, contributes the progression of myeloid malignancies.

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Section: Resultsmentioning

confidence: 99%

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Zhang

Chen

et al. 2018

Cell Discov

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“…Many cytokines, chemokines, and growth factors found in the BM have a chemoattractive effect on multiple myeloma cells (39,40). In contrast, surveillance by immune cells within the BM is critical in preventing multiple myeloma cell invasion (41).…”

Section: Discussionmentioning

confidence: 99%

Runx2 Deficiency in Osteoblasts Promotes Myeloma Progression by Altering the Bone Microenvironment at New Bone Sites

Zhang

Trotter

et al. 2020

Cancer Research

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◥Multiple myeloma is a plasma cell malignancy that thrives in the bone marrow (BM), with frequent progression to new local and distant bone sites. Our previous studies demonstrated that multiple myeloma cells at primary sites secrete soluble factors and suppress osteoblastogenesis via the inhibition of Runt-related transcription factor 2 (Runx2) in pre-and immature osteoblasts (OB) in new bone sites, prior to the arrival of metastatic tumor cells. However, it is unknown whether OB-Runx2 suppression in new bone sites feeds back to promote multiple myeloma dissemination to and progression in these areas. Hence, we developed a syngeneic mouse model of multiple myeloma in which Runx2 is specifically deleted in the immature OBs of C57BL6/KaLwRij mice (OB-Runx2 À/À mice) to study the effect of OB-Runx2 deficiency on multiple myeloma progression in new bone sites. In vivo studies with this model demonstrated that OB-Runx2 deficiency attracts multiple myeloma cells and promotes multiple myeloma tumor growth in bone. Mechanistic studies further revealed that OB-Runx2 deficiency induces an immu-nosuppressive microenvironment in BM that is marked by an increase in the concentration and activation of myeloid-derived suppressor cells (MDSC) and the suppression and exhaustion of cytotoxic CD8 þ T cells. In contrast, MDSC depletion by either gemcitabine or 5-fluorouracil treatment in OB-Runx2 À/À mice prevented these effects and inhibited multiple myeloma tumor growth in BM. These novel discoveries demonstrate that OB-Runx2 deficiency in new bone sites promotes multiple myeloma dissemination and progression by increasing metastatic cytokines and MDSCs in BM and inhibiting BM immunity. Importantly, MDSC depletion can block multiple myeloma progression promoted by OB-Runx2 deficiency.Significance: This study demonstrates that Runx2 deficiency in immature osteoblasts at distant bone sites attracts myeloma cells and allows myeloma progression in new bone sites via OB-secreted metastatic cytokines and MDSC-mediated suppression of bone marrow immunity.

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“…The bone microenvironment consists of mineralized extracellular matrix and several specialized cell types, including osteoblasts (OBs), OCLs, mesenchymal stem cells, bone marrow endothelial cells, hematopoietic cells, and adipocytes ( 27 , 28 ). OBs are one of the major cellular components of bone and they are responsible for depositing collagen and the mineralized calcium phosphate (hydroxyapatite) that gives the bone extracellular matrix its structural strength.…”

Section: Bone Microenvironmentmentioning

confidence: 99%

Role of Tumor-Derived Chemokines in Osteolytic Bone Metastasis

Coniglio

2018

Front. Endocrinol.

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Metastasis is the primary cause of mortality and morbidity in cancer patients. The bone marrow is a common destination for many malignant cancers, including breast carcinoma (BC), prostate carcinoma, multiple myeloma, lung carcinoma, uterine cancer, thyroid cancer, bladder cancer, and neuroblastoma. The molecular mechanism by which metastatic cancer are able to recognize, infiltrate, and colonize bone are still unclear. Chemokines are small soluble proteins which under normal physiological conditions mediate chemotactic trafficking of leukocytes to specific tissues in the body. In the context of metastasis, the best characterized role for the chemokine system is in the regulation of primary tumor growth, survival, invasion, and homing to specific secondary sites. However, there is ample evidence that metastatic tumors exploit chemokines to modulate the metastatic niche within bone which ultimately results in osteolytic bone disease. In this review, we examine the role of chemokines in metastatic tumor growth within bone. In particular, the chemokines CCL2, CCL3, IL-8/CXCL8, and CXCL12 are consistently involved in promoting osteoclastogenesis and tumor growth. We will also evaluate the suitability of chemokines as targets for chemotherapy with the use of neutralizing antibodies and chemokine receptor-specific antagonists.

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Regulatory effect of chemokines in bone marrow niche

Cited by 15 publications

References 99 publications

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates

Runx2 Deficiency in Osteoblasts Promotes Myeloma Progression by Altering the Bone Microenvironment at New Bone Sites

Role of Tumor-Derived Chemokines in Osteolytic Bone Metastasis

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