scholarly journals Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts

2012 ◽  
Vol 209 (10) ◽  
pp. 1883-1899 ◽  
Author(s):  
Alexandre P.A. Theocharides ◽  
Liqing Jin ◽  
Po-Yan Cheng ◽  
Tatiana K. Prasolava ◽  
Andrei V. Malko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Leukemia Stem Cell ◽  
Tumor Surveillance ◽  
Human Acute Myeloid Leukemia ◽  
Differential Ability ◽  
Acute Myeloid

Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPα signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPα-Fc fusion protein to disrupt SIRPα–CD47 engagement. Treatment with SIRPα-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPα-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.

MicroRNA Profiling of Human Acute Myeloid Leukemia and Normal Hematopoietic Stem/Progenitor Cells Reveals a Leukemia Stem Cell Signature.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 779-779
Author(s):  
Christopher Y. Park ◽  
Yulei Wang ◽  
Susan Prohaska ◽  
Diane Tseng ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Supervised Clustering ◽  
Differentially Expressed Mirnas ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract While numerous studies have contributed important insights into the molecular origins of human acute myeloid leukemia (AML), many may not accurately reflect molecular pathways critical to AML development or maintenance because they ignore the inherent heterogeneity among AML blasts. One subset of blasts - leukemia stem cells (LSCs) - exhibits the unique ability to self-renew and to engraft disease in immunodeficient mouse hosts, suggesting that their elimination is critical to developing curative therapies. In addition, there is little information regarding the role of microRNAs (miRNAs) in regulating gene expression or biologic function in AML. In order to assess the potential contribution of miRNAs to AML LSC biology, we have evaluated the expression profile of 315 mature miRNAs in FACS-purified AML LSC and compared it to both non-LSC blasts as well as normal human bone marrow (BM) derived hematopoietic stem cells (HSC) and committed progenitors using a multiplexed TaqMan-based real-time PCR strategy. SAM analysis with stringent criteria (at least 25% samples with Ct <30, FDR <1%) reveals that AML LSC and non-LSC blasts are more similar to one another than to normal HSC or committed progenitors. Among the BM populations tested, AML LSC and non-LSC populations are most similar to the granulocyte-macrophage progenitor (GMP). A set of miRNAs distinguishes AML LSC and non-LSC from normal HSC and committed progenitors, including 35 miRNAs that are under-expressed and 33 miRNAs that are over-expressed in both AML fractions versus the normal populations; many of these differentially expressed miRNAs show a range of expression exceeding 3 orders of magnitude. Supervised clustering analysis of AML LSC and non-LSC blasts reveals an LSC signature composed of 89 miRNAs, with nearly all differentially expressed miRNAs (86/89) exhibiting lower expression levels in AML LSC than non-LSC blasts. Finally, supervised clustering identifies a “stem-cell” signature composed of 17 miRNAs that are over-expressed in AML LSC and HSC versus committed progenitors. This group of miRNAs does not include miRNAs previously described as being highly expressed in embryonic stem cells. Together, these studies represent the first direct comparison of miRNA expression in a human cancer stem cell to its normal counterpart, thereby identifying miRNAs that may regulate AML LSC and/or normal HSC/committed progenitor function. Initial functional studies in vivo using LNA knockdown strategies indicate that a subset of miRNAs highly expressed in HSC and LSC is important in regulating normal HSC function. We are currently expanding these studies to test the role of these miRNAs in maintaining engrafted AMLs in the xenotransplant setting.

scholarly journals High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Li ◽  
Zheng Ge
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Adverse Outcomes ◽  
High Expression ◽  
Micro Rnas ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

scholarly journals 1018 - CD97 IS A CRITICAL REGULATOR OF ACUTE MYELOID LEUKEMIA STEM CELL FUNCTION

2019 ◽  
Vol 76 ◽  
pp. S31
Author(s):  
Christopher Park ◽  
Gaelle Martin ◽  
Nainita Roy ◽  
Sohini Chakraborty ◽  
Alexis Desrichard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Leukemia Stem Cell ◽  
Acute Myeloid

scholarly journals Gpr44 Mediates the Selenium-Dependent Anti-Leukemic Effect in Acute Myeloid Leukemia

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1835-1835
Author(s):  
Fenghua Qian ◽  
Fenghua Qian ◽  
Diwakar Tukaramrao ◽  
Jiayan Zhou ◽  
Nicole Palmiero ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Murine Model ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Pparγ Agonist ◽  
Acute Myeloid

Abstract Objectives The relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia stem cells (LSCs) that are not targeted by existing therapies. LSCs show sensitivity to endogenous cyclopentenone prostaglandin J (CyPG) metabolites that are increased by dietary trace element selenium (Se), which is significantly decreased in AML patients. We investigated the anti-leukemic effect of Se supplementation in AML via mechanisms involving the activation of the membrane-bound G-protein coupled receptor 44 (Gpr44) and the intracellular receptor, peroxisome proliferator-activated receptor gamma (PPARγ), by endogenous CyPGs. Methods A murine model of AML generated by transplantation of hematopoietic stem cells (HSCs- WT or Gpr44−/−) expressing human MLL-AF9 fusion oncoprotein, in the following experiments: To investigate the effect of Se supplementation on the outcome of AML, donor mice were maintained on either Se-adequate (Se-A; 0.08–0.1 ppm Se) or Se-supplemented (Se-S; 0.4 ppm Se) diets. Complete cell counts in peripheral blood were analyzed by hemavet. LSCs in bone marrow and spleen were analyzed by flow cytometry. To determine the role of Gpr44 activation in AML, mice were treated with Gpr44 agonists, CyPGs. LSCs in bone marrow and spleen were analyzed. Mice transplanted with Gpr44−/- AML cells were compared with mice transplanted with wild type AML cells and the progression of the disease was followed as above. To determine the role of PPARγ activation in AML, PPARγ agonist (Rosiglitazone, 6 mg/kg, i.p, 14 d) and antagonist (GW9662, 1 mg/kg, i.p. once every other day, 7 injections) were applied to Se-S mice transplanted with Gpr44−/- AML cells and disease progression was followed. Results Se supplementation at supraphysiological levels alleviated the disease via the elimination of LSCs in a murine model of AML. CyPGs induced by Se supplementation mediate the apoptosis in LSCs via the activation of Gpr44 and PPARγ. Conclusions Endogenous CyPGs produced upon supplementation with Se at supraphysiological levels improved the outcome of AML by targeting LSCs to apoptosis via the activation of two receptors, Gpr44 and PPARg. Funding Sources NIH DK 07,7152; CA 175,576; CA 162,665. Office of Dietary Supplements, USDA Hatch funds PEN04605, Accession # 1,010,021 (KSP, RFP).

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