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Matthias Schröder, Simone Loos, Svenja Kerstin Naumann, Christopher Bachran, Marit Krötschel, Viktor Umansky, Laura Helming, Lee Kim Swee
Tumors are infiltrated by cells of the immune system that interact through complex regulatory networks. Although tumor-specific CD8(+) T cells can be found in peripheral blood and tumor samples from cancer patients, their function is inhibited by immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). Recent clinical successes have demonstrated that alleviating immunosuppression and T cell exhaustion translates into long-term clinical benefits...
2017: Oncoimmunology
Yi-Fen Lu, Patrick Cahan, Samantha Ross, Julie Sahalie, Patricia M Sousa, Brandon K Hadland, Wenqing Cai, Erik Serrao, Alan N Engelman, Irwin D Bernstein, George Q Daley
Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients...
December 20, 2016: Cell Reports
Monica Cusan, Naidu M Vegi, Medhanie A Mulaw, Shiva Bamezai, Lisa M Kaiser, Aniruddha J Deshpande, Philipp A Greif, Leticia Quintanilla-Fend, Stefanie Göllner, Carsten Müller-Tidow, Keith R Humphries, Scott A Armstrong, Wolfgang Hiddemann, Michaela Feuring-Buske, Christian Buske
There is high interest to understand mechanisms driving self-renewal of stem cells. HOXB4 is one of the few transcription factors able to amplify long-term repopulating hematopoietic stem cells in a controlled way. Here we show in mice that this characteristic of HOXB4 depends on proline-rich sequence near the N-terminus, which is unique among HOX genes and highly conserved in higher mammals. Deletion of this domain substantially enhanced the oncogenicity of HOXB4, inducing acute leukemia in mice. Vice versa, insertion of the domain into Hoxa9 impaired leukemogenicity of this homeobox gene...
November 8, 2016: Blood
Iben Daugaard, Diana Dominguez, Tina E Kjeldsen, Lasse S Kristensen, Henrik Hager, Tomasz K Wojdacz, Lise Lotte Hansen
Lung cancer is the number one cause of cancer-related deaths worldwide. DNA methylation is an epigenetic mechanism that regulates gene expression, and disease-specific methylation changes can be targeted as biomarkers. We have compared the genome-wide methylation pattern in tumor and tumor-adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32 patients by methylation-sensitive high resolution melting (MS-HRM) analysis...
October 26, 2016: Scientific Reports
Hong Wang, Xiu-Hong Jia, Jie-Ru Chen, Ying-Jie Yi, Jian-Yong Wang, You-Jie Li, Shu-Yang Xie
Multidrug resistance (MDR) plays a pivotal role in human chronic myelogenous leukemia (CML) chemotherapy failure. MDR is mainly associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) proteins. Phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) expression in many human malignancies...
December 2016: International Journal of Oncology
Steffen Jørgensen, Mehmet Coskun, Keld Mikkelsen Homburg, Ole B V Pedersen, Jesper T Troelsen
The mammalian Caudal-related homeobox transcription factor 2 (CDX2) plays a key role in the homeobox regulatory network and is essential in regulating the expression of several homeobox (HOX) genes during embryonic development, particularly in the gut. Genome-wide CDX2 chromatin immunoprecipitation analysis and expression data from Caco2 cells also suggests a role for CDX2 in the regulation of HOXB4 gene expression in the intestinal epithelium. Thus, the aim of this study was to investigate whether HOXB4 gene expression is regulated by CDX2 in the intestinal epithelium...
2016: PloS One
Shin'ichiro Yasunaga, Yoshinori Ohno, Naoto Shirasu, Bo Zhang, Kyoko Suzuki-Takedachi, Motoaki Ohtsubo, Yoshihiro Takihara
Geminin exerts two distinct molecular roles. Geminin negatively regulates DNA replication licensing through the direct interaction with Cdt1 to prevent re-replication in proliferating cells. Geminin also regulates chromatin remodeling through the direct interaction with Brahma/Brg1 to maintain undifferentiated states of stem cells. We previously uncovered that Polycomb-group complex 1 and Hoxb4/Hoxa9, well-known intrinsic factors that are essential for maintaining the hematopoietic stem cell (HSC) activity, alternatively act as ubiquitin-proteasome systems for Geminin protein to reduce the protein expression level, and sustain the HSC activity...
September 2016: International Journal of Hematology
Melany Jackson, Rui Ma, A Helen Taylor, Richard A Axton, Jennifer Easterbrook, Maria Kydonaki, Emmanuel Olivier, Lamin Marenah, Edouard G Stanley, Andrew G Elefanty, Joanne C Mountford, Lesley M Forrester
UNLABELLED: : We have developed a robust, Good Manufacturing Practice-compatible differentiation protocol capable of producing scalable quantities of red blood cells (RBCs) from human pluripotent stem cells (hPSCs). However, translation of this protocol to the clinic has been compromised because the RBCs produced are not fully mature; thus, they express embryonic and fetal, rather than adult globins, and they do not enucleate efficiently. Based on previous studies, we predicted that activation of exogenous HOXB4 would increase the production of hematopoietic progenitor cells (HPCs) from hPSCs and hypothesized that it might also promote the production of more mature, definitive RBCs...
August 2016: Stem Cells Translational Medicine
Josiane Lilian Dos Santos Schiavinato, Lucila Habib Bourguignon Oliveira, Amélia Goes Araujo, Maristela Delgado Orellana, Patrícia Viana Bonini de Palma, Dimas Tadeu Covas, Marco Antonio Zago, Rodrigo Alexandre Panepucci
During the early thymus colonization, Notch signaling activation on hematopoietic progenitor cells (HPCs) drives proliferation and T cell commitment. Although these processes are driven by transcription factors such as HOXB4 and GATA3, there is no evidence that Notch directly regulates their transcription. To evaluate the role of NOTCH and TNF signaling in this process, human CD34(+) HPCs were cocultured with OP9-DL1 cells, in the presence or absence of TNF. The use of a Notch signaling inhibitor and a protein synthesis inhibitor allowed us to distinguish primary effects, mediated by direct signaling downstream Notch and TNF, from secondary effects, mediated by de novo synthesized proteins...
October 2016: In Vitro Cellular & Developmental Biology. Animal
Zoe Kelly, Carla Moller-Levet, Sophie McGrath, Simon Butler-Manuel, Thumuluru Kavitha Madhuri, Andrzej M Kierzek, Hardev Pandha, Richard Morgan, Agnieszka Michael
HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples...
October 1, 2016: International Journal of Cancer. Journal International du Cancer
Alessa Kühn, Denise Löscher, Rolf Marschalek
One hallmark of MLL-r leukemia is the highly specific gene expression signature indicative for commonly deregulated target genes. An usual read-out for this transcriptional deregulation is the HOXA gene cluster, where upregulated HOXA genes are detected in MLL-r AML and ALL patients. In case of t(4;11) leukemia, this simple picture becomes challenged, because these patients separate into HOXAhi- and HOXAlo-patients. HOXAlo-patients showed a reduced HOXA gene transcription, but instead overexpressed the homeobox gene IRX1...
June 7, 2016: Oncotarget
Lin Li, Chun-Ting Zhao, Bo-Li Cui, Shao-Ling Wu, Xiao-Dan Liu, Zhan Su, Jie Yang, Wei Wang, Zhong-Guang Cui, Hong-Guo Zhao
OBJECTIVE: To investigate HOXB4, PRDM16 and HOXA9 gene expression in patients with acute myeloid leukemia (AML) and its clinical significance. METHODS: Real-time quantitative PCR (RT-qPCR) with SYBR Green assay was used to detect the expression of HOXB4, PRDM16 and HOXA9 gene in AML patients (40 cases), the patients with complete remission (9 cases) and patients with non-malignant hematologic diseases as control (10 cases). The relationship between the expression levels of gene HOXB4, PRDM16, HOXA9 and clinical features was investigated by statistical analysis...
April 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Xiaolin Guo, Sijia He, Xiaoyi Lv, Haibo Ding, Sha Li, Jing Kang, Jing Liu, Chaolong Qin, Wenqing Geng, Yongjun Jiang, Hong Shang
HIV-1 causes chronic infection characterized by the depletion of CD4+ T lymphocytes and the development of AIDS. Current antiretroviral drugs inhibit viral spread, but they do not lead to a full immune recovery. Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitor cells (HPCs) give rise to all blood and immune cells, and in HIV infection, hematological abnormalities frequently occur in patients. Here, we used bone marrow samples from HIV-1-infected people to study the relationship between the proliferation ability of HSCs/HPCs and peripheral CD4+ T lymphocytes...
April 15, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Chunlei Xin, Chunting Zhao, Xiangcong Yin, Shaoling Wu, Zhan Su
OBJECTIVES: We aimed to identify the potential HOXB4/HOXC4 downstream effectors and elucidate their regulatory mechanism in the expansion of hematopoietic stem cell (HSC). METHODS: The microarray data GSE24379 were downloaded from Gene Expression Omnibus database, including 12 human CD34(+) hematopoietic cells with irradiated EGFP-, HOXB4-, or HOXC4-transduced MS-5 cells, respectively. Then common differentially expressed genes (DEGs) in HOXB4- and HOXC4-treated hematopoietic cells (HOXB4&HOXC4...
September 2016: Hematology (Amsterdam, Netherlands)
Li-Ping Shu, Zhi-Wei Zhou, Ting Zhou, Min Deng, Mei Dong, Yi Chen, Yan-Fang Fu, Yi Jin, Shu-Feng Zhou, Zhi-Xu He
Hemangioblast, including primitive hematopoietic progenitor cells, play an important role in hematopoietic development, however, the underlying mechanism for the propagation of hematopoietic progenitor cells remains elusive. A variety of regulatory molecules activated in early embryonic development play a critical role in the maintenance of function of hematopoietic progenitor cells. Homeobox transcription factors are an important class of early embryonic developmental regulators determining hematopoietic development...
December 2015: Clinical and Experimental Pharmacology & Physiology
X Huang, M-R Lee, S Cooper, G Hangoc, K-S Hong, H-M Chung, H E Broxmeyer
Although hematopoietic stem cells (HSC) are the best characterized and the most clinically used adult stem cells, efforts are still needed to understand how to best ex vivo expand these cells. Here we present our unexpected finding that OCT4 is involved in the enhancement of cytokine-induced expansion capabilities of human cord blood (CB) HSC. Activation of OCT4 by Oct4-activating compound 1 (OAC1) in CB CD34(+) cells enhanced ex vivo expansion of HSC, as determined by a rigorously defined set of markers for human HSC, and in vivo short-term and long-term repopulating ability in NSG mice...
January 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Farhad Oubari, Naser Amirizade, Hemn Mohammadpour, Mozhdeh Nakhlestani, Mahin Nikougoftar Zarif
OBJECTIVE: Hematopoietic stem cells (HSCs) transplantation using umbilical cord blood (UCB) has improved during the last decade. Because of cell limitations, several studies focused on the ex vivo expansion of HSCs. Numerous investigations were performed to introduce the best cytokine cocktails for HSC expansion The majority used the Fms-related tyrosine kinase 3 ligand (FLT3-L) as a critical component. According to FLT3-L biology, in this study we have investigated the hypothesis that FLT3-L only effectively induces HSCs expansion in the presence of a mesenchymal stem cell (MSC) feeder...
2015: Cell Journal
Elena Cano, Rita Carmona, Víctor Velecela, Ofelia Martínez-Estrada, Ramón Muñoz-Chápuli
The proepicardium is the embryonic primordium of the epicardium. This transient structure is essential for cardiac development giving rise to the epicardium and supplying the heart with vascular and cardiac connective tissue progenitors. However, their nature and evolutionary origin are poorly-known. We have suggested elsewhere (Pombal et al. Evol. Dev. 10: 210-216, 2008; Cano et al., J. Dev. Biol. 1: 3-19, 2013) that the proepicardium is an evolutionary derivative of the primordium of an ancient external pronephric glomerulus, devoid of its original excretory function...
July 2015: Evolution & Development
Marilaine Fournier, Charles-Étienne Lebert-Ghali, Janetta J Bijl
Genes of the HOX4 paralog group have been shown to expand hematopoietic stem cells (HSCs). Endogenous expression of HOXA4 is 10-fold higher than HOXB4 in embryonic primitive hematopoietic cells undergoing self-renewal suggesting a more potent capacity of HOXA4 to expand HSC. In this study, we provide evidence by direct competitive bone marrow cultures that HOXA4 and HOXB4 induce self-renewal of primitive hematopoietic cells with identical kinetics. Transplantation assays show that short-term repopulation by HOXA4-overexpressing multilineage progenitors was significantly greater than HOXB4-overexpressing progenitors in vivo, indicating differences in the sensitivity of the cells to external signals...
October 15, 2015: Stem Cells and Development
Xiaoyu Qu, Jerry Davison, Liping Du, Barry Storer, Derek L Stirewalt, Shelly Heimfeld, Elihu Estey, Frederick R Appelbaum, Min Fang
Aberrant DNA methylation is known to occur in cancer, including hematological malignancies such as acute myeloid leukemia (AML). However, less is known about whether specific methylation profiles characterize specific subcategories of AML. We examined this issue by using comprehensive high-throughput array-based relative methylation analysis (CHARM) to compare methylation profiles among patients in different AML cytogenetic risk groups. We found distinct profiles in each group, with the high-risk group showing overall increased methylation compared with low- and mid-risk groups...
2015: Epigenetics: Official Journal of the DNA Methylation Society
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