IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

Schinke, Carolina; Giricz, Orsi; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Bhagat, Tushar D.; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit

doi:10.1182/blood-2015-01-621631

Cited by 149 publications

(146 citation statements)

References 59 publications

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“…Furthermore, leukemic blasts from the majority of patients with AML constitutively express IL8 (17). In addition, inhibition of the IL8 receptor, CXCR2, selectively inhibits proliferation of MDS/AML cell lines and patient samples (18). Together, these studies suggest that MIF and IL8 are functionally important in regulating the survival and proliferation of multiple tumors, including AML.…”

Section: Introductionmentioning

confidence: 78%

“…colleagues have reported that inhibition of the IL8 receptor CXCR2 selectively inhibits immature hematopoietic stem cells from MDS/AML samples (17,18). In other malignancies, IL8 has been characterized in endothelial cells and tumor-associated macrophages, suggesting that IL8 has a function in the liver and prostate tumor microenvironments (38,39).…”

Section: Discussionmentioning

confidence: 99%

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MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

et al. 2017

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Acute myeloid leukemia (AML) cells exhibit a high level of spontaneous apoptosis when cultured in vitro but have a prolonged survival time in vivo, indicating that tissue microenvironment plays a critical role in promoting AML cell survival. In vitro studies have shown that bone marrow mesenchymal stromal cells (BM-MSC) protect AML blasts from spontaneous and chemotherapy-induced apoptosis. Here, we report a novel interaction between AML blasts and BM-MSCs, which benefits AML proliferation and survival. We initially examined the cytokine profile in cultured human AML compared with AML cultured with BM-MSCs and found that macrophage migration inhibitory factor (MIF) was highly expressed by primary AML, and that IL8 was increased in AML/BM-MSC cocultures. Recombinant MIF increased IL8 expression in BMMSCs via its receptor CD74. Moreover, the MIF inhibitor ISO-1 inhibited AML-induced IL8 expression by BM-MSCs as well as BM-MSC-induced AML survival. Protein kinase C b (PKCb) regulated MIF-induced IL8 in BM-MSCs. Finally, targeted IL8 shRNA inhibited BM-MSC-induced AML survival. These results describe a novel, bidirectional, prosurvival mechanism between AML blasts and BM-MSCs. Furthermore, they provide biologic rationale for therapeutic strategies in AML targeting the microenvironment, specifically MIF and IL8.

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Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

et al. 2017

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“…A recent study provided evidence that interleukin-8 (IL-8) and its membrane receptor CXCR2 are expressed on LSCs, but not in their normal HSC counterpart [130]. This study was based on a transcriptomic profiling of leukemic stem/progenitor cells, in comparison with their normal counterpart, showing that IL-8 was one of the most significantly upregulated genes in leukemic cells [130].…”

Section: Il-8/cxcr2mentioning

confidence: 97%

“…This study was based on a transcriptomic profiling of leukemic stem/progenitor cells, in comparison with their normal counterpart, showing that IL-8 was one of the most significantly upregulated genes in leukemic cells [130]. IL-8 and CXCR2 were constantly observed to be overexpressed in leukemic CD34 + cells isolated from AML and myelodysplasia patients, compared to the levels observed in normal CD34 + cells [130]. Inhibition of CXCR2 expression reduced the viability of leukemic CD34 + /CD38 − cells and the capacity of these cells to induce leukemic growth in vivo in immunodeficient mice [130].…”

Section: Il-8/cxcr2mentioning

confidence: 99%

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

Pelosi

Castelli

Testa

2015

Blood Cells, Molecules, and Diseases

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“…Later, Schinke et al detected the elevated IL8 transcripts in AML/MDS BM samples. 36 Moreover, they found that IL8 supports growth and survival of leukemic cell lines and that the short-hairpin RNA-mediated downregulation of IL8 receptor CXCR2 resulted in increased survival of mice xenografted with lymphoma U-937 cells. 36 IL8 is elevated in blood also during other inflammatory diseases such as cystic fibrosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, etc.…”

Section: Discussionmentioning

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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IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

Abstract: Key Points IL8-CXCR2 is overexpressed in purified stem cells from AML and MDS, and CXCR2 expression is associated with worse prognosis. Inhibition of CXCR2 by genetic and pharmacologic means leads to decreased viability in AML/MDS stem cells and in vitro and in vivo models.

Cited by 149 publications

References 59 publications

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells

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

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