Bone marrow niche in the myelodysplastic syndromes

Cogle, Christopher R.; Saki, Najmaldin; Khodadi, Elahe; Li, June; Shahjahani, Mohammad; Azizidoost, Shirin

doi:10.1016/j.leukres.2015.06.017

Cited by 65 publications

(34 citation statements)

References 55 publications

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“…A close and dynamic cooperation exists between the hematopoietic stem cell compartment and BM stroma, which maintain and adapt to the needs of hematopoiesis and tissue turnover (23). At higher doses where direct effects dominate, the damage of the stem cells determines both the level of BM damage and the long-term health consequences.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

et al. 2017

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Radiation-induced bystander effects refer to the induction of biological changes in cells not directly hit by radiation implying that the number of cells affected by radiation is larger than the actual number of irradiated cells. Recent in vitro studies suggest the role of extracellular vesicles (EVs) in mediating radiation-induced bystander signals, but in vivo investigations are still lacking. Here, we report an in vivo study investigating the role of EVs in mediating radiation effects. C57BL/6 mice were total-body irradiated with X-rays (0.1, 0.25, 2 Gy), and 24 h later, EVs were isolated from the bone marrow (BM) and were intravenously injected into unirradiated (so-called bystander) animals. EV-induced systemic effects were compared to radiation effects in the directly irradiated animals. Similar to direct radiation, EVs from irradiated mice induced complex DNA damage in EV-recipient animals, manifested in an increased level of chromosomal aberrations and the activation of the DNA damage response. However, while DNA damage after direct irradiation increased with the dose, EV-induced effects peaked at lower doses. A significantly reduced hematopoietic stem cell pool in the BM as well as CD4+ and CD8+ lymphocyte pool in the spleen was detected in mice injected with EVs isolated from animals irradiated with 2 Gy. These EV-induced alterations were comparable to changes present in the directly irradiated mice. The pool of TLR4-expressing dendritic cells was different in the directly irradiated mice, where it increased after 2 Gy and in the EV-recipient animals, where it strongly decreased in a dose-independent manner. A panel of eight differentially expressed microRNAs (miRNA) was identified in the EVs originating from both low- and high-dose-irradiated mice, with a predicted involvement in pathways related to DNA damage repair, hematopoietic, and immune system regulation, suggesting a direct involvement of these pathways in mediating radiation-induced systemic effects. In conclusion, we proved the role of EVs in transmitting certain radiation effects, identified miRNAs carried by EVs potentially responsible for these effects, and showed that the pattern of changes was often different in the directly irradiated and EV-recipient bystander mice, suggesting different mechanisms.

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Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

et al. 2017

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“…[1,2] Mortality associated with cytopenia and risk of transformation to acute myeloblastic leukemia (AML) are important problems for MDS patients. In fact, one-third of MDS patients become AML patients, and the remaining two-thirds succumb to progressive BM failure, which leads to bleeding, frequent infections, and severe anemia.…”

Section: Introductionmentioning

confidence: 99%

Cytogenetic and molecular basis of BCR-ABL myelodysplastic syndrome: diagnosis and prognostic approach

Paridar¹,

Ghalesardi²,

Seghatoleslami³

et al. 2017

JCMT

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“…Besides cytogenetic, molecular and genetic abnormalities in hematopoietic stem cells (HSC), extrinsic factors such as interaction with immune system and bone marrow (BM) microenvironment alterations are involved not only in the BM failure, but also in clonal expansion of the aberrant HSC and impaired cellular differentiation. [1][2][3][4] There is growing evidence implicating inflammation-related changes, inhibitory cytokines and increased intramedullary apoptosis as contributors to ineffective hematopoiesis, specifically in the early stages of MDS. [5][6][7] Moreover, several recent studies implicate aberrant BM microenvironment and inflammation-related changes in progression of the MDS.…”

Section: Introductionmentioning

confidence: 99%

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

et al. 2016

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Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammationrelated changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC.

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Bone marrow niche in the myelodysplastic syndromes

Cited by 65 publications

References 55 publications

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

Extracellular Vesicles Mediate Radiation-Induced Systemic Bystander Signals in the Bone Marrow and Spleen

Cytogenetic and molecular basis of BCR-ABL myelodysplastic syndrome: diagnosis and prognostic approach

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

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