Artykuły w czasopismach: „HMGA2”

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Ismail, A. A., S. Wagner, H. Murua Escobar, S. Willenbrock, K. A. Sterenczak, M. T. Samy, A. M. Abd El-Aal, I. Nolte i P. Wefstaedt. "Effects of High-Mobility Group A Protein Application on Canine Adipose-Derived Mesenchymal Stem CellsIn Vitro". Veterinary Medicine International 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/752083.

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Multipotency and self-renewal are considered as most important features of stem cells to persist throughout life in tissues. In this context, the role of HMGA proteins to influence proliferation of adipose-derived mesenchymal stem cell (ASCs) while maintaining their multipotent and self-renewal capacities has not yet been investigated. Therefore, extracellular HMGA1 and HMGA2 application alone (10–200 ng/mL) and in combination with each other (100, 200 ng/mL each) was investigated with regard to proliferative effects on canine ASCs (cASCs) after 48 hours of cultivation. Furthermore, mRNA expression of multipotency marker genes in unstimulated and HMGA2-stimulated cASCs (50, 100 ng/mL) was analyzed by RT-qPCR. HMGA1 significantly reduced cASCs proliferation in concentrations of 10–200 ng/mL culture medium. A combination of HMGA1 and HMGA2 protein (100 and 200 ng/mL each) caused the same effects, whereas no significant effect on cASCs proliferation was shown after HMGA2 protein application alone. RT-qPCR results showed that expression levels of marker genes including KLF4, SOX2, OCT4, HMGA2, and cMYC mRNAs were on the same level in both HMGA2-protein-stimulated and -unstimulated cASCs. Extracellular HMGA protein application might be valuable to control proliferation of cASCs in context with their employment in regenerative approaches without affecting their self-renewal and multipotency abilities.

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Palumbo Júnior, Antonio, Vanessa Paiva Leite de Sousa, Francesco Esposito, Marco De Martino, Floriana Forzati, Fábio Carvalho de Barros Moreira, Tatiana de Almeida Simão i in. "Overexpression of HMGA1 Figures as a Potential Prognostic Factor in Endometrioid Endometrial Carcinoma (EEC)". Genes 10, nr 5 (15.05.2019): 372. http://dx.doi.org/10.3390/genes10050372.

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Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease’s development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only HMGA1 expression is associated with increased histological grade and tumor size. Moreover, HMGA1 but not HMGA2 overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of HMGA1 pseudogenes—HMGA1-P6 and HMGA1-P7—and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that HMGA1 overexpression possesses a potential role as a prognostic biomarker for EEC.

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Li, Liping, Wenyan Lu, Alison R. Moliterno, Lingling Xian, Joseph Kim, Ophelia Rogers, Jerry L. Spivak i Linda Resar. "High Mobility Group A1 Chromatin Regulators: Key Epigenetic Switches and Therapeutic Targets Required for Leukemic Transformation in JAK2 Mutant MPN". Blood 134, Supplement_1 (13.11.2019): 1680. http://dx.doi.org/10.1182/blood-2019-130262.

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Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by hyperactive JAK/STAT signaling and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). However, mechanisms driving progression remain elusive and therapies are ineffective after leukemia develops. The High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins which are overexpressed in aggressive solid tumors where they portend adverse outcomes. HMGA1/2 genes are also up-regulated in hematologic malignancies and MPN with disease progression. In murine models, Hmga1/2 overexpression drives clonal expansion and deregulated proliferation while Hmga1 overexpression is sufficient for lymphoid leukemic transformation. We therefore sought to: 1) test the hypothesis that HMGA1/2 proteins are rational therapeutic targets required for leukemic transformation in MPN, 2) elucidate mechanisms mediated by HMGA1/2 during disease progression, and, 3) identify therapeutic approaches to disrupt HMGA function and intercept the transition from chronic disease to aggressive leukemia. Methods: We compared HMGA1/2 in JAK2V617F mutant AML cell lines from MPN patients (DAMI, SET-2), CD34+ cells from PV patients during chronic and transformation phases, and JAK2V617F murine models of PV (transgenic JAK2V617F) and PV-AML (transgenic JAK2V617F/MPLSV). To elucidate HMGA1/2 function, we silenced HMGA1 or HMGA2 via short hairpin RNA in human MPN-AML cells and generated murine models of PV-AML with heterozygous Hmga1 or Hmga2 deficiency. To dissect molecular mechanisms underlying HMGA, we compared RNA-Seq from MPN-AML cell lines after gene silencing. Finally, to identify therapies to target HMGA pathways, we integrated the RNA-Seq data with the Broad Connectivity Map (cMAP). Results: There is a marked up-regulation in HMGA1/2 in CD34+ cells from PV patients after transformation to AML and in leukemic blasts from our PV-AML mouse model. Conversely, silencing HMGA1 or HMGA2 in human MPN-AML cell lines (DAMI, SET-2) dramatically halts proliferation, disrupts clonogenicity, and prevents leukemia development in mice. Further, heterozygous Hmga1 deficiency prolongs survival in the transgenic PV-AML murine model with fulminant leukemia and early mortality, although Hmga2 deficiency has no effect. RNA-Seq analyses from human MPN-AML cell lines revealed that HMGA1 up-regulates transcriptional networks involved in cell cycle progressions (E2F targets, mitotic spindle, G2M checkpoint, MYC targets) while repressing immune pathways (inflammation, interferon gamma) and oxidative phosphorylation. HMGA2 up-regulates similar pathways, but represses TNFalpha signaling. cMAP identified inhibitors of histone deacetylation and cell cycle progression as potential agents to target HMGA1 pathways; DNA synthesis inhibitors were predicted to target HMGA2 pathways. Cytotoxicity assays demonstrate that epigenetic therapy with HDAC inhibitors synergizes with Ruxolitinib in JAK2 mutant MPN cells after transformation to leukemia. Conclusions: HMGA1/2 genes are overexpressed in MPN with highest levels after leukemic transformation. Further, silencing HMGA1/2 disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. In addition, heterozygous deficiency of Hmga1 prolongs survival in a fulminant MPN-AML model. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression, which can be targeted with epigenetic therapies. Our findings further underscore the key role for HMGA as an epigenetic switch required for leukemic transformation in MPN and opens the door to novel therapeutic approaches to intercept the transition from chronic indolent disease to aggressive leukemia. Disclosures No relevant conflicts of interest to declare.

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Parisi, Silvia, Silvia Piscitelli, Fabiana Passaro i Tommaso Russo. "HMGA Proteins in Stemness and Differentiation of Embryonic and Adult Stem Cells". International Journal of Molecular Sciences 21, nr 1 (6.01.2020): 362. http://dx.doi.org/10.3390/ijms21010362.

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HMGA1 and HMGA2 are chromatin architectural proteins that do not have transcriptional activity per se, but are able to modify chromatin structure by interacting with the transcriptional machinery and thus negatively or positively regulate the transcription of several genes. They have been extensively studied in cancer where they are often found to be overexpressed but their functions under physiologic conditions have still not been completely addressed. Hmga1 and Hmga2 are expressed during the early stages of mouse development, whereas they are not detectable in most adult tissues. Hmga overexpression or knockout studies in mouse have pointed to a key function in the development of the embryo and of various tissues. HMGA proteins are expressed in embryonic stem cells and in some adult stem cells and numerous experimental data have indicated that they play a fundamental role in the maintenance of stemness and in the regulation of differentiation. In this review, we discuss available experimental data on HMGA1 and HMGA2 functions in governing embryonic and adult stem cell fate. Moreover, based on the available evidence, we will aim to outline how HMGA expression is regulated in different contexts and how these two proteins contribute to the regulation of gene expression and chromatin architecture in stem cells.

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Vignali, Robert, i Silvia Marracci. "HMGA Genes and Proteins in Development and Evolution". International Journal of Molecular Sciences 21, nr 2 (19.01.2020): 654. http://dx.doi.org/10.3390/ijms21020654.

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HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology.

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Meireles Da Costa, Nathalia, Luis Felipe Ribeiro Pinto, Luiz Eurico Nasciutti i Antonio Palumbo Jr. "The Prominent Role of HMGA Proteins in the Early Management of Gastrointestinal Cancers". BioMed Research International 2019 (13.10.2019): 1–7. http://dx.doi.org/10.1155/2019/2059516.

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GI tumors represent a heterogeneous group of neoplasms concerning their natural history and molecular alterations harbored. Nevertheless, these tumors share very high incidence and mortality rates worldwide and patients’ poor prognosis. Therefore, the identification of specific biomarkers could increase the development of personalized medicine, in order to improve GI cancer management. In this sense, HMGA family members (HMGA1 and HMGA2) comprise an important group of genes involved in the genesis and progression of malignant tumors. Additionally, it has also been reported that HMGA1 and HMGA2 display an important role in the detection and progression of GI tumors. In this way, HMGA family members could be used as reliable biomarkers able to efficiently track not only the tumor per se but also the main risk conditions related with their development of GI cancers in the future. Finally, it shall be a promising option to revert the current scenario, once HMGA genes and proteins could represent a convergence point in the complex landscape of GI tumors.

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Tessari, Michela A., Monica Gostissa, Sandro Altamura, Riccardo Sgarra, Alessandra Rustighi, Clio Salvagno, Giuseppina Caretti i in. "Transcriptional Activation of the Cyclin A Gene by the Architectural Transcription Factor HMGA2". Molecular and Cellular Biology 23, nr 24 (15.12.2003): 9104–16. http://dx.doi.org/10.1128/mcb.23.24.9104-9116.2003.

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ABSTRACT The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization. HMGA proteins are overexpressed in several experimental and human tumors and have been implicated in the process of neoplastic transformation. Hmga2 knockout results in the pygmy phenotype in mice and in a decreased growth rate of embryonic fibroblasts, thus indicating a role for HMGA2 in cell proliferation. Here we show that HMGA2 associates with the E1A-regulated transcriptional repressor p120E4F, interfering with p120E4F binding to the cyclin A promoter. Ectopic expression of HMGA2 results in the activation of the cyclin A promoter and induction of the endogenous cyclin A gene. In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated. These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation.

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Resar, Linda, Donna Marie Williams, Zhizhuang Joe Zhao, Ophelia Rogers, Lingling Xian, Jerry L. Spivak i Alison R. Moliterno. "High Mobility Group A1/2 Chromatin Remodeling Proteins Associate with Polycythemia Vera Transformation to Acute Leukemia in Humans and a JAK2 V617F Transgenic Mouse Model". Blood 128, nr 22 (2.12.2016): 1958. http://dx.doi.org/10.1182/blood.v128.22.1958.1958.

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Abstract Introduction: The MPN are clonal hematopoietic stem cell (HSC) disorders characterized by an overproduction of blood cells and an increased risk of transformation to an aggressive phase with myelofibrosis (MF) and/or acute myeloid leukemia (AML). Polycythemia vera (PV) is the most common clinical subtype, and while PV starts as an indolent process, nearly 25% of patients will progress to MF and/or AML. PV is caused by acquired mutations of JAK2, yet JAK2 mutations alone do not account for MF or AML transformation. Mutations in genes encoding epigenetic regulators are associated with MPN transformation, but the mechanism of action is not understood. HMGA1/2 chromatin binding proteins are potent oncogenes that drive tumor progression by activating oncogenic and stem cell transcriptional networks. Both HMGA1/2 are overexpressed in acute leukemia and have been shown to be drivers of clonal expansion in myeloid disease in humans and in murine myeloproliferative disease models. We hypothesized that HMGA proteins could be critical drivers of transformation in PV and therefore tested the association of HMGA1/2 expression to transformation in human and murine PV. Methods: We examined the HSC genomic context and clonal evolution in 49 JAK2V617F-positive PV patients using standard and SNP-array karyotyping and a targeted resequencing panel of 163 genes associated with myeloid cancers. We examined HSC clonal burden by examining JAK2V617F HSC genotypes on a single cell basis. We measured HMGA1 and HMGA2 expression in a JAK2V617F positive human cell line, in isolated CD34+ HSCs from PV patients during chronic and transformation phases, in JAK2V617F transgenic murine models of PV (tgJAK2V617F) and PV-AML (tgJAK2V617F/MPLSV; Blood 2015;126:484) using a real-time quantitative RT-PCR (qRT-PCR) assay. Results: Both HMGA1 and HMGA2 mRNA were up-regulated in all JAK2V617F-positive contexts. In primary human PV CD34+ HSCs, HMGA1 and HMGA2 were found to be increased by 7 and 100 fold, respectively, compared to controls. Moreover, there was a dramatic up-regulation in both HMGA1/2 in patients who transformed from PV to MF or AML compared to chronic phase PV, whether analyzed cross-sectionally (Figure) or prospectively in selected patients. In addition to disease phase, over-expression of HMGA1/2 correlated with clonal dominance of JAK2V617F-homozygous stem cells, and additional mutations of epigenetic regulators including EZH2 and SETBP1. Similarly, when assessed in unfractionated bone marrow or in tumor samples in the two transgenic mouse models for PV and PV-AML, Hmga1/2 were overexpressed compared to wild-type littermates, with highest levels in the PV-AML transgenic mouse model. Conclusion: HMGA1 and HMGA2 are overexpressed in PV, and higher levels associate with disease progression to MF and AML, both in human PV and in transgenic murine models of PV. These data suggest HMGA proteins are critical drivers of PV transformation and that the mechanism of HMGA1/2 overexpression is a consequence of aberrant JAK/STAT signaling and epigenetic dysregulation. Our findings indicate that HMGA1/2 overexpression may function as a necessary molecular switch for PV leukemic transformation. Therefore, HMGA proteins and their transcriptional pathways offer novel therapeutic targets aimed at the prevention of PV progression to MF and AML. Disclosures No relevant conflicts of interest to declare.

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Moliterno, Alison R., Donna Marie Williams, Liping Li, Lingling Xian, Li Luo, Amy S. Duffield, Ophelia Rogers, Jerry L. Spivak i Linda Resar. "The High Mobility Group A1 Chromatin Regulator Is Required for Pathologic Megakaryocyte Development and Progression to Myelofibrosis in JAK2V617F Murine Models". Blood 134, Supplement_1 (13.11.2019): 472. http://dx.doi.org/10.1182/blood-2019-131432.

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Introduction: JAK2V617F-positive myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by unregulated JAK2/STAT signaling and increased risk of transformation to myelofibrosis (MF). Pathologic JAK2/STAT signaling of the thrombopoietin/thrombopoietin receptor pathway in HSC, progenitors, and megakaryocytes drives megakaryocytic proliferation, megakaryocytic hypertrophy, thrombocytosis, HSC niche damage, osteosclerosis, myelofibrosis, and extramedullary hematopoiesis (EMH). The High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins that foster aberrant STAT3 signaling in diverse contexts. In murine models, Hmga1/2 overexpression drives clonal expansion and deregulated proliferation. In patients with MPN, HMGA1/2 genes are overexpressed with disease progression to MF. We therefore sought to: 1) elucidate mechanisms mediated by HMGA1/2 in JAK2V617F-associated MF transformation and 2) test the hypothesis that HMGA proteins are rational therapeutic targets for MF progression. Methods: We used a JAK2V617F transgenic murine model (VF) in which 13 copies of the human JAK2V617F cDNA are driven by the Vav promoter (Blood 2008; 111:5109-5117). To elucidate the function of Hmga1 or Hmga2 in the JAK2V617F context, we crossed VF mice onto a background deficient for Hmga1 or Hmga2 to generate VF/Hmga1+/- and VF/Hmga2+/- progeny. We also generated a tissue specific model whereby Hmga1 was deleted in HSC via Vav-cre (Vav-cre Hmga1+/-) and crossed these mice onto the VF model (VF/Vav-cre Hmga1+/-). Serial blood counts, histology of marrow and spleen, and immunohistochemistry with CD61 antibodies were compared in each model at 8, 16, and/or 40 weeks of age. We also performed flow cytometric analysis of HSC and progenitor populations in mice with these genotypes. Results: The VF mice develop an MPN phenotype by 8 weeks with marked thrombocytosis and erythrocytosis. By 33 weeks, VF mice progress to MF characterized by anemia, splenomegaly due to extramedullary hematopoiesis (EMH), marked megakaryocytic hyperplasia, megakaryocytic hypertrophy, increased platelet size, and osteosclerosis with reticulin fibrosis (Figure A and B). ). The VF mouse also develops an expansion of megakaryocyte-erythroid progenitors (MEP) compared to wildtype mice (P<0.01). Neither mice with Hmga1deficiency (Hmga1+/- or Hmga1-/-) nor Hmga2+/- mice develop thrombocytopenia or other blood count abnormalities at one year of age, and preliminary data suggests that the MEP compartment is normal in Hmga1+/- and Hmga1-/- mice. However, VF/Hmga1+/- mice had reduction of both megakaryocyte hypertrophy and hyperplasia, bone marrow fibrosis, and osteosclerosis compared to VF mice at corresponding age ranges (Figure A). Further, there was mitigation of thrombocytosis, reduction in platelet size, and decreased spleen weight in VF/Hmga1+/- mice compared to VF mice at corresponding age ranges (Figure B). Importantly, VF/Hmga1+/- mice fail to develop anemia which occurs after 33 weeks in the VF model (VF hemoglobin 12.9 g/dl, VF/Hmga1+/- hemoglobin 15.1 g/dl, P<.05). In VF/Hmga1-/- mice, there was no expansion in MEP. The MPN progression to MF was prevented by both global or HSC-specific heterozygous Hmga1 deficiency, demonstrating that the effects of Hmga1 are specific to the hematopoietic cell context rather than the bone marrow microenvironment. In addition, similar degrees of mitigation were observed in VF mice with heterozygous or homozygous Hmga1 deficiency. In contrast, Hmga2 deficiency failed to prevent progression in the VF model. Unexpectedly, Hmga2 deficiency exacerbated megakaryocyte hypertrophy and reticulin fibrosis in VF mice. Conclusions: In a JAK2V617F murine model, heterozygous deficiency of Hmga1 prevents MPN progression to MF, interrupting both the development of megakaryocytic hyperplasia and fibrosis, which are hallmarks of murine and human JAK2V617F disease. While Hmga1 is not required for megakaryocyte or platelet development under steady state conditions, it is critical to the amplification of aberrant signaling in MF associated VF. Further, our findings underscore a key role for HMGA1 as a mediator of aberrant JAK2/STAT3 signaling and a therapeutic target to quell myeloproliferation and prevent MF progression. Disclosures Duffield: Boston Biomedical/Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; MedImmune: Consultancy.

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Huang, Shaoyue, Zhen Hong, Leguo Zhang, Jian Guo, Yanhua Li i Kuo Li. "HMGA2 Promotes Brain Injury in Rats with Cerebral Infarction by Activating TLR4/NF-κB Signaling Pathway". Mediators of Inflammation 2022 (4.08.2022): 1–8. http://dx.doi.org/10.1155/2022/1376959.

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Cerebral infarction is a common disease with a higher disability and fatality rates. The incidence rates of cerebral infarction or cerebral ischemic stroke gradually increase with aging and cerebrovascular disease progression. This study is aimed at evaluating the effects of HMGA2 on cerebral infarction-induced brain tissue damage and its underlying mechanisms. Adult Sprague Dawley rats were pretreated with sh-HMGA2 before cerebral infarction operation. The effect of HMGA2 on the arrangement, distribution, and morphological structure of neurons and the cell apoptosis ratio in brain tissue were detected via hematoxylin and eosin staining, brain-water content, TTC staining, and TUNEL staining. The results from ELISA assay, qPCR, and western blot indicated that downregulation of HMGA2 mitigated inflammatory stress via regulating the expression of TLR4/NF-κB. In addition, results showed that suppressed HMGA2 attenuated the neurological dysfunction of brain injury rats and markedly reduced infarct volume. HMGA2 might be able to alleviate the damage associated with cerebral infarction-induced inflammatory response and cell apoptosis. Moreover, downregulation of HMGA2 had a protective effect on the brain damage derived from cerebral infarction by mediating the TLR4/NF-κB pathway. In conclusion, the current study demonstrated that downregulation of HMGB2 decreased the infarct size, inflammatory responses, and apoptosis in cerebral injury and further had neuroprotective effects against cerebral infarction-induced brain damage. Finally, these results indicated that the downregulation of the TLR4/NF-κB pathway after ischemia by HMGB2 inhibition is a potential mechanism of the neuroprotective effect of cerebral injury.

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Balachandran, Akilandeswari, Ajit Zambre, Jagjot Singh Kainth, Lakshmi Dhevi Nagarajha Selvan, Sowmya Parameswaran, Zahra Afrasiabi, Subramanian Krishnakumar, Raghuraman Kannan i Anandhi Upendran. "Targeting HMGA protein inhibits retinoblastoma cell proliferation". RSC Advances 8, nr 55 (2018): 31510–14. http://dx.doi.org/10.1039/c8ra06026f.

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Pierre-Louis, Olivier, Joris Andrieux, Christophe Desterke, Eric Lippert, Vincent Praloran, Jean-Loup Demory, Marie-Caroline Le Bousse-Kerdiles i Chrystele Bilhou-Nabera. "Discriminative HMGA2 Isoform Expression in CD15+ Granulocytic Cells in Myeloid Metaplasia with Myelofibrosis (MMM)." Blood 104, nr 11 (16.11.2004): 2429. http://dx.doi.org/10.1182/blood.v104.11.2429.2429.

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Abstract MMM is a myeloproliferative disorder characterized by extramedullary hematopoiesis and reactive myelofibrosis. Recently, HMGA2 dysregulation has been demonstrated in 2 MMM patients showing 12q15 rearrangement and confirmed in 25 consecutive MMM patients without cytogenetic abnormalities (Andrieux, 2004). HMGA2 proteins belong to the high mobility group A (HMGA) family of architectural transcription factors regulating the expression of several genes. As MMM is a clonal disorder of CD34+ hematopoietic progenitors, we analyzed HMGA2 expression in peripheral blood sub-populations of 5 MMM patients and 7 healthy donors to determine in which sub-population HMGA2 was dysregulated. RNA was extracted from peripheral blood mononuclear cells (PBMC) and CD15+ granulocytic cells (PBCD15+) separated through Ficoll centrifugation or from immunomagnetically selected circulating CD34+ cells (PBCD34+). Real-time quantitative PCR (RQ-PCR) using Taqman technology was performed on cDNA. As different isoforms were described in malignancies, we used two primer sets : the first one allowing the amplification of all HMGA2 isoforms (exon 1 to 3) (HMGA2 1–3), the second one allowing the amplification of the full length HMGA2 isoform (exon 1 to 5)(HMGA2 1–5). In healthy donors and in MMM, PBMC HMGA2 expression levels were heterogeneous, depending of the cellular sub-population purity. HMGA2 1–3 or HMGA2 1–5 were both expressed in MMM and normal PBCD34+ cells, but with a higher expression level for HMGA2 1–3 as compared to HMGA2 1–5. Furthermore, both HMGA2 1–3 and HMGA2 1–5 expression levels were significantly increased in PBCD34+ MMM patients (p<10−6) compared to healthy donors. In MMM, HMGA2 expression level was significantly increased (p<10−5) in PBCD15+ as compared to PBCD34+. Moreover, PBCD15+ HMGA2 1–3 expression level was significantly higher in MMM patients compared to PBCD15+ from healthy donors (p<10−7). A persistence of HMGA2 1–5 expression was only observed in MMM PBCD15+ but was undetectable neither in normal PB neutrophils (purity>98%) nor in PB neutrophils from other myeloproliferative disorders (Polycythemia Vera and Essential Thrombocythemia). To determine if HMGA2 level was modified during hematopoietic differentiation, we quantified HMGA2 1–3 and 1–5 isoform expression on purified healthy donor PB CD34+ and MMM CD34+ before and after culture with specific lineage growth factors (12 day-culture). Primary results showed that both HMGA2 isoform expression levels were higher during granulocytic differentiation. Our results demonstrate that HMGA2 1–5 isoform is discriminately overexpressed in MMM PBCD15+. The persistence of this HMGA2 full length expression in MMM myeloid lineage could be considered as a marker of the disease.

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Palmieri, Dario, Teresa Valentino, Ivana De Martino, Francesco Esposito, Paolo Cappabianca, Anne Wierinckx, Michela Vitiello i in. "PIT1 upregulation by HMGA proteins has a role in pituitary tumorigenesis". Endocrine-Related Cancer 19, nr 2 (23.12.2011): 123–35. http://dx.doi.org/10.1530/erc-11-0135.

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We have previously demonstrated that HMGA1B and HMGA2 overexpression in mice induces the development of GH and prolactin (PRL) pituitary adenomas mainly by increasing E2F1 transcriptional activity. Interestingly, these adenomas showed very high expression levels of PIT1, a transcriptional factor that regulates the gene expression ofGh,Prl,GhrhrandPit1itself, playing a key role in pituitary gland development and physiology. Therefore, the aim of our study was to identify the role ofPit1overexpression in pituitary tumour development induced by HMGA1B and HMGA2. First, we demonstrated that HMGA1B and HMGA2 directly interact with both PIT1 and its gene promoterin vivo, and that these proteins positively regulatePit1promoter activity, also co-operating with PIT1 itself. Subsequently, we showed, by colony-forming assays on two different pituitary adenoma cell lines, GH3 and αT3, thatPit1overexpression increases pituitary cell proliferation. Finally, the expression analysis ofHMGA1,HMGA2andPIT1in human pituitary adenomas of different histological types revealed a direct correlation betweenPIT1and HMGA expression levels. Taken together, our data indicate a role ofPit1upregulation by HMGA proteins in pituitary tumours.

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Resar, Linda, Donna Marie Williams, Lingling Xian, Wenyan Lu, Briyana Chisholm, Li Luo, Zhizhuang Joe Zhao, Ophelia Rogers, Jerry L. Spivak i Alison R. Moliterno. "High Mobility Group A1 Chromatin Remodeling Proteins Amplify Inflammatory Networks to Drive Leukemic Transformation in Chronic Myeloproliferative Neoplasia in Humans and JAK2V617F Transgenic Mouse Models". Blood 132, Supplement 1 (29.11.2018): 102. http://dx.doi.org/10.1182/blood-2018-99-119549.

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Abstract Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by overproduction of mature blood cells and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML), although molecular mechanisms driving disease progression remain elusive. While most patients who acquire a JAK2V617F mutation in CD34+ cells present with chronic, indolent Polycythemia Vera (PV), ~25% will progress to MF or AML. High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins which are overexpressed in aggressive leukemia where they portend adverse outcomes. In murine models, Hmga1/2 overexpression drives clonal expansion and uncontrolled proliferation. HMGA1/2 genes are also overexpressed in MPN with disease progression. We therefore sought to: 1) test the hypothesis that HMGA proteins are required for leukemic transformation and rational therapeutic targets in MPN progression, and, 2) identify mechanisms mediated by HMGA1/2 during disease progression. Methods: We measured HMGA1/2 in JAK2V617F mutant human AML cell lines from MPN patients (DAMI, SET-2), CD34+ cells from PV patients during chronic and transformation phases, and JAK2V617F transgenic murine models of PV (transgenic JAK2V617F) and PV-AML (transgenic JAK2V617F/MPLSV; Blood 2015;126:484). To elucidate HMGA1/2 function, we silenced HMGA1 or HMGA2 via short hairpin RNA in human MPN-AML cell lines (DAMI, SET-2) and assessed proliferation, colony formation, and leukemic engraftment in immunodeficient mice. To further assess Hmga1 function in vivo, we crossed mice with heterozygous Hmga1 deficiency onto murine models of PV and PV-AML. Finally, to dissect molecular mechanisms underlying HMGA1, we compared RNA-Seq from MPN-AML cell lines (DAMI, SET-2) after silencing HMGA1/2 to that of controls and applied Ingenuity Pathway Analysis. Results: HMGA1/2 mRNA are up-regulated in all JAK2V617F-positive contexts, including primary human PV CD34+ cells and total bone marrow from JAK2V617F mouse models for PV compared to controls. Further, there is a marked up-regulation in both HMGA1/2 in CD34+ cells from PV patients after transformation to MF or AML and in leukemic blasts from our PV-AML mouse model compared to PV mice. Overexpression of HMGA1/2 also correlates with clonal dominance of human JAK2V617F-homozygous stem cells and additional mutations of epigenetic regulators (EZH2, SETBP1). Silencing HMGA1 or HMGA2 in human MPN-AML cell lines (DAMI, SET-2) dramatically halts proliferation, disrupts clonogenicity, and prevents leukemic engraftment in mice. Further, heterozygous Hmga1 deficiency decreases splenic enlargement in PV mouse models with advancing age. Moreover, heterozygous Hmga1 deficiency prolongs survival in the transgenic PV-AML murine model with fulminant leukemia and early mortality. PV-AML mice survived a median of 5 weeks whereas PV-AML mice with heterozygous Hmga1 deficiency survive a median of 12 weeks (P< 0.002). The leukemic burden was also decreased in mice with Hmga1 deficiency. Preliminary RNA-Seq analyses from DAMI and SET-2 cells show that HMGA1 drives pathways involved in Th1/Th2 activation, chemotaxis, cell-cell signaling, myeloid cell accumulation and other immune cell trafficking, inflammation, and injury, suggesting that HMGA1 co-opts immune and inflammatory networks to drive tumor progression. Surprisingly, atherosclerosis pathways are also induced by HMGA1. Conclusions: HMGA1/2 genes are overexpressed in MPN with highest levels in more advanced disease (MF, AML) both in primary human tumors and murine models. Strikingly, silencing HMGA1 or HMGA2 halts proliferation and clonogenicity in vitro and prevents leukemic engraftment in vivo. Further, heterozygous Hmga1 deficiency prolongs survival in a murine model of fulminant MPN AML and decreases tumor burdens. Finally, preliminary RNA-Seq analyses suggest that HMGA1 amplifies transcriptional networks involved in immune cell trafficking and inflammation to drive tumor progression. Unexpectedly, HMGA1 also regulates pathways involved in atherosclerosis, implicating HMGA1 as a novel link between clonal hematopoiesis and cardiovascular disease. Our findings further highlight HMGA1/2 as a key molecular switch for leukemic transformation in MPN and opens the door to novel therapeutic approaches to prevent disease progression. Disclosures No relevant conflicts of interest to declare.

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De Martino, Ivana, Rosa Visone, Dario Palmieri, Paolo Cappabianca, Paolo Chieffi, Floriana Forzati, Antonio Barbieri i in. "The Mia/Cd-rap gene expression is downregulated by the high-mobility group A proteins in mouse pituitary adenomas". Endocrine-Related Cancer 14, nr 3 (wrzesień 2007): 875–86. http://dx.doi.org/10.1677/erc-07-0036.

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The high-mobility group A (HMGA) family of proteins orchestrates the assembly of nucleoprotein structures playing important roles in gene transcription, recombination, and chromatin structure through a complex network of protein–DNA and protein–protein interactions. Recently, we have generated transgenic mice carrying wild type or truncated HMGA2 genes under the transcriptional control of the cytomegalovirus promoter. These mice developed pituitary adenomas secreting prolactin and GH mainly due to an increased E2F1 activity, directly consequent to the HMGA2 overexpression. To identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA2 gene, in this study we have analyzed the gene expression profile of three HMGA2-pituitary adenomas in comparison with a pool of ten normal pituitary glands from control mice, using the Affymetrix MG MU11K oligonucleotide array representing ~13 000 unique genes. We have identified 82 transcripts that increased and 72 transcripts that decreased at least four-fold in all the mice pituitary adenomas analyzed compared with normal pituitary glands. Among these genes, we focused our attention on the Mia/Cd-rap gene, whose expression was essentially suppressed in all of the pituitary adenomas tested by the microarray. We demonstrated that the HMGA proteins directly bind to the promoter of the Mia/Cd-rap gene and are able to downregulate its expression. In order to understand a possible role of Mia/Cd-rap in pituitary cell growth, we performed a colony assay in GH3 and GH4 cells. Interestingly, Mia/Cd-rap expression inhibits their proliferation, suggesting a potential tumor suppressor role of Mia/Cd-rap in pituitary cells.

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Chieffi, Paolo, Sabrina Battista, Marco Barchi, Silvia Di Agostino, Giovanna Maria Pierantoni, Monica Fedele, Lorenzo Chiariotti, Donatella Tramontano i Alfredo Fusco. "HMGA1 and HMGA2 protein expression in mouse spermatogenesis". Oncogene 21, nr 22 (maj 2002): 3644–50. http://dx.doi.org/10.1038/sj.onc.1205501.

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Chung, Jaewook, Xia Zhang, Bruce Collins, Renan B. Sper, Katherine Gleason, Sean Simpson, Sehwon Koh i in. "High mobility group A2 (HMGA2) deficiency in pigs leads to dwarfism, abnormal fetal resource allocation, and cryptorchidism". Proceedings of the National Academy of Sciences 115, nr 21 (7.05.2018): 5420–25. http://dx.doi.org/10.1073/pnas.1721630115.

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Expression of HMGA2 is strongly associated with body size and growth in mice and humans. In mice, inactivation of one or both alleles of Hmga2 results in body-size reductions of 20% and 60%, respectively. In humans, microdeletions involving the HMGA2 locus result in short stature, suggesting the function of the HMGA2 protein is conserved among mammals. To test this hypothesis, we generated HMGA2-deficient pigs via gene editing and somatic cell nuclear transfer (SCNT). Examination of growth parameters revealed that HMGA2−/+ male and female pigs were on average 20% lighter and smaller than HMGA2+/+ matched controls (P < 0.05). HMGA2−/− boars showed significant size reduction ranging from 35 to 85% of controls depending on age (P < 0.05), and organ weights were also affected (P < 0.05). HMGA2−/+ gilts and boars exhibited normal reproductive development and fertility, while HMGA2−/− boars were sterile due to undescended testes (cryptorchidism). Crossbreeding HMGA2−/+ boars and gilts produced litters lacking the HMGA2−/− genotype. However, analysis of day (D) D40 and D78 pregnancies indicated that HMGA2−/− fetuses were present at the expected Mendelian ratio, but placental abnormalities were seen in the D78 HMGA2−/− concepti. Additionally, HMGA2−/− embryos generated by gene editing and SCNT produced multiple pregnancies and viable offspring, indicating that lack of HMGA2 is not lethal per se. Overall, our results show that the effect of HMGA2 with respect to growth regulation is highly conserved among mammals and opens up the possibility of regulating body and organ size in a variety of mammalian species including food and companion animals.

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Bai, Jie, Sho Kubota, Takako Yokomizo, Akinori Kanai, Yuqi Sun, Mihoko Iimori, Hironori Harada, Naomi Nakagata, Atsushi Iwama i Goro Sashida. "Hmga2 Functions As an Oncogene upon the Deletion of Tet2 and Promotes the Pathogenesis of Myelodysplastic Syndrome". Blood 134, Supplement_1 (13.11.2019): 3782. http://dx.doi.org/10.1182/blood-2019-127583.

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High Mobility Group AT-hook 2 (HMGA2) is a chromatin modifier and its overexpression has been found in a subset of patients with myelodysplastic syndrome (MDS). The high level of HMGA2 expression appears to predict poor prognosis in various tumors; however, it remains unclear how HMGA2 dysregulates expression of target genes to facilitate the transformation. To elucidate the mechanisms by which the overexpression of Hmga2 promotes the development of MDS, we generated an Hmga2-expressing Tet2-deficient (Hmga2-Tet2Δ/Δ) mouse model showing the progressive phenotype of MDS. We found that Hmga2-Tet2Δ/Δ mice had neutropenia and anemia, but variable platelet counts, accompanied by elevated frequencies of mutant cells in myeloid cells. Hmga2-Tet2Δ/Δ mice showed a similar median survival to Tet2Δ/Δ mice (274 days vs 290 days), but shorter survival than Hmga2-Tet2wt/wt mice (274 days vs undetermined). Moribund Hmga2-Tet2Δ/Δ mice showed progressive leukopenia and anemia, accompanied by the emergence of dysplastic neutrophils, myeloblasts and anisocytosis in the PB and BM and dysplastic megakaryocytes in the BM. Hmga2-Tet2Δ/Δ mice had mildly increased spleen weights, and expanded myeloid cells and HSPCs in the spleen without the deposition of fibrosis. During a 12-month observation, we found that Hmga2-Tet2Δ/Δ mice developed lethal MDS/MPN overlap disease (47%), MDS (33%), MPN (13%), and AML (7%), while 6 out of 11 Tet2Δ/Δ mice developed MPN (55%). Hmga2-Tet2wt/wt mice subsequently showed similar blood counts in PB and died without the expansion of leukemic or dysplastic blood cells. Therefore, Hmga2 overexpression did not transform wild-type HSCs but promoted the development of MDS in the absence of Tet2 in vivo. In order to elucidate the molecular mechanisms underlying the transformation of Hmga2-Tet2Δ/Δ cells, we initially performed gene expression profiling by a RNA sequencing analysis in LSK HSPCs isolated from WT, Hmga2-Tet2wt/wt, Tet2Δ/Δ, and Hmga2-Tet2Δ/Δ mice at a pre-disease stage and those isolated from two Hmga2-Tet2Δ/Δ MDS/MPN and AML mice. Hmga2-Tet2Δ/Δ leukemic cells were placed closer to one out of two Hmga2-Tet2Δ/Δ cells at the pre-disease stage, but clearly apart from the other genotype cells, indicating that Hmga2 overexpression and Tet2 loss result in the accumulation of alterations in the transcriptional program during the development of MDS.In order to clarify the mechanisms by which the overexpression of Hmga2 alters the transcriptional program in Tet2-deficient cells, we performed the ChIP-sequencing of FLAG-tagged Hmga2 in bone marrow progenitor cells isolated from WT, Hmga2-Tet2wt/wt, and Hmga2-Tet2Δ/Δ mice. The numbers of Hmga2-binding peaks were markedly lower in Tet2-deficient cells than in Hmga2-Tet2wt/wt cells (2227 peaks versus 11500 peaks). Furthermore, annotated genes adjacent to Hmga2-binding sites partially overlapped in both genotype cells, whereas 2965 out of 3843 genes identified in Tet2 wild-type cells lost the binding peaks of Hmga2 upon the deletion of Tet2. Based on the DNA-binding capacity of Hmga2, the loss of Tet2 remodeled the binding sites of Hmga2 via change in DNA methylation in Hmga2-binding flanking regions, which were not observed in the presence of Tet2, leading to significant enrichments in genes involved in cell-to-cell adhesion and cell morphogenesis in Hmga2-Tet2Δ/Δ cells. Furthermore, we found that the overexpression of Hmga2 and loss of Tet2 resulted in the activation of oncogenic pathways (e.g. TGF-b, TNF-a), but suppressed the expression of genes in the unfolded protein response. Notably, the inhibition of bile acid metabolism to reactivate the unfolded protein response markedly attenuated the proliferation of Hmga2-Tet2Δ/Δ cells. These combinatory effects on the transcriptional program and cellular functions were not redundant to those in either single mutant cell, supporting Hmga2 being a proto-oncogene because its overexpression alone was not sufficient to develop MDS in vivo. Thus, Hmga2 overexpression exerts synergistic, but also gain-of-function effects with the loss of Tet2 to target these key biological pathways and promotes the transformation of Tet2-deficient stem cells. This study also provides a new rationale for targeting the unfolded protein response in MDS cells expressing HMGA2. Disclosures No relevant conflicts of interest to declare.

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Wu, Yue, Xue Wang, Feifei Xu, Lu Zhang, Tianjiao Wang, Xueli Fu, Tianzhi Jin, Weiying Zhang i Lihong Ye. "The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt–PCAF pathway in promotion of esophageal squamous cell carcinoma growth". Nucleic Acids Research 48, nr 9 (20.04.2020): 4858–76. http://dx.doi.org/10.1093/nar/gkaa232.

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Abstract High-mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that plays essential roles in embryonic development and cancer progression. However, the mechanism of HMGA2 regulation remains largely uncharacterized. Here, we demonstrate that HMGA2 can be modulated by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, in esophageal squamous cell carcinoma (ESCC). HMGA2 expression was positively associated with HBXIP expression in clinical ESCC tissues, and their high levels were associated with advanced tumor stage and reduced overall and disease-free survival. We found that oncogenic HBXIP could posttranslationally upregulate HMGA2 protein level in ESCC cells. HBXIP induced HMGA2 acetylation at the lysine 26 (K26), resulting in HMGA2 protein accumulation. In this process, HBXIP increased the acetyltransferase p300/CBP-associated factor (PCAF) phosphorylation and activation via the Akt pathway, then PCAF directly interacted with HMGA2, leading to HMGA2 acetylation in the cells. HMGA2 K26 acetylation enhanced its DNA binding capacity and blocked its ubiquitination and then inhibited proteasome-dependent degradation. Functionally, HBXIP-stabilized HMGA2 could promote ESCC cell growth in vitro and in vivo. Strikingly, aspirin suppressed ESCC growth by inhibiting HBXIP and HMGA2. Collectively, our findings disclose a new mechanism for the posttranslational regulation of HMGA2 mediated by HBXIP in ESCC.

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Kubota, Sho, Yuqi Sun, Jie Bai, Takako Yokomizo-Nakano, Mariko Morii, Takako Ideue, Motomi Osato, Terumasa Umemoto, Kimi Araki i Goro Sashida. "HMGA2 Maintains Hematopoietic Stem Cell Via Pleiotropic Regulation of the Transcription in Stress Conditions". Blood 138, Supplement 1 (5.11.2021): 3262. http://dx.doi.org/10.1182/blood-2021-152472.

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Abstract High-mobility group AT-hook 2 (Hmga2), an epigenetic modifier, opens the chromatin and modulate the transcription. Hmga2 is highly expressed in fetal and adult hematopoietic stem cells (HSCs). Hmga2 over-expression has been shown to promote self-renewal of HSC, however the molecular mechanism of how Hmga2 enhanced the self-renewal of HSC is still unclear. In this study, we assessed the function of Hmga2 in HSCs in steady and stress conditions by utilizing new Hmga2 conditional knock-in (KI) mouse and Hmga2 conditional knock-out mouse, which were crossed with either Cre-ERT2 mouse or Vav1-iCre mouse. Hmga2 KI mice showed a mild elevation in platelet counts, but did not develop malignancies in one year observation period. We performed a competitive transplantation assay by using purified HSCs, and found that wild-type HSCs diminished the repopulating capacity at the tertiary transplantation, Hmga2 KI HSCs maintained higher chimerism in myeloid cells and platelets in the PB and HSCs in the BM. We found that Hmga2 KO cells reduced the repopulating capacity, compared to wild-type cells. Thus, the expression of Hmga2 is critical for the self-renewal of HSC upon the transplantation. By performing RNA-sequencing of HSCs in homeostatic condition, we found that Hmga2 KI HSCs showed positive enrichments in cell cycle and proliferative signature, but maintained a stem cell signature, compared to wild-type HSCs. Since Hmga2 has been shown to globally open the chromatin in neural stem cells, we performed ATAC-sequence analysis in HSCs. Notably, Hmga2 KI HSCs showed 539 opened and 387 closed chromatin in H3K27ac-marked active regulatory regions, compared to wild-type HSCs. Among these opened genes by Hmga2, we generated a virus vector for fifteen genes, which were highly expressed in Hmga2 KI HSCs, and found that ectopic expression of Igf2bp2, an RNA binding protein, increased self-renewal capacity of HSC, but did not induce the enhanced production of myeloid cells and platelets that were observed in Hmga2 KI cells, in in vitro and in vivo settings. Indeed, Hmga2-ChIP-sequencing revealed that Hmga2 was directly bound to a proximal region of the Igf2bp2 gene, and CRISPR/Cas9-mediated deletion of the Igf2bp2 gene canceled the enhanced self-renewal capacity of Hmga2 KI HSCs, indicating that the Hmga2-Igf2bp2 axis is critical for the self-renewal of HSC. We next assessed function of Hmga2 in stress hematopoiesis after in vivo treatment of 5-FU. Hmga2 KI mice showed faster recoveries of reduction of platelets in the PB and increased CD41+HSCs and megakaryocyte progenitors in the BM in twelve days, in which WT mice reduced numbers of those cells in this condition. RNA-sequencing revealed that Hmga2 KI HSCs maintained expression levels of genes in stem cell- and proliferation-signatures at 3 days and 6 days post 5-FU injection, compared to WT HSCs that reduced expression of stem cell genes but activated inflammatory response genes. In contrast, Hgma2 KO HSCs enhanced expression of inflammatory response genes post the 5-FU injection, indicating Hmga2 represses expression of inflammatory response genes in the stress condition. Indeed, Hmga2-ChIP-sequencing revealed that Hmga2 was bound to larger numbers of genes involved in inflammatory responses in Kit+ cells post the 5-FU treatment from those in the control cells. Given increased expression of and a post-translational modification of Hmga2 protein in Kit+ cells post the 5-FU treatment, the remodeling of Hmga2 binding regions was appeared to depend on the modification of Hmga2 at downstream of the stress signal. Thus, Hmga2 directly activates Igf2bp2 to enhance the self-renew of HSC, but also represses the inflammatory response, leading to the enhanced megakaryopoiesis in the stress condition. Disclosures No relevant conflicts of interest to declare.

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Kao, Chun-Yu, Pei-Ming Yang, Ming-Heng Wu, Chi-Chen Huang, Yi-Chao Lee i Kuen-Haur Lee. "Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells". PeerJ 4 (11.02.2016): e1683. http://dx.doi.org/10.7717/peerj.1683.

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High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.

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Mansoori, Behzad, Mikkel Green Terp, Ali Mohammadi, Christina Bøg Pedersen, Henrik Jørn Ditzel, Behzad Baradaran i Morten Frier Gjerstorff. "HMGA2 Supports Cancer Hallmarks in Triple-Negative Breast Cancer". Cancers 13, nr 20 (16.10.2021): 5197. http://dx.doi.org/10.3390/cancers13205197.

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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that exhibits a high proliferation rate and early metastasis leading to a poor prognosis. HMGA2 is a DNA binding transcriptional regulator implicated in tumorigenesis. Here, we demonstrate that the HMGA2 promoter is demethylated in TNBC tumors, leading to increased expression of HMGA2 at both mRNA and protein levels. Importantly, high HMGA2 levels in TNBC tumors are correlated with poor prognosis. To detail the role of HMGA2 in TNBC development and progression, we studied its effect on core cancer phenotypes. Stable knockdown of HMGA2 in TNBC cells revealed that HMGA2 may support cell proliferation, cell migration and invasion. In addition, HMGA2 knockdown decreased cancer stem cell (CSC) features. Importantly, we found that silencing HMGA2 inhibited NF-kB signaling and lead to decreased expression of the downstream molecules IL-6 and IL-8 and reduced STAT3 pathway activation. Our results demonstrate that HMGA2 supports cancer hallmarks in TNBC and may represent a promising target for TNBC treatment.

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Pierantoni, Giovanna Maria, Palma Finelli, Emanuele Valtorta, Daniela Giardino, Ornella Rodeschini, Francesco Esposito, Marco Losa, Alfredo Fusco i Lidia Larizza. "High-mobility group A2 gene expression is frequently induced in non-functioning pituitary adenomas (NFPAs), even in the absence of chromosome 12 polysomy". Endocrine-Related Cancer 12, nr 4 (grudzień 2005): 867–74. http://dx.doi.org/10.1677/erc.1.01049.

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The high-mobility group A2 (HMGA2) gene has a critical role in benign tumors where it is frequently rearranged, and in malignant tumors, where it is overexpressed in the absence of structural modification of the HMGA2 locus. By previous fluorescence in situ hybridization (FISH) and reverse transcriptase PCR analyses on human prolactin-secreting pituitary adenomas we detected rearrangement of the HMGA2 gene and amplification of its native region associated with activated expression. These data indicated a role for the HMGA2 gene in the development of human pituitary prolactinomas, since they are consistent with the appearance of prolactin/growth hormone adenomas in transgenic mice overexpressing the HMGA2 gene. To assess a more general role for HMGA2 in pituitary oncogenesis, we investigated HMGA2 amplification and expression in a panel of non-functioning pituitary adenomas (NFPAs) which account for 25% of all pituitary adenomas. We provide evidence that out of 18 NFPA tumors tested, 12 expressed HMGA2, but, different from prolactinomas, only in two cases the upregulation of the gene could be associated with amplification and/or rearrangement of the HMGA2 locus. Increased dosage of chromosome 12 was found in the expressing and non-expressing NFPAs, confirming that this sole event is insufficient to drive up activation of the HMGA2 gene. A role for chromosome 12 polysomy to promote structural instability of HMGA2 is confirmed, but the mechanism via trisomy is less prevalent in the frequently diploid NFPAs than in the usually hyperdiploid prolactinomas. Micro-rearrangements of HMGA2 gene not detectable by FISH analysis and/or sequence alterations could contribute to upregulation of HMGA2 gene in pituitary adenomas of the NFPA subtype. However, it cannot be excluded that the HMGA2 overexpression may be due, in some NFPA patients, to the same, still mainly unknown, mechanisms responsible for HMGA2 overexpression in malignant neoplasias.

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Leung, Chou, Huang i Yang. "An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer". Cancers 11, nr 10 (2.10.2019): 1482. http://dx.doi.org/10.3390/cancers11101482.

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Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

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Hwang, Bor-Jang, Mojisoluwa Awolowo, Taaliah Campbell, Ohuod Hawsawi, Sharon Harrison, Denise Gibbs, Camille Ragin i Valerie Odero-Marah. "Abstract C017: Detection of wild-type and truncated HMGA2 in prostate cancer tissues using RNA in situ hybridization". Cancer Epidemiology, Biomarkers & Prevention 32, nr 1_Supplement (1.01.2023): C017. http://dx.doi.org/10.1158/1538-7755.disp22-c017.

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Abstract High mobility group A2 (HMGA2), a non-histone protein, is known to promote epithelial-mesenchymal transition (EMT), which plays a critical role in prostate cancer progression and metastasis. Both full-length HMGA2 (WT-HMGA2) and truncated (lacking the 3’UTR) HMGA2 (TR-HMGA2) isoforms are overexpressed in several cancers such as lung carcinomas, ovarian cancer, breast cancer, and gastric cancer. However, there is no study investigating the expression and differential roles of WT vs truncated HMGA2 isoforms in prostate cancer. Our previous results indicated that the overexpression of HMGA2 in LNCaP cells increased cell viability and migration for both wild-type and truncated HMGA2. Promotion of EMT was observed in wild-type, but not truncated HMGA2. Reactive oxygen species (ROS) levels were increased with truncated HMGA2 more than wild-type HMGA2. Therefore, wild-type and truncated HMGA2 may play different roles on cancer progression and metastasis. The goal of this study is to examine the expression of wild-type vs. truncated HMGA2 in prostate cancer patient tissue. We have developed a way to detect location and expression of wild-type and truncated HMGA2 using RNA in situ hybridization (RISH). The specific probes’ hybridization followed by a serial signal amplification process allows us to locate and quantify the HMGA2 isoforms in Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens from cancer patients. Several prostate tissue samples and a prostate cancer tissue microarray that includes 35 patients from different races, stages of cancer, and metastasis status was analyzed. Our results showed increased HMGA2 expression (both wild-type and truncated) in several prostate cancer samples with higher stage cancer. We also observed that most wild-type and truncated HMGA2 is located within the nucleus, while some wild-type isoforms were detected within the cytoplasm. We will further quantify the expression levels to examine whether they are associated with tumor stage and/or race. These studies are the first to examine HMGA2 isoform expression and localization in prostate patient tissue and may offer novel therapeutic intervention strategies based on HMGA2 isoform expression. Citation Format: Bor-Jang Hwang, Mojisoluwa Awolowo, Taaliah Campbell, Ohuod Hawsawi, Sharon Harrison, Denise Gibbs, Camille Ragin, Valerie Odero-Marah. Detection of wild-type and truncated HMGA2 in prostate cancer tissues using RNA in situ hybridization [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C017.

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Gaudreau-Lapierre, Antoine, Thomas Klonisch, Hannah Nicolas, Thatchawan Thanasupawat, Laura Trinkle-Mulcahy i Sabine Hombach-Klonisch. "Nuclear High Mobility Group A2 (HMGA2) Interactome Revealed by Biotin Proximity Labeling". International Journal of Molecular Sciences 24, nr 4 (20.02.2023): 4246. http://dx.doi.org/10.3390/ijms24044246.

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The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) has important functions in chromatin remodeling, and genome maintenance and protection. Expression of HMGA2 is highest in embryonic stem cells, declines during cell differentiation and cell aging, but it is re-expressed in some cancers, where high HMGA2 expression frequently coincides with a poor prognosis. The nuclear functions of HMGA2 cannot be explained by binding to chromatin alone but involve complex interactions with other proteins that are incompletely understood. The present study used biotin proximity labeling, followed by proteomic analysis, to identify the nuclear interaction partners of HMGA2. We tested two different biotin ligase HMGA2 constructs (BioID2 and miniTurbo) with similar results, and identified known and new HMGA2 interaction partners, with functionalities mainly in chromatin biology. These HMGA2 biotin ligase fusion constructs offer exciting new possibilities for interactome discovery research, enabling the monitoring of nuclear HMGA2 interactomes during drug treatments.

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Ueda, Koki, Kazuhiko Ikeda, Kazuei Ogawa, Akiko Shichishima-Nakamura, Kotaro Shide, Kazuya Shimoda, Yuko Hashimoto, Philip J. Mason, Monica Bessler i Yasuchika Takeishi. "Expression of HMGA2 Collaborates with JAK2V617F to Progress Myeloproliferative Neoplasms". Blood 126, nr 23 (3.12.2015): 482. http://dx.doi.org/10.1182/blood.v126.23.482.482.

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Abstract Myeloproliferative neoplasms (MPN) are characterized by chronic proliferation of myeloid cells, extramedullary hematopoiesis and occasional leukemic transformation. Mutations in JAK2, CALR and MPL have been established as drivers of myeloproliferative phenotype, but their roles in disease progression with clonal expansion remain unclear. In addition, studies have shown mutations in epigenetic modifiers including TET2, DNMT3A, ASXL1 and EZH2, and aberrant expressions of microRNAs in MPN, but downstream of these changes is also largely unknown. Recently, we showed high expression of HMGA2 mRNA partly correlated with reduced microRNA let-7 in granulocytes of patients with MPN, including 100% patients with primary myelofibrosis (MF) and 20% polycythemia vera and essential thrombocythemia (Harada-Shirado et al, Brit J Haematol, 2015). In mice, loss of epigenetic modifiers such as BMI1 and EZH2, along with the Arf/Ink4a knockout (Oguro et al, J Exp Med, 2012) or the JAK2 V617F (Sashida et al, ASH, 2013), leads to overexpression of HMGA2 with accelerating MPN. We have generated transgenic (Tg) mice of Hmga2 cDNA with truncated 3'UTR (ΔHmga2) lacking binding sites of let-7 thatrepresses expression of HMGA2 (Ikeda et al, Blood, 2011). Δ Hmga2 mice overexpress HMGA2 and develop MPN-like disease, and represent a clonal advantage in competitive repopulations with serial bone marrow (BM) transplants (BMT). Here, to clarify if HMGA2 affect JAK2 V617F+ hematopoiesis, we crossed Δ Hmga2+/- mice with JAK2 V617F+/- Tg mice (Shide et al, Leukemia, 2008). Δ Hmga2-/-JAK2 V617F-/- wild type (WT), Δ Hmga2+/-JAK2 V617F-/- (Δ Hmga2 -Tg), Δ Hmga2-/-JAK2 V617F+/- (JAK2 V617F-Tg) and Δ Hmga2+/-JAK2 V617F+/- (double-Tg) mice were born at expected Mendelian ratios and we could analyze 5 - 6 of each. At 3 months old, leukocytosis, thrombocytosis, anemia and splenomegaly were most severe in double-Tg compared with JAK2 V617F-Tg or Δ Hmga2 -Tg mice. Relative to WT, peripheral leukocyte and platelet counts were nearly 16- and 4-fold higher in double-Tg, while 3- and 2-fold higher in JAK2 V617F-Tg mice, respectively. Mean spleen weights were 0.067, 0.10, 0.83 and 2.8 g in WT, Δ Hmga2 -Tg, JAK2 V617F-Tg and double-Tg mice, while BM cell counts were 2.4, 2.8, 0.4 and 1.2 x 107/femur, respectively. However, JAK2 V617F-Tg and double-Tg equally showed MF whereas no MF was detected in WT and DHmga2-Tg, suggesting that HMGA2 partly recovers cellularity in fibrotic BM. In the absence and presence of JAK2 V617F, HMGA2 augments lineage- Sca1+ Kit+ cells (WT: Δ Hmga2-Tg: JAK2 V617F-Tg: double-Tg= 0.17%: 0.19%: 0.17%: 0.27% in BM cells), endogenous erythroid colonies (1: 11: 13: 21 CFU-E/104 BM cells) and CD71+ Ter119+ erythroblasts (23%: 29%: 5.7%: 10% in BM and 2.0%: 4.4%: 7.9%: 16% in spleen cells), indicating HMGA2 contributes to expansion of hematopoietic stem/progenitor cells (HSPC) and erythroid commitment in JAK2 V617F+ hematopoiesis. Most Δ Hmga2-Tg and JAK2 V617F-Tg survived for over one year, but all double-Tg mice died within 4 months after birth due to severe splenomegaly and MF with no acute leukemia. To study the effect of HMGA2 on JAK2 V617F+ HSPC activity, we performed BMT with 0.25 x 106 Ly5.2+Δ Hmga2-Tg, JAK2 V617F-Tg or double-Tg cells with 0.75 x 106 Ly5.1+ competitor WT cells to lethally irradiated Ly5.1+ WT mice. Proportions of Ly5.2+ cells were higher in recipients of Δ Hmga2 -Tg than double-Tg cells, while JAK2 V617F-Tg cells were almost rejected at 8 weeks after BMT. To confirm role of HMGA2 without let-7 repression in JAK2 V617F+ hematopoiesis, we performed another BMT with 1 x 104 KIT+ cells of JAK2 V617F-Tg mice transduced with retroviral vector of Hmga2 with each let-7 -site-mutated full-length 3'UTR (Hmga2-m7) to sublethally irradiated WT mice. Recipients of JAK2 V617F-Tg cells with Hmga2-m7 developed MPN-like disease, whereas donor cells were rejected in recipients of JAK2 V617F cells with empty vector. In conclusion, HMGA2 may play a crucial role in hematopoiesis harboring JAK2 V617F by expanding HSPC, leading to disease progression. Disclosures No relevant conflicts of interest to declare.

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de Vasconcellos, Jaira F., Y. Terry Lee, Colleen Byrnes, Laxminath Tumburu, Antoinette Rabel i Jeffery L. Miller. "Erythroid-Expression of HMGA2 Increases Fetal Hemoglobin in Human Adult Erythroblasts". Blood 126, nr 23 (3.12.2015): 2161. http://dx.doi.org/10.1182/blood.v126.23.2161.2161.

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Abstract HMGA2 is a member of the high-mobility group A family and plays a role in the regulation of gene transcription and chromatin structure. HMGA2 is a validated target of the let-7 family of miRNAs. Let-7 miRNAs are highly regulated in erythroid cells during the fetal-to-adult developmental transition (1). Recent studies demonstrated that the LIN28 -let-7 axis mediated up-regulation of fetal hemoglobin (HbF) expression to >30% of the total globin levels in cultured erythroblasts from adult humans (2) and the amelioration of hypoxia-related sickling of cultured mature erythrocytes from pediatric patients with sickle cell disease (3). Interestingly, increased expression of endogenous HbF in a patient receiving gene therapy was also associated with truncated HMGA2 protein expression after lentiviral integration and disruption of let-7 targeting at the HMGA2 gene locus (4). Therefore, we hypothesized that HMGA2 may be involved in fetal hemoglobin regulation as a downstream target of the let-7 miRNAs. To study the effects of HMGA2 upon erythropoiesis and globin expression, lentiviral constructs were designed for let-7 resistant expression of HMGA2 driven by the erythroid-specific gene promoter region of the human SPTA1 gene (HMGA2 -SPTA1-OE), with a matched empty vector control. Transductions were performed in CD34+ cells from four adult healthy volunteers cultivated ex vivo in erythropoietin-supplemented serum-free media for 21 days. Overexpression of HMGA2 was confirmedby Q-RT-PCR (control: below detection limits; HMGA2 -SPTA1-OE: 2.51E+04 ± 3.44E+04 copies/ng) and Western blot analyses at culture day 14. Cell counting revealed no significant changes between HMGA2 -SPTA1-OE and control (empty vector) transductions at culture day 14. Terminal maturation with loss of CD71 from the erythroblast cell surface and enucleation assessed by thiazole orange staining were analyzed in the control and HMGA2 -SPTA1 -OE samples at the end of the culture period. Globin genes expression levels were evaluated for HMGA2 -SPTA1-OE by Q-RT-PCR. HMGA2 -SPTA1-OE caused a significant increase in gamma-globin mRNA expression levels compared to controls (control: 5.02E+05 ± 8.62E+04 copies/ng; HMGA2 -SPTA1-OE: 1.45E+06 ± 7.31E+05 copies/ng; p=0.037). Consistent with the increase in gamma-globin mRNA levels, HPLC analyses at culture day 21 demonstrated modest but significant increases in HbF levels in HMGA2 -SPTA1-OE compared to controls (HbF control: 5.41 ± 2.15%; HMGA2 -SPTA1-OE: 16.53 ± 4.43%; p=0.006). Possible effect(s) and downstream mechanism(s) triggered by HMGA2 -SPTA1-OE were investigated. Q-RT-PCR analyses demonstrated no significant changes in the let-7 family of miRNAs in HMGA2 -SPTA1-OE compared to controls. Expression patterns of several transcription factors such as BCL11A, KLF1, SOX6 and GATA1 were investigated by Q-RT-PCR and no significant changes were detected in HMGA2 -SPTA1-OE compared to controls. While BCL11A mRNA levels were decreased by HMGA2 -SPTA1 -OE, the differences did not reach statistical significance (control: 4.26E+02 ± 8.18E+01 copies/ng; HMGA2 -SPTA1 -OE: 2.84E+02 ± 1.48E+02 copies/ng; p=0.104). However, nuclear BCL11A protein levels assessed by Western analysis were suppressed in HMGA2 -SPTA1 -OE. In summary, these results demonstrate that HMGA2, a validated target of let-7 miRNAs, causes moderately increased gamma-globin gene and protein expression in human erythroblasts, and reduces levels of BCL11A protein. These data thus support the notion that suppression of let-7 miRNAs increases fetal hemoglobin, in part, by the targeting of erythroblast HMGA2 mRNA. (1) Noh SJ et al. J Transl Med. 7:98 (2009). (2) Lee YT et al. Blood. 122:1034-41 (2013). (3) Vasconcellos JF et al. PLoS One. 9:e106924 (2014). (4) Cavazzana-Calvo M et al. Nature. 467:318-22 (2010). Disclosures No relevant conflicts of interest to declare.

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Campos Gudiño, Rubi, Kirk J. McManus i Sabine Hombach-Klonisch. "Aberrant HMGA2 Expression Sustains Genome Instability That Promotes Metastasis and Therapeutic Resistance in Colorectal Cancer". Cancers 15, nr 6 (13.03.2023): 1735. http://dx.doi.org/10.3390/cancers15061735.

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Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, metastatic CRC, where 5-year survival rates drop to 6–13% and treatment options are limited. Genome instability is an enabling hallmark of cancer that confers increased acquisition of genetic alterations, mutations, copy number variations and chromosomal rearrangements. In that regard, research has shown a clear association between genome instability and CRC, as the accumulation of aberrations in cancer-related genes provides subpopulations of cells with several advantages, such as increased proliferation rates, metastatic potential and therapeutic resistance. Although numerous genes have been associated with CRC, few have been validated as predictive biomarkers of metastasis or therapeutic resistance. A growing body of evidence suggests a member of the High-Mobility Group A (HMGA) gene family, HMGA2, is a potential biomarker of metastatic spread and therapeutic resistance. HMGA2 is expressed in embryonic tissues and is frequently upregulated in aggressively growing cancers, including CRC. As an architectural, non-histone chromatin binding factor, it initiates chromatin decompaction to facilitate transcriptional regulation. HMGA2 maintains the capacity for stem cell renewal in embryonic and cancer tissues and is a known promoter of epithelial-to-mesenchymal transition in tumor cells. This review will focus on the known molecular mechanisms by which HMGA2 exerts genome protective functions that contribute to cancer cell survival and chemoresistance in CRC.

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Mansoori, Behzad, Ali Mohammadi, Henrik J. Ditzel, Pascal H. G. Duijf, Vahid Khaze, Morten F. Gjerstorff i Behzad Baradaran. "HMGA2 as a Critical Regulator in Cancer Development". Genes 12, nr 2 (13.02.2021): 269. http://dx.doi.org/10.3390/genes12020269.

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The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes.

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Campbell, Taaliah, Ohuod Hawsawi, Nathan Bowen i Valerie Odero-Marah. "Abstract 113: Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells". Cancer Research 82, nr 12_Supplement (15.06.2022): 113. http://dx.doi.org/10.1158/1538-7445.am2022-113.

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Abstract Prostate cancer (PCa) is one of the most commonly diagnosed malignancies among men worldwide and remains the second leading cause of cancer related death in the United States. Oxidative stress has been shown to be increase in several cancers including prostate cancer. In fact, oxidative stress in prostate cancer is suggested to be a direct result of cell exposure to reactive oxygen species (ROS). High mobility group A 2 (HMGA2), a non-histone protein, is an oncogene that is up-regulated in several cancers. This protein has ability to undergo chromosomal rearrangement and alternative splicing, causing its full length/wild type HMGA2 (HMGA2-WT) to become the truncated losing its 3’UTR leading to the generation of HMGA2 truncated (HMGA2-TR). We have previously shown HMGA2-WT’s involvement in epithelial mesenchymal transition (EMT), however, the functional role of HMGA2-TR has not yet been dissected. We hypothesize that truncated HMGA2’s involvement with oxidative stress leads to prostate cancer progression. We analyzed the baseline expression of wild-type vs.truncated HMGA2 in prostate patient tissue and cells lines by real-time PCR and western blot analyses. Prostate cancer patient tissue and some cell lines expressed increasing amounts of both wild-type and truncated HMGA2with increasing tumor grade, when compared to normal epithelial cells. RNA-Seq analysis of LNCaP prostate cancer cells stably overexpressing HMGA2-WT, HMGA2-TR, or empty vector (Neo) control revealed thatHMGA2-TR cells display increased oxidative stress compared to HMGA2-WT or Neo control cells. This was also confirmed by analysis of basal reactive oxygen species (ROS) levels, and the ratio of GSH/GSSG andNADP/NADPH utilizing metabolomics. Additionally, proteomic analysis showed that HMGA2-TR protein interacted with several proteins, including a cytoplasmic stress granule protein G3BP1 that responds to oxidative stress. Transient knockdown of G3BP1 increased ROS in HMGA2-TR cells. These studies may therefore uncover novel role for truncated HMGA2 in oxidative stress. Acknowledgements: These studies were supported by the NIH/NIMHD/RCI Grant #5G12MD007590-31,NIH/NIGMS/RISE Grant #5R25GM060414 Citation Format: Taaliah Campbell, Ohuod Hawsawi, Nathan Bowen, Valerie Odero-Marah. Investigating the role of high mobility group a2 (HMGA2) truncated isoform in promoting oxidative stress in PCa cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 113.

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Minakawa, Keiji, Koki Ueda, Akiko Shichishima, Hiroshi Ohkawara, Kazuei Ogawa, Takayuki Ikezoe, Yayoi Shikama, Kenneth E. Nollet i Kazuhiko Ikeda. "HMGA2 mRNA Expression in Patients with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)". Blood 132, Supplement 1 (29.11.2018): 4384. http://dx.doi.org/10.1182/blood-2018-99-114399.

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Abstract MDS/MPN comprise a group of uncommon myeloid neoplasms with clinical and hematological features overlapping MDS and MPN. Pathogenesis remain elusive. HMGA2 on chromosome 12q plays a crucial role in self-renewal and proliferation of fetal hematopoietic stem cells (HSCs), but not adult HSCs because of repression by binding of MIRLET-7 with the 3'-untranslated region (3'UTR) of HMGA2 (Copley et al, Nat Cell Biol, 2013). Trimethylation of histone H3 at lysine 27, which is catalyzed by EZH2 - a member of polycomb recessive complex 2 (PRC2) - also suppresses HMGA2 (Sashida et al, JEM, 2016). We have demonstrated that expression of Hmga2 cDNA lacking 3'UTR caused proliferative hematopoiesis mimicking MPN in young mice and led to anemia with ineffective erythropoiesis and leukocytosis like MDS/MPN in old mice (Ikeda et al, Blood, 2011; Ueda et al, Blood Adv, 2017), suggesting that HMGA2 may contribute to the pathogenesis of MDS/MPN. In fact, we found high HMGA2 mRNA levels in granulocytes of MPN including >90% of patients with myelofibrosis (MF) and about 30% with essential thrombocythemia (ET), and either reduced MIRLET-7c levels or PRC2-related mutations were correlated with high HMGA2 mRNA in MF, while reduced MIRLET-7c with no particular mutation was correlated with high HMGA2 mRNA in ET (Harada-Shirado et al, BJH, 2015; Blood Adv, 2017). However, in MDS/MPN, only one case series has reported high HMGA2 mRNA due to the 12q rearrangement that removed the 3'UTR of HMGA2 in a few patients (Odero et al, Leukemia, 2005). So far, expression of HMGA2 has not been studied in MDS/MPN without the 12q rearrangement. To clarify the expression of HMGA2 in MDS/MPN in relation to clinical and other genetic findings, we investigated HMGA2 mRNA and MIRLET-7c levels by real-time RT-PCR and sought PRC2-related mutations by targeted deep sequencing in peripheral leukocytes of 11 patients with MDS/MPN [5 chronic myelomonocytic leukemia (CMML), 2 atypical chronic myeloid leukemia (aCML), and 4 unclassifiable MDS/MPN (MDS/MPN-u)]. In addition, to identify the features specific for MDS/MPN, we also evaluated 10 patients with low-risk MDS [MDS with multilineage dysplasia (MDS-MLD)]. No MDS/MPN or MDS-MLD patients had 12q rearrangement. In MDS/MPN, high HMGA2 mRNA [>1.0 relative to HPRT1 mRNA above mean + 2SD of healthy volunteers, per our previous study (Blood Adv, 2017)] was found in each subtype: 2 of 5 (40%) in CMML, 1 of 2 (50%) in aCML, and 3 of 4 (75%) in MDS/MPN-u. Therefore, more than half of patients with MDS/MPN (6 of 11, 54.5%) showed high HMGA2 mRNA levels. In contrast, high HMGA2 mRNA was found in only 1 of 10 (10%) patients with MDS-MLD (P = 0.06). Reduction in MIRLET-7c was seen in 5 of 11 (45.5%) MDS/MPN and 3 of 10 (30.0%) MDS-MLD (P = 0.16). Among these 5 MDS/MPN patients with low MIRLET-7c, only 2 patients had high HMGA2 mRNA. Thus, MIRLET-7c reduction did not correlate with deregulation of HMGA2 mRNA in MDS/MPN as frequently as in MPN. In contrast, HMGA2 mRNA levels were high in all 3 patients with MDS/MPN carrying EZH2 mutations, suggesting that loss of EZH2 might augment HMGA2 in MDS/MPN. Laboratory findings of MDS/MPN patients with high HMGA2 mRNA were not different from those without high HMGA2 mRNA. However, MDS/MPN patients with both high HMGA2 mRNA and an EZH2 mutation showed more severe anemia compared with those with high HMGA2 mRNA without an EZH2 mutation (hemoglobin level: 9.6±2.0 vs. 11.0±2.3 g/dL, P = 0.05). In conclusion, we demonstrated that MDS/MPN cases highly express HMGA2 mRNA even without 12q rearrangement, more often than MDS-MLD. Unlike MPN, HMGA2 mRNA levels did not correlate with reduced MIRLET-7c, but probably with mutations in EZH2, which may also contribute to anemia in MDS/MPN. Disclosures No relevant conflicts of interest to declare.

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Dike, Precious Elechi, Taaliah Campbell, Mojisoluwa Awolowo i Valerie Odero-Marah. "Abstract 1562: HMGA2 regulates GPX4 expression and oxidative stress". Cancer Research 84, nr 6_Supplement (22.03.2024): 1562. http://dx.doi.org/10.1158/1538-7445.am2024-1562.

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Abstract Prostate cancer (PCa) is a leading cause of mortality, primarily due to its ability to metastasize to the bone. The High Mobility Group AT-Hook 2 (HMGA2) plays a crucial role in regulating gene expression and has been implicated in tumorigenesis and the metastatic process. Our recent study revealed that overexpression of the wild-type/full-length HMGA2 isoform in PCa cells promotes cancer progression by triggering epithelial mesenchymal transition (EMT), whereas truncated HMGA2 isoform promotes progression through oxidative stress signaling. We hypothesize that HMGA2 regulates GPX4 expression and oxidative stress in PCa. We studied the expression of HMGA2 and GPX4 in various PCa cell lines including enzalutamide resistant cell line (C4-2B MDVR), LNCaP cells overexpressing HMGA2 isoforms (wild type and truncated HMGA2). Our analysis of HMGA2 and GPX4 expression in diverse PCa cell lines, shows an inverse relationship between HMGA2 and GPX4 levels. Elevated HMGA2 expression coincides with reduced GPX4 expression, leading to heightened oxidative stress and susceptibility to ferroptosis. Moreover, treatment of enzalutamide resistant cell line C4-2B MDVR with ferroptosis inducer RSL3, further suppresses GPX4 expression, resulting in decreased cell proliferation. Our results unveils the intricate relationship between HMGA2, GPX4 regulation and oxidative stress in the context of prostate cancer progression. Exploiting this oxidative stress pathway offers a promising therapeutic approach for cancer treatment, especially for enzalutamide-resistant cancer cells. Acknowledgements: These studies were supported by NIH/NIGMS/RISE SR25GM060414 and NIH/NIMHD 2U54MD007590; 5U54MD013376. Citation Format: Precious Elechi Dike, Taaliah Campbell, Mojisoluwa Awolowo, Valerie Odero-Marah. HMGA2 regulates GPX4 expression and oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1562.

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Ueda, Koki, Kazuhiko Ikeda, Takayuki Ikezoe, Kazuei Ogawa, Yuko Hashimoto, Kayo Harada-Shirado, Hiroshi Ohkawara i in. "HMGA2 Orchestrates the Tumorgenesis of Myeloproliferative Neoplasms (MPN) in Corporation with JAK2V617F". Blood 128, nr 22 (2.12.2016): 796. http://dx.doi.org/10.1182/blood.v128.22.796.796.

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Abstract MPN harbors altered hematopoietic stem cell (HSC) function, resulting in skewed hematopoiesis and extramedullary hematopoiesis with splenomegaly. Mutations such as JAK2V617F and insertion/deletion of CALR exon9 have been established as phenotypic drivers of MPN. In addition, mutations in epigenetic modifiers and aberrant expressions of microRNAs play a crucial role in disease progression and clonal expansion. We have shown that almost all patients with myelofibrosis (MF) highly express HMGA2 (Harada-Shirado et al, BJH, 2015) and that transgenic mice expressing HMGA2 without 3'UTR including let7 binding sites (∆Hmga2 : H) (Ikeda et al, Blood, 2011) develop mild MPN. Moreover, we (Sashida et al, JEM, 2016) and other groups (Shimizu et al, JEM, 2016; Yang et al, Blood, 2016) showed that loss of EZH2 induces endogenous expression of HMGA2 and provokes severe MF in mice carrying JAK2V617F. Thus, we hypothesized that HMGA2 plays a central role in the disease progression of MPN. To clarify this, we generated ∆Hmga2/JAK2V617F transgenic mice (HJ), which developed severe leukocytosis, thrombocytosis, anemia, giant splenomegaly and shorter survival period, but did not progress fibrosis compared with transgenic mice carrying JAK2V617F alone (J) (Ueda et al, ASH, 2015). Compared with J, HJ also showed an increased bone marrow (BM) lineage-Sca1+Kit+(LSK) cells and growth advantage in competitive serial BM transplants. Encouraged by these findings, we further investigated the mechanism that HMGA2 exacerbates disease phenotype, and elucidated up-stream and down-stream factors of HMGA2. First, we sought cause of aggressive phenotypes. In BM cells of HJ mice, STAT3 and STAT5 were drastically upregulated in both expression and phosphorylation. Despite severer anemia, formations of EPO-independent erythroid colonies and proportions of CD71+Ter119+ erythroblasts in BM were not different between HJ and J. To explain this discrepancy, we measured spontaneous apoptosis. Erythroblasts were more susceptible to apoptosis in HJ as well as aged H, compared with J, suggesting that HMGA2 contributes to apoptosis under stressed condition. Next, we compared gene expression profiles of BM LSK cells between HJ and J by RNA sequence to seek genes altered by addition of HMGA2 expression to JAK2V617F. To clarify the role of endogenous expression of HMGA2 induced by EZH2 deletion in hematopoiesis with JAK2V617F in addition to direct effects of EZH2 deletion, we also studied RNA sequence in BM LSK cells of Ezh2-/-JAK2V617F-Tg mice (EJ). Upregulated genes were highly overlapped in between HJ and EJ. Relative to J, 200 genes including oncogenic Lmo1 were commonly upregulated, while 314 and 739 were exclusively upregulated in HJ and EJ, respectively. Thus, some of the EZH2 targets may be also targets of HMGA2. Pathway analysis revealed that chaperon-related pathways involving SCAP1 and SREBF1/2 were commonly upregulated. On the other hand, TGFB pathway was upregulated in EJ but not in HJ, and it may explain the discrepancy that addition of HMGA2 in JAK2V617F hematopoiesis did not progress fibrosis despite severe phenotype of MPN, but deletion of EZH2 exacerbated fibrosis as well as MF patients with high expression of HMGA2. To verify this finding, we measured expression of HMGA2 and its main suppressor let7, and performed target sequencing in blood samples from 16 MF patients. Because all of them highly expressed HMGA2, we also evaluated selected essential thrombocythemia (ET) patients (N=10 for HMGA2 low, 10 for HMGA2 high). While high HMGA2 expression was consistently correlated with low let-7 expression in ET, only half of MF showed low expression of let7. The other half of MF harbored mutations in components or modifiers of polycomb, including EZH2, ASXL1 and spliceosomes. These findings are compatible with the finding that loss of polycomb function upregulates HMGA2. In fact, the genetic depletion of HMGA2 or administration of HMGA2 inhibitor neuropsin diminished phenotype of EJ mice and prolonged survival. Our findings suggest importance of HMGA2 as a therapeutic target of MPN. Disclosures Komatsu: Shire: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Heilmann, Thorsten, Florian Vondung, Christoph Borzikowsky, Sandra Krüger, Mohamed Elessawy, Ibrahim Alkatout, Antonia Wenners i in. "Cytoplasmic levels of high mobility group A2 determine survival prognoses in breast cancer patients". International Journal of Biological Markers 35, nr 2 (12.05.2020): 20–28. http://dx.doi.org/10.1177/1724600820917990.

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Background: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. Objective: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. Methods: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. Results: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. Conclusion: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

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Möller, Katharina, Florian Lutz, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Guido Sauter i in. "Abstract 6450: High mobility group protein 2 (HMGA2) is highly expressed in a broad range of human cancers". Cancer Research 84, nr 6_Supplement (22.03.2024): 6450. http://dx.doi.org/10.1158/1538-7445.am2024-6450.

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Abstract The high mobility group protein 2 (HMGA2) is an essential component of the enhanceosome. It can attach to AT-rich binding sites in the DNA minor groove, affect the conformation of the DNA, and thereby modify the transcription of numerous genes. HMGA2 is preferentially expressed during organogenesis. Aberrant expression of HMGA2 in adult tissues is commonly associated with tumor formation and cancer aggressiveness. Accordingly, HMGA2 represents a potential drug target. To better comprehend the role of HMGA2 expression in cancer, a tissue microarray containing 8,344 samples from 115 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, a strong nuclear HMGA2 staining was limited to few cell types from the amnion, placenta, seminal vesicle, endocervix, fallopian tube, and respiratory epithelium. HMGA2 expression was generally markedly higher in cancer than in corresponding normal tissues. HMGA2 staining was found in 2,695 (42.7%) of the 6,313 interpretable tumor samples, including 701 (11.1%) with weak, 769 (12.2%) with moderate, and 1,225 (19.4%) with strong positivity. A total of 93 of 115 tumor categories showed HMGA2 expression in at least one case, and 69 tumor categories included at least one case with strong HMGA2 staining. The frequency of HMGA2 positivity was particularly high in cancers of the ovary and the endometrium (52.6-92.6%), pancreatico-biliary cancers (48.1-75.5%), thyroidal neoplasms (53.4-95%), salivary gland neoplasms (66.7-98%), nonseminomatous testicular germ cell tumors (73.5-93.5%), colorectal adenocarcinoma (81.6%), papillary renal cell carcinoma (68.2%), and in squamous cell carcinomas (36-81.5%). Tumor entities with a particularly low expression of HMGA2 included prostatic adenocarcinomas (1.3-4%), non-invasive urothelial carcinomas (1.8-4.3%), hepatocellular carcinoma (3.2%), and non-Hodgkin’s lymphomas (0%) It is concluded, that HMGA2 is highly expressed in a very broad range of tumor entities. These findings emphasize a potential role of HMGA2 as a drug target and demonstrate utility for HMGA2 IHC for the distinction of neoplastic from non-neoplastic tissues in several organs. Citation Format: Katharina Möller, Florian Lutz, Florian Viehweger, Martina Kluth, Claudia Hube-Magg, Christian Bernreuther, Guido Sauter, Andreas H. Marx, Ronald Simon, Till Krech, Stefan Steurer, Christoph Fraune, Sarah Minner, Natalia Gorbokon, Maximilian Lennartz, Eike Burandt, Anne Menz. High mobility group protein 2 (HMGA2) is highly expressed in a broad range of human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6450.

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Dutta, Avik, Robert E. Hutchison i Golam Mohi. "Expression of HMGA2 Cooperates with Jak2V617F in the Development of Myelofibrosis". Blood 128, nr 22 (2.12.2016): 797. http://dx.doi.org/10.1182/blood.v128.22.797.797.

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Abstract High Mobility Group AT Hook 2 (HMGA2) is a non-histone chromatin protein that regulates gene transcription and controls cell proliferation, survival and self-renewal of stem cells. HMGA2 is expressed at a low level in normal adult hematopoietic progenitors but is highly expressed in hematopoietic progenitors of patients with Myelofibrosis (MF). However, the contribution of HMGA2 to the pathogenesis of MF remains unknown. MF is the deadliest form of myeloprolifearative neoplasm (MPN) characterized by deposition of fibrous tissues in the bone marrow, increased megakaryopoiesis, ineffective erythropoiesis and extramedullary hematopoiesis. Median survival of patients with MF is less than 6 years. The JAK2V617F mutation has been found in 50-60% patients with MF. However, it is not clear whether JAK2V617F mutation alone is sufficient to cause MF. Interestingly, up-regulation of HMGA2 expression has been found in association with the JAK2V617F mutation in a significant percentage of patients with MF. To understand the role of JAK2V617F mutation in the pathogenesis of MPN, we previously generated a conditional Jak2V617F knock-in mouse. We observed that expression of heterozygous Jak2V617F in mouse hematopoietic compartments is sufficient to induce a polycythemia vera (PV)-like MPN. Recently, we have shown that deletion of EZH2 promotes the development of MF in Jak2V617F knock-in mice and EZH2 deletion increases the expression of HMGA2 in hematopoietic progenitors of EZH2-deleted Jak2V617F mice. To directly assess the effects of concomitant expression of HMGA2 and heterozygous Jak2V617F in mice hematopoietic compartments, we expressed control vector or HMGA2 in wild type and heterozygous Jak2V617F knock-in mice BM by lentiviral transduction and performed bone marrow transplantation into lethally irradiated C57BL/6 recipient mice. Whereas recipients of vector-transduced Jak2V617F knock-in BM cells exhibited a PV-like MPN characterized by increased red blood cells (RBC), hemoglobin, hematocrit and platelets in their peripheral blood, recipients of HMGA2-transduced Jak2V617F knock-in BM showed reduced hemoglobin and hematocrit parameters compared with recipients of vector-expressing Jak2V617F BM cells. Interestingly, peripheral blood neutrophil and platelet counts were further increased in transplanted animals receiving HMGA2-transduced Jak2V617F BM cells. Expression of HMGA2 also resulted in significantly larger spleen size in the transplanted animals receiving HMGA2-expressing Jak2V617F BM cells. Flow cytometric analysis showed significant increase in megakaryocytic precursors (CD41+) but decrease in erythroid precursors (CD71+/Ter119+) in the BM and spleens of transplanted animals receiving HMGA2-expressing Jak2V617F BM compared with control vector-expressing Jak2V617F BM. Furthermore, the frequency of hematopoietic stem/progenitor cells (LSK; Lin-Sca-1+c-kit+) was significantly increased in recipients of HMGA2-transduced Jak2V617F knock-in BM compared with control vector-transduced Jak2V617F knock-in BM or HMGA2-transduced wild type BM. Histopathologic analysis revealed extensive fibrosis in the BM and spleens from recipients of HMGA2-expressing Jak2V617F mice at 32 weeks after transplantation while BM and spleens from recipients of vector-transduced Jak2V617F knock-in BM or HMGA2-transduced wild type BM showed very little or no fibrosis at this age. Together, these data suggest that expression of HMGA2 promotes megakaryopoiesis and accelerates the development of MF in mice expressing Jak2V617F. To gain insights into the mechanisms by which expression of HMGA2 accelerates the development of MF in Jak2V617F mice, we performed RNA-sequencing analysis on purified LSK (Lin-Sca-1+c-kit+) cells. Gene set enrichment and pathway analyses revealed that the genes related to chemokine, TGF-β, MAP Kinase, PI3 kinase-Akt, mTOR and WNT signaling pathways were up-regulated in HMGA2-expressing Jak2V617F mice LSK compared with vector-expressing Jak2V617F LSK cells. We also found that HMGA2 directly binds to the promoter regions of some of these target genes and regulate their expression. Further studies will validate the targets of HMGA2 and determine their contribution in MF mediated by Jak2V617F. In conclusion, our studies show that expression of HMGA2 cooperates with Jak2V617F in the development of MF. Disclosures No relevant conflicts of interest to declare.

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Sato, Katsuaki, Koichi Terai, Mamoru Ozaki, Yoshimichi Ueda i Shogo Katsuda. "Odontogenic myxofibroma with HMGA2 overexpression and HMGA2 rearrangement". Pathology International 60, nr 11 (13.08.2010): 760–64. http://dx.doi.org/10.1111/j.1440-1827.2010.02589.x.

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Dong, Shaoyong, Chenghong Zhang, Hefei Li, Nan Yang, Qi Zhao i Tao Guo. "MiR-129 Weakens Proliferation of Non-Small Cell Lung Cancer Cells via Targeted Regulation of High-Mobility Group AT-Hook 2". Journal of Biomedical Nanotechnology 20, nr 1 (1.01.2024): 183–89. http://dx.doi.org/10.1166/jbn.2024.3736.

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This study investigated the role of micro ribonucleic acid (miR)-129 in non-small cell lung cancer (NSCLC) by examining its effects on cell proliferation and apoptosis, as well as its relationship with the high-mobility group AT-hook 2 (HMGA2) target gene. Human NSCLC tissues were collected, and cancerous cells and normal cells were isolated and cultured. In vitro cultured NSCLC cells were transfected with miR-129 mimics or HMGA2-small interfering RNA (siRNA). The expression levels of miR-129 and HMGA2 were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), while cell proliferation was assessed using the cell counting kit-8 (CCK-8) assay. The targeted regulation between miR-129 and HMGA2 was examined using a luciferase reporter assay system, and protein expression was determined by Western blotting (WB). Flow cytometry was utilized to measure the cell apoptosis rate. NSCLC tissues and cells exhibited significantly decreased miR-129 expression and increased HMGA2 expression compared to normal tissues and cells. Transfection with miR-129 mimics and HMGA2-siRNA effectively reduced HMGA2 gene and protein expression in NSCLC cells, leading to decreased proliferation and increased apoptosis. The luciferase reporter assay confirmed targeted regulation between miR-129 and HMGA2. In summary, miR-129 may suppress NSCLC cell proliferation and induce apoptosis by targeting HMGA2 expression.

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Harada, Kayo Shirado, Kazuhiko Ikeda, Kazuei Ogawa, Hideyoshi Noji, Hideo Kimura, Tatsuyuki Kai, Soji Morishita, Norio Komatsu i Yasuchika Takeishi. "The Role Of Deregulated HMGA2 Expression With Promoter Methylation Of p16 In Myeloproliferative Neoplasms". Blood 122, nr 21 (15.11.2013): 1606. http://dx.doi.org/10.1182/blood.v122.21.1606.1606.

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Abstract Myeloproliferative Neoplasms (MPNs) are characterized by clonal proliferative hematopoiesis with increased mature blood cells. The signal-activating mutations such as JAK2V617F increase blood cells, but it remains uncertain how an abnormal hematopoietic cell clone expands in MPNs. We have recently showed that overexpression of the high mobility group AT-hook 2 (HMGA2) causes proliferative hematopoiesis with providing a clonal growth advantage to hematopoietic cells in mice (Ikeda et al, Blood, 2011), suggesting the possibility that HMGA2 contributes to the pathogenesis of MPNs. However, since only a few studies have evaluated expression of HMGA2 mRNA in patients with MPNs, the role of HMGA2 in the pathogenesis of MPNs is yet unclear. MPNs also show mutations in epigenetic modifiers involving DNA methylation such as polycomb group genes (PcG) and aberrant expressions of micro RNAs (miRNA) that negatively regulate expressions of targeted genes. Interestingly, deficiency in either PcG-related BMI1 (Oguro et al, J Exp Med, 2012) or let-7-family miRNA (Mayr et al, Science, 2007) causes deregulation of HMGA2 expression, leading to its oncogenic activity in part by negatively regulating tumor suppressor p16. Thus, in this study, to clarify the role of HMGA2 in MPNs, we investigated expression of HMGA2 mRNA in peripheral granulocytes of 56 patients with MPNs including 23 polycythemia vera (PV), 26 essential thrombocythemia (ET) and 7 primary myelofibrosis (PMF) along with clinical findings, JAK2V617F allele burden, expressions of BMI1 mRNA and let-7-family miRNAs, and promoter methylation of p16. Quantitative RT-PCR (qPCR) showed significantly higher expression of HMGA2 mRNA relative to internal control HPRT1 mRNA in PMF (mean ± SD; 31.7 ± 42.8, p<0.01), but not PV (15.7 ± 53.2) or ET (2.14 ± 7.70), compared with 12 healthy volunteers (HV; 0.431 ± 0.366). In addition, deregulated HMGA2 expression (>1.2), which was determined as relative expression level above mean + 2SD of HMGA2 mRNA in 12 HV, was most frequently detected in patients with PMF [7/7 (100%)] (p<0.01), compared with PV [5/23 (21.7%)] and ET [6/26 (23.1%)]. We also found a significant positive correlation in expression levels of HMGA2 mRNA with serum LDH values (r=0.531, p<0.01) rather than JAK2V617F allele burden (r=0.25, p=0.08). These data suggested that expression of HMGA2 mRNA independently correlated with disease phenotype and status in MPNs. We next explored the cause of deregulated expression of HMGA2 mRNA and found lower expression of let-7a (0.19 ± 0.13 vs. 0.42 ± 0.39, p=0.04) and -7c (0.57 ± 0.60 vs. 1.14 ± 0.94, p=0.06) rather than -7b (p=0.2) by qPCR, in patients with deregulated expression of HMGA2 mRNA compared with other patients. However, HMGA2-involved chromosomal abnormality in 12q13-15 was not detected in any patient, and there was no difference in expression of BMI1 mRNA between patients with deregulated expression of HMGA2 mRNA and other patients. Thus, decreased expression of let-7 miRNAs might contribute to deregulated expression of HMGA2 mRNA in MPNs. Finally, we investigated correlation of deregulated expression of HMGA2 mRNA with promoter methylation of p16. Methylation-specific PCR assay detected promoter methylation of p16 in 17/56 (30.4%) patients with MPNs. Strikingly, patients with deregulated expression of HMGA2 mRNA significantly more often showed promoter methylation of p16 compared with other patients [10/18 (55.6%) vs. 7/38 (18.4%), p<0.01]. Furthermore, patients with promoter methylation of p16 showed higher expression levels of HMGA2 mRNA than patients without the methylation, especially in patients with PMF (2.33 ± 0.90 vs. 70.9 ± 38.3, p=0.01). In conclusion, deregulated expression of HMGA2 in association with decreased expression of let-7 miRNAs may play a crucial role in the pathogenesis of MPNs possibly through p16. Disclosures: No relevant conflicts of interest to declare.

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Harada, Kayo Shirado, Kazuhiko Ikeda, Kazuei Ogawa, Hiroshi Ohkawara i Yasuchika Takeishi. "Dysregulation of the Let-7/HMGA2 Axis with Methylation of p16 Promoter As a Possible Target of Histone Deacetylase Inhibitor in Myeloproliferative Neoplasms". Blood 124, nr 21 (6.12.2014): 3213. http://dx.doi.org/10.1182/blood.v124.21.3213.3213.

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Abstract Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), are clonal hematological disorders characterized by proliferation of mature blood cells. Recently, several agents that influence epigenetic modifications, such as histone deacetylase inhibitors (HDACi), as well as JAK2 inhibitors, have been investigated for high-risk MPNs. For example, an HDACi, panobinostat has shown significant efficacy including nearly complete response in PMF (Mascarenhas et al, BJH, 2013), but molecular targets of HDACi remain largely unknown. The High Mobility Group AT-hook 2 (HMGA2) is a non-histone chromatin protein that modulates transcriptions of various genes and contributes to chromatin modification and epigenetic regulation including DNA methylation (Fusco et al, Nat Rev Cancer, 2007; Sun et al, PNAS 2013). Let-7 micro RNAs (miRNAs) negatively regulate expression of HMGA2 through 3’UTR of HMGA2 mRNA, although HMGA2 mRNA consists of both the major variant containing 3’UTR with let-7-specific sites (variant 1) and some minor variants without 3’UTR. We previously reported that overexpression of HMGA2 due to transgenic expression of Hmga2 cDNA without 3’UTR caused proliferative hematopoiesis with providing a clonal advantage to hematopoietic stem cells in mice (Ikeda et al, Blood, 2011). We also showed a deregulation of HMGA2 mRNA expression due to reduced let-7 miRNA level in granulocytes from patients with almost all of PMF and over 20% of PV and ET (Harada-Shirado et al, Blood [Abst], 2013), being associated with splenomegaly, elevated serum LDH values, and methylation of p16 promoter. Thus, we hypothesized that HMGA2 may be a candidate gene as a therapeutic target in MPNs. Since association of HDAC with HMGA2 has been reported in cord blood-derived cells (Lee et al, Cell Mol Life Sci, 2011), we here studied effects of the panobinostat on expressions of HMGA2 and let-7 in HMGA2-expressing myeloid cells including PMF-derived CD34+ cells. First, we found significantly higher HMGA2 mRNA levels in CD34+ cells from 2 PMF patients compared with CD34+ cells from 2 healthy individuals (P<0.001), as well as U937 cells compared with HL60 cells (P<0.001). Thus, we used CD34+ cells from one of these 2 PMF patients and U937 cells for further experiments. Interestingly, treatment with panobinostat at the concentration of 40 nM for 8 hours significantly increased expressions of let-7a (P<0.001 and P=0.003, respectively), -7b (P<0.001 and P<0.001), and -7c (P<0.001 and P=0.06) in U937 cells and PMF CD34+ cells, compared with samples without the treatment. In contrast, Western blotting showed clearly reduced expression of HMGA2 protein in U937 cells after the treatment with panobinostat. Moreover, we found that variant 1 of HMGA2 mRNA with 3’UTR was significantly reduced by the treatment with panobinostat, compared with samples without the treatment in both U937 cells and PMF CD34+ cells (P<0.001 and P<0.001, respectively), while expression levels of variant 2 lacking let-7-specific sites were not changed by the treatment. These findings strongly suggested that panobinostat decreased expression of HMGA2 through 3’UTR of HMGA2 mRNA by increasing expressions of let-7 miRNAs. Of note, we next found much higher expression of variant 1 of HMGA2 mRNA than variant 2 in granulocytes from 15 of 17 (88%) MPN patients whose HMGA2 mRNA levels were higher than controls in our previous study (Blood [Abst], 2013). We also assessed if treatment by panobinostat for the dysregulated let-7/HMGA2 axis may be a therapeutic option for MPNs with respect to DNA methylation. Panobinostat treatment substantially reduced the expressions of DNMT1 and DNMT3a as well as HMGA2 proteins, significantly demethylated the p16 promoter (P<0.001), and decreased survival (P<0.001) in U937 cells. Moreover, knocking-down of HMGA2 with small interfering RNA in U937 cells significantly increased expression of TET3 mRNA and demethylated the p16 promoter, suggesting that HMGA2 expression may contribute to methylation of the p16 promoter. In conclusion, deregulated expression of HMGA2 due to downregulation of let-7 miRNAs, which may lead to some epigenetic modifications such as methylation of the p16 promoter, is a possible therapeutic target of HDACi in MPNs. Disclosures Ikeda: Novartis Pharmaceuticals: Other.

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Unachukwu, Uchenna, Kiran Chada i Jeanine D’Armiento. "High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia". International Journal of Molecular Sciences 21, nr 9 (29.04.2020): 3151. http://dx.doi.org/10.3390/ijms21093151.

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High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.

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Huang, Yu-Min, Chia-Hsiung Cheng, Shiow-Lin Pan, Pei-Ming Yang, Ding-Yen Lin i Kuen-Haur Lee. "Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer". Biomolecules 9, nr 11 (2.11.2019): 688. http://dx.doi.org/10.3390/biom9110688.

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Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy. Thus, HMGA2 is an important molecular target for many types of malignancies. Our recent studies revealed the positive connections between heat shock protein 90 (Hsp90) and HMGA2 and that the Hsp90 inhibitor has therapeutic potential to inhibit HMGA2-triggered tumorigenesis. However, 43% of patients suffered visual disturbances in a phase I trial of the second-generation Hsp90 inhibitor, NVP-AUY922. To identify a specific inhibitor to target HMGA2, the Gene Expression Omnibus (GEO) database and the Library of Integrated Network-based Cellular Signatures (LINCS) L1000platform were both analyzed. We identified the approved small-molecule antifungal agent ciclopirox (CPX) as a novel potential inhibitor of HMGA2. In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients.

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Chen, Qian, Qizhong Fu, Lin Pu, Xianfeng Liu i Ying Liu. "Effects of HMGA2 gene silencing on cell cycle and apoptosis in the metastatic renal carcinoma cell line ACHN". Journal of International Medical Research 50, nr 2 (luty 2022): 030006052210755. http://dx.doi.org/10.1177/03000605221075511.

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Objective To explore the role of high mobility group AT-hook 2 (HMGA2) in the regulation of the cell cycle and apoptosis. Methods The renal carcinoma cell line ACHN was transiently transfected with small interfering RNA to knock down the expression of the HMGA2 gene. Cell cycle analysis was undertaken using flow cytometry. The mRNA and protein levels of HMGA2, E2F transcription factor 1 (E2F1), cyclin D1, cyclin dependent kinase 6 (CDK6), B-cell lymphoma-2 (Bcl-2), caspase-3 and caspase-9 were analysed using reverse transcription quantitative real-time polymerase chain reaction and Western blot analysis. Results The mRNA and protein levels of HMGA2 were significantly higher in renal carcinoma cell lines compared with the human renal proximal tubular epithelial cell line HKC. After HMGA2 gene-specific silencing, more cells entered the G0/G1 phase, while fewer cells entered the G2/M phase; and the cells exhibited early and late apoptosis. HMGA2 gene-specific silencing significantly reduced the mRNA and protein levels of E2F1, cyclin D1, CDK6 and Bcl-2; and increased the mRNA and protein levels of caspase-3 and caspase-9. Conclusion The HMGA2 gene may be involved in the tumorigenesis and development of renal cancer, thus inhibiting HMGA2 gene expression might provide a potential therapeutic target in the future.

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Sakata, Junki, Akiyuki Hirosue, Ryoji Yoshida, Kenta Kawahara, Yuichiro Matsuoka, Tatsuro Yamamoto, Masafumi Nakamoto i in. "HMGA2 Contributes to Distant Metastasis and Poor Prognosis by Promoting Angiogenesis in Oral Squamous Cell Carcinoma". International Journal of Molecular Sciences 20, nr 10 (19.05.2019): 2473. http://dx.doi.org/10.3390/ijms20102473.

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The highly malignant phenotype of oral squamous cell carcinoma (OSCC), including the presence of nodal and distant metastasis, reduces patient survival. High-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is involved in advanced malignant phenotypes and poor prognosis in several human cancers. However, its biological role in OSCC remains to be elucidated. The purpose of this study was to determine the clinical significance and role of HMGA2 in the malignant potential of OSCC. We first investigated the expression pattern of HMGA2 and its clinical relevance in 110 OSCC specimens using immunohistochemical staining. In addition, we examined the effects HMGA2 on the regulation of vascular endothelial growth factor (VEGF)-A, VEGF-C, and fibroblast growth factor (FGF)-2, which are related to angiogenesis, in vitro. High expression of HMGA2 was significantly correlated with distant metastasis and poor prognosis. Further, HMGA2 depletion in OSCC cells reduced the expression of angiogenesis genes. In OSCC tissues with high HMGA2 expression, angiogenesis genes were increased and a high proportion of blood vessels was observed. These findings suggest that HMGA2 plays a significant role in the regulation of angiogenesis and might be a potential biomarker to predict distant metastasis and prognosis in OSCC.

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Su, Linjia, Zifang Deng i Fenfei Leng. "The Mammalian High Mobility Group Protein AT-Hook 2 (HMGA2): Biochemical and Biophysical Properties, and Its Association with Adipogenesis". International Journal of Molecular Sciences 21, nr 10 (25.05.2020): 3710. http://dx.doi.org/10.3390/ijms21103710.

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The mammalian high-mobility-group protein AT-hook 2 (HMGA2) is a small DNA-binding protein and consists of three “AT-hook” DNA-binding motifs and a negatively charged C-terminal motif. It is a multifunctional nuclear protein directly linked to obesity, human height, stem cell youth, human intelligence, and tumorigenesis. Biochemical and biophysical studies showed that HMGA2 is an intrinsically disordered protein (IDP) and could form homodimers in aqueous buffer solution. The “AT-hook” DNA-binding motifs specifically bind to the minor groove of AT-rich DNA sequences and induce DNA-bending. HMGA2 plays an important role in adipogenesis most likely through stimulating the proliferative expansion of preadipocytes and also through regulating the expression of transcriptional factor Peroxisome proliferator-activated receptor γ (PPARγ) at the clonal expansion step from preadipocytes to adipocytes. Current evidence suggests that a main function of HMGA2 is to maintain stemness and renewal capacity of stem cells by which HMGA2 binds to chromosome and lock chromosome into a specific state, to allow the human embryonic stem cells to maintain their stem cell potency. Due to the importance of HMGA2 in adipogenesis and tumorigenesis, HMGA2 is considered a potential therapeutic target for anticancer and anti-obesity drugs. Efforts are taken to identify inhibitors targeting HMGA2.

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Di Agostino, Silvia, Monica Fedele, Paolo Chieffi, Alfredo Fusco, Pellegrino Rossi, Raffaele Geremia i Claudio Sette. "Phosphorylation of High-Mobility Group Protein A2 by Nek2 Kinase during the First Meiotic Division in Mouse Spermatocytes". Molecular Biology of the Cell 15, nr 3 (marzec 2004): 1224–32. http://dx.doi.org/10.1091/mbc.e03-09-0638.

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The mitogen-activated protein kinase (MAPK) pathway is required for maintaining the chromatin condensed during the two meiotic divisions and to avoid a second round of DNA duplication. However, molecular targets of the MAPK pathway on chromatin have not yet been identified. Here, we show that the architectural chromatin protein HMGA2 is highly expressed in male meiotic cells. Furthermore, Nek2, a serine-threonine kinase activated by the MAPK pathway in mouse pachytene spermatocytes, directly interacts with HMGA2 in vitro and in mouse spermatocytes. The interaction does not depend on the activity of Nek2 and seems constitutive. On progression from pachytene to metaphase, Nek2 is activated and HMGA2 is phosphorylated in an MAPK-dependent manner. We also show that Nek2 phosphorylates in vitro HMGA2 and that this phosphorylation decreases the affinity of HMGA2 for DNA and might favor its release from the chromatin. Indeed, we find that most HMGA2 associates with chromatin in mouse pachytene spermatocytes, whereas it is excluded from the chromatin upon the G2/M progression. Because hmga2-/- mice are sterile and show a dramatic impairment of spermatogenesis, it is possible that the functional interaction between HMGA2 and Nek2 plays a crucial role in the correct process of chromatin condensation in meiosis.

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Liu, Ying, Qi-Zhong Fu, Lin Pu, Qing-Guo Meng, Xian-Feng Liu, Sheng-Fang Dong, Jian-Xun Yang i Guang-Yao Lv. "Hmga2 Expression in Renal Carcinoma and its Clinical Significance / Ekspresija Hmga2 U Karcinomu Bubrega I Njen Klinički Značaj". Journal of Medical Biochemistry 34, nr 3 (1.07.2015): 338–43. http://dx.doi.org/10.2478/jomb-2014-0036.

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Summary Background: The objective of this study is to detect HMGA2 expression in renal carcinoma to explore its relationship with clinicopathology and its significance in prognosis. Expressions of HMGA2 mRNA and protein were detected in 50 renal carcinoma specimens, 50 corresponding adjacent normal kidney tissue samples and 40 renal benign tumour specimens via reverse transcription polymerase chain reaction and immunohistochemical assay. Methods: Expression analysis was performed along with clinical data analysis. The relative expression levels of HMGA2 mRNA in renal carcinoma, renal benign tumour tissues and adjacent normal renal tissues were 0.84±0.23, 0.19±0.06 and 0.08±0.04, respectively. HMGA2 protein positive rates were 68.0%, 7.5% and 2.0%, with a significant difference (P<0.05). HMGA2 expression was not significantly correlated with gender, age, tumour size and histological type (P>0.05), but was significantly correlated with TNM stages and lymph node metastasis (P<0.05). Conclusions: The expressions of HMGA2 gene and protein in renal carcinoma were closely correlated with tumour formation, progression and metastasis. HMGA2 may become a powerful new pathological marker and prognostic factor for renal carcinoma.

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Federico, A., F. Forzati, F. Esposito, C. Arra, G. Palma, A. Barbieri, D. Palmieri i in. "Hmga1/Hmga2 double knock-out mice display a "superpygmy" phenotype". Biology Open 3, nr 5 (11.04.2014): 372–78. http://dx.doi.org/10.1242/bio.20146759.

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Portovedo, Sérgio, Nadja Gaido, Bruno de Almeida Nunes, Ana Giselia Nascimento, Allysson Rocha, Marcelo Magalhães, Gilvan Cortes Nascimento i in. "Differential Expression of HMGA1 and HMGA2 in pituitary neuroendocrine tumors". Molecular and Cellular Endocrinology 490 (czerwiec 2019): 80–87. http://dx.doi.org/10.1016/j.mce.2019.04.010.

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