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      Downregulation of GLI3 Expression Mediates Chemotherapy Resistance in Acute Myeloid Leukemia

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          Abstract

          Aberrant activation of the hedgehog (HH) pathway is observed in many neoplasms, including acute myeloid leukemia (AML). The glioma-associated oncogene homolog (GLI) transcription factors are the main downstream effectors of the HH signaling cascade and are responsible for the proliferation and maintenance of leukemic stem cells, which support chemotherapy resistance and leukemia relapse. Cytarabine (Ara-C)-resistant variants of AML cell lines were established through long-term cultivation with successively increasing Ara-C concentrations. Subsequently, differences in GLI expression were analyzed by RT-qPCR. GLI3 mRNA levels were detectable in parental Kasumi-1, OCI-AML3, and OCI-AML5 cells, whereas GLI3 expression was completely silenced in all resistant counterparts. Therefore, we generated GLI3-knockdown cell lines using small hairpin RNAs (shRNA) and evaluated their sensitivity to Ara-C in vitro. The knockdown of GLI3 partly abolished the effect of Ara-C on colony formation and induction of apoptosis, indicating that GLI3 downregulation results in Ara-C resistance. Moreover, we analyzed the expression of several genes involved in Ara-C metabolism and transport. Knockdown of GLI3 resulted in the upregulation of SAM and HD domain-containing protein 1 ( SAMHD1), cytidine deaminase ( CDA), and ATP-binding cassette C11 ( ABCC11)/multidrug resistance-associated protein 8 ( MRP8), each of which has been identified as a predictive marker for Ara-C response in acute myeloid leukemia. Our results demonstrate that GLI3 downregulation is a potential mechanism to induce chemotherapy resistance in AML.

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          Dual and opposing roles of primary cilia in medulloblastoma development

          Young-Goo Han, Hong Joo Kim, Andrzej A Dlugosz … (2009)
          Recent work has shown that primary cilia are essential for Hh signaling during mammalian development1–9. It is also known that aberrant Hedgehog (Hh) signaling can lead to cancer10, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children11,12. The primary cilium and Hh signaling are required for GNPs proliferation8,13–16. We asked whether primary cilia in GNPs play a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma growth when this tumor was driven by a constitutively active Smoothened (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active Gli2, a downstream transcription factor. Thus, primary cilia are required for, or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, presence or absence of cilia were associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling, but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.
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            Hedgehog beyond medulloblastoma and basal cell carcinoma.

            Stephan Teglund, Rune Toftgård (2010)
            The Hedgehog (Hh) signaling pathway is of central importance during embryo development in metazoans and governs a diverse array of processes including cell proliferation, differentiation, and tissue patterning. In normal adult physiology, the pathway is implicated in stem cell maintenance, tissue repair and regeneration. However, the pathway's darker side is its involvement in several types of human cancer, to which it confers growth promoting and/or survival capabilities to the cancer cell to varying degrees, and by different mechanisms. The Hh pathway is firmly linked to the etiology of basal cell carcinoma and to at least a subset of medulloblastoma. There is increasing evidence that other sporadic cancers, including those in pancreas, prostate, lung, and breast, could also be dependent on Hh pathway activity. In this review, we provide an overview of the pathway's role in various tumor types, where much of the framework for Hh-dependent malignancies has been elucidated in experimental mouse models. We discuss three different signal transduction models for the pathway's involvement in cancer: i) ligand-independent signaling, ii) ligand-dependent autocrine/juxtacrine signaling, and iii) ligand-dependent paracrine signaling. These different modes of signaling may have implications for future therapeutic interventions aimed at inhibiting the pathway during disease. In addition, crosstalk with other pathways, and indications of non-canonical Hh signaling in cancer cells may further cause complications, or perhaps possibilities, in the treatment regimen. Finally, we review the rapid progress and promising results in the development of small-molecule inhibitors of the Hh pathway.
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              Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia.

              Andrew Gentles, Sylvia K Plevritis, Ravindra Majeti … (2010)
              In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined. To identify an LSC gene expression signature and test its association with clinical outcomes in AML. Retrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n = 1047). Identification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSC-specific genes with overall, event-free, and relapse-free survival and with therapeutic response. Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n = 163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.08-1.22; log-likelihood P <.001). The absolute risk of death by 3 years was 57% (95% CI, 43%-67%) for the low LSC score group compared with 78% (95% CI, 66%-86%) for the high LSC score group (HR, 1.9 [95% CI, 1.3-2.7]; log-rank P = .002). In another cohort with available data on event-free survival for 70 patients with normal karyotypes, the risk of an event by 3 years was 48% (95% CI, 27%-63%) in the low LSC score group vs 81% (95% CI, 60%-91%) in the high LSC score group (HR, 2.4 [95% CI, 1.3-4.5]; log-rank P = .006). In multivariate Cox regression including age, mutations in FLT3 and NPM1, and cytogenetic abnormalities, the HRs for LSC score in the 3 cohorts with data on all variables were 1.07 (95% CI, 1.01-1.13; P = .02), 1.10 (95% CI, 1.03-1.17; P = .005), and 1.17 (95% CI, 1.05-1.30; P = .005). High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 18 July 2020
                Publication date Collection: July 2020
                Volume: 21
                Issue: 14
                Electronic Location Identifier: 5084
                Affiliations
                Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; freisleben.fabian@ 123456gmail.com (F.F.); le.behrmann@ 123456uke.de (L.B.); v.thaden@ 123456uke.de (V.T.); j.muschhammer@ 123456uke.de (J.M.); c.bokemeyer@ 123456uke.de (C.B.); fiedler@ 123456uke.de (W.F.)
                Author notes
                [* ]Correspondence: j.wellbrock@ 123456uke.de ; Tel.: +49-40-7410-55606
                Author information
                https://orcid.org/0000-0002-0724-656X
                https://orcid.org/0000-0001-6071-7810
                Article
                Publisher ID: ijms-21-05084
                DOI: 10.3390/ijms21145084
                PMC ID: 7404064
                PubMed ID: 32708452
                SO-VID: e00768e9-73bf-4681-9819-2e369f4e2007
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 26 June 2020
                Date accepted : 17 July 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: aml,gli3,hh,cytarabine,ara-c,resistance,samhd1,cda,abcc11
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: aml, gli3, hh, cytarabine, ara-c, resistance, samhd1, cda, abcc11

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