Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells

Wang, Yin; Liu, Yan; Tang, Fei; Bernot, Kelsie M.; Schore, Reuven J.; Marcucci, Guido; Caligiuri, Michael A.; Zheng, Pan; Liu, Yang

doi:10.1182/blood-2013-12-544221

Cited by 57 publications

(61 citation statements)

References 48 publications

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“…Furthermore, our data indicating that HIF-1α is a main player in the hypoxia-mediated control of miR-146a and CXCR4 support the findings of previous studies 24,25 that used chemotherapy and HIF-inhibitors in combination to restore the drug sensitivity of leukemic cells in hypoxia, indicating a new therapeutic possibility to decrease leukemic cell resistance to cytotoxic drug treatment. Wang et al showed that HIF-1α is constitutively expressed in enriched populations of leukemic stem cells purified from AML, and its targeting eliminates these cells.…”

supporting

confidence: 89%

“…21,22 The use of HIF inhibitors represents a new strategy for the development of therapies targeting the hypoxic cancer microenvironment. [23][24][25][26][27] Stabilization of HIF proteins by dimethyloxalyl glycine treatment, increases hematopoietic stem cell quiescence in vivo, improves blood recovery and enhances hematopoietic stem cell survival in the bone marrow of irradiated mice. 23 Echinomycin, a DNA-intercalating agent that blocks HIF DNA-binding activity, selectively eradicates cancer stem cells in mouse models of lymphoma and human AML 24 and selectively kills leukemia-initiating cells, inducing long-term remission in a murine model of relapsed AML.…”

Section: Introductionmentioning

confidence: 99%

“…23 Echinomycin, a DNA-intercalating agent that blocks HIF DNA-binding activity, selectively eradicates cancer stem cells in mouse models of lymphoma and human AML 24 and selectively kills leukemia-initiating cells, inducing long-term remission in a murine model of relapsed AML. 25 The chemokine receptor CXCR4 and its ligand stromalderived factor-1α (SDF-1/CXCL12) are both major players in the cross-talk between leukemic cells and the bone marrow microenvironment. [10][11][12] In patients with AML, hypoxiainduced CXCR4 expression is associated with poor prognosis, independently of the presence or not of the mutated FLT3 gene.…”

Section: Introductionmentioning

confidence: 99%

“…Wang et al showed that HIF-1α is constitutively expressed in enriched populations of leukemic stem cells purified from AML, and its targeting eliminates these cells. 25 Interestingly, compared with normal hematopoietic stem cells, 46 leukemic stem cells appear to be more dependent on the HIF-1α pathway. 49 On the other hand, Zhang et al showed that treatment of AML cells with CXCR4 inhibitors markedly reduced their leukemia-initiating capacity in xenotransplantation assays in NOD/SCID mice.…”

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confidence: 99%

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Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o ndromes for its deletion on chromosome 5 37 and in the progression of chronic myeloid leukemia. 38 We previously identified the molecular mechanism that regulates the level of CXCR4 protein expression by miR146a targeting 29 (miR-146a/CXCR4) during monocytopoiesis. 39 We also reported that in acute monocytic leukemia (AML-M5), a high CXCR4 protein level is associated with low/absent miR-146a expression. 39 We then showed that enforced miR-146a expression in leukemic cells decreases the level of CXCR4 protein and improves the sensitivity of these cells to drugs. 39CXCR4 is a target gene of HIF-1α and a post-transcriptional target of miR-146a, 9,39 in monocytic cells, known to originate from a common myeloid precursor in the bone marrow giving rise to tissue macrophages and dendritic cells 40 and subject to very different oxygen (O 2 ) levels. 41In this study, we investigated the impact of chronic hypoxia on the miR-146a/CXCR4 regulatory axis during monocytopoiesis and in monocytic leukemic cells. The levels of hypoxia studied were mild (5% O 2 ), such as that present in the sinusoidal cavity of bone marrow, and more severe (1% O 2 ), such as that in hypoxic niches in bone marrow.Altogether, our data demonstrated how the differential expression of HIF-1α and HIF-2α is mediated by O 2 level (mild or severe) and down-regulates CXCR4 expression through a post-transcriptional mechanism mediated by up-regulation of miR-146a in normal monocytic cells and in monocytic leukemia cell lines, expressing a moderate level of CXCR4. However, this mechanism is dysregulated in primary AML-M5 blast cells that fail to decrease CXCR4 expression significantly in response to hypoxia. This dysregulation helps to explain why leukemic blasts express high CXCR4 levels, even in hypoxic conditions, and how they are protected from anti-leukemic drugs through CXCR4 activation mediated by SDF-1α secreted in the hypoxic bone marrow microenvironment. MethodsAdditional information is provided in the Online Supplement. Cell culturesAfter obtaining informed consent, human cord blood was taken from healthy donors and samples of blood were taken from patients with AML. This study was approved by the local ethical committees of the Italian National Institute of Health and the University of Tor Vergata.Cord blood CD34 + hematopoietic progenitor cell purification, unilineage monocytic differentiation and morphological analyses were performed as previously described. 39 Human primary AML-M5 blasts were maintained in culture in vitro in Iscove medium supplemented with 10% fetal calf serum, granulocyte-macrophage colony-stimulating factor (10 ng/mL), stem cell factor (50 ng/mL), and interleukin-3 (10 ng/mL) (PeproTech Inc. Rocky Hill, NJ, USA). RNA and protein samples were prepared as described elsewhere. 39 Leukemic cell lines, U937 and HL-60, were grown in RPMI medium supplemented with 10% fetal calf serum (Gibco, Carlsbad, CA, USA). HypoxiaTo provide a mild or more severe hypoxic environment, acute ...

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supporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

et al. 2015

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“…Echinomycin has no impact on selfrenewal and differentiation of HSCs, which makes it a perfect drug to eradicate leukemia. 58 Another well-known drug, L-ascorbic acid in high concentrations, has also been shown to inhibit the expression of HIF-1α in CML cells. It is particularly important in CML treatment to find a molecule capable of impacting LSCs that are completely resistant to TKI-based modalities.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

The role of hypoxia-inducible factors in leukemias

Szymczak¹,

Dybko²,

Kuliczkowski³

2018

Adv Clin Exp Med

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Hypoxia, understood as low partial oxygen pressure, has become one of the most explored fields in recent years. Cellular response to hypoxia is mediated by hypoxia-inducible factors (HIFs) -potent transcription regulators, and their downstream pathways. In general, HIFs modify energy metabolism, inflammation and immune response, enhance cancer invasion, metastasis, resistance to treatment, and relapse. The influence of HIFs on the progression of leukemia is still under investigation in various studies, but in mice and some human models HIFs have been recognized as leukemia immortalizers by promoting leukemic stem cell quiescence and inhibiting their cell cycle. This makes leukemic stem cells resistant to most known treatment approaches. The role of HIFs in solid tumors and leukemia makes them almost ideal targets for an anticancer treatment. Although the first attempts with new molecules are encouraging, there is a need to investigate the ambiguous role of HIFs to develop a modern antileukemic treatment.

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Insights into DNA‐drug interactions in the era of omics

Portugal

2020

Biopolymers

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Despite the rise of sophisticated new targeting strategies in cancer chemotherapy, many classic DNA-binding drugs remain on the front line of the therapy against cancer. Based on examples primarily from the author's laboratory, this article reviews the capabilities of several DNA-binding drugs to alter gene expression. Research is ongoing about the molecular bases of the inhibition of gene expression and how alteration of the cellular transcriptome can commit cancer cells to die. The development of a variety of omic techniques allows us to gain insights into the effect of antitumor drugs. Genome-wide approaches provide unbiased genomic data that can facilitate a deeper understanding of the cellular response to DNA-binding drugs. Moreover, the results of large-scale genomic studies are gathered in publicly available databases that can be used in developing precision medicine in cancer treatment.

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Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells

Cited by 57 publications

References 48 publications

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

The role of hypoxia-inducible factors in leukemias

Insights into DNA‐drug interactions in the era of omics

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