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

Abstract

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.

Impact of exercise on psychological burden in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

“…24,[49][50][51][52] Exercise may ameliorate treatment-related or stressrelated chronic inflammation, 53,54 oxidative stress, 55,56 impaired neurotransmission, 57,58 or cytokine and hormonal derangements. 59 Cognitive impairment is a common late effect in childhood and adult cancer survivors and is widely attributed to certain systemic therapies as well as cranial radiation therapy 60 through a variety of mechanisms, including impaired neurogenesis. 61,62 Intriguingly, in a murine model of whole-body radiation, exercise blunted an anticipated decline in memory through increases in hippocampal plasticity 62 ; other investigations suggest that cardiorespiratory fitness may directly impact brain function or that the psychological benefit of exercise may be from improved sleep duration or quality.…”

Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes

“…WNT11 mRNA overexpression was associated with poor prognosis in a subset of patients with AML [ 32 ], and thus WNT11 may have an antiapoptotic function in Tim-3 + blasts in prostate and breast cancer [ 33 , 34 ]. Plasma CCL2 upregulation in the peripheral blood (PB) and BM was reported in AML patients [ 35 , 36 ], and CCL2 expression levels in the tumor microenvironment were elevated in MDS as well as AML [ 37 ]. CCL2 may decrease the apoptosis of Tim-3 + blasts as in neurons and astrocytes [ 38 ].…”

Chronic immune response dysregulation in MDS pathogenesis

“…Nevertheless, tumor necrosis factor a, transforming growth factor b, interferon g, IL-6, IL-8, IL-1b, and granulocyte-macrophage colony-stimulating factor are commonly increased in MDS patients, and in certain cases their expression correlates with disease outcome. [102][103][104][105] One of the clinical features of MDS is anemia. Proinflammatory cytokines were shown to mediate hepcidin expression in the liver, which negatively regulates iron availability in erythroblasts.…”