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Article: Protein Kinases in Leukemias.

De Sepulveda, Paulo / Pasquet, Jean-Max

2021 Volume 13, Issue 11

Abstract: Protein kinases (PK) make up around 2% of the human genome and their expression profile varies depending on the organ and tissue [ ... ]. ...

Abstract	Protein kinases (PK) make up around 2% of the human genome and their expression profile varies depending on the organ and tissue [...].
Language	English
Publishing date	2021-06-01
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13112747
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Article: Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.

Dupont, Marine / Huart, Mathilde / Lauvinerie, Claire / Bidet, Audrey / Guitart, Amélie Valérie / Villacreces, Arnaud / Vigon, Isabelle / Desplat, Vanessa / El Habhab, Ali / Pigneux, Arnaud / Ivanovic, Zoran / Brunet De la Grange, Philippe / Dumas, Pierre-Yves / Pasquet, Jean-Max

Cancers

2022 Volume 14, Issue 2

Abstract: Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic ... ...

Abstract	Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.
Language	English
Publishing date	2022-01-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14020453
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Article ; Online: α-Tocopherol Attenuates Oxidative Phosphorylation of CD34

Rodriguez, Laura / Duchez, Pascale / Touya, Nicolas / Debeissat, Christelle / Guitart, Amélie V / Pasquet, Jean-Max / Vlaski-Lafarge, Marija / Brunet de la Grange, Philippe / Ivanovic, Zoran

Biomolecules

2021 Volume 11, Issue 4

Abstract: Alpha tocopherol acetate (αTOA) is an analogue of alpha tocopherol (αTOC) that exists in the form of an injectable drug. In the context of the metabolic hypothesis of stem cells, we studied the impact of αTOA on the metabolic energetic profile and ... ...

Abstract	Alpha tocopherol acetate (αTOA) is an analogue of alpha tocopherol (αTOC) that exists in the form of an injectable drug. In the context of the metabolic hypothesis of stem cells, we studied the impact of αTOA on the metabolic energetic profile and functional properties of hematopoietic stem and progenitor cells. In ex vivo experiments performed on cord blood CD34
MeSH term(s)	Animals ; Antigens, CD34/genetics ; Antigens, CD34/metabolism ; Antioxidants/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Self Renewal ; Cells, Cultured ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Oxidative Phosphorylation ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle ; Vitamins/pharmacology ; alpha-Tocopherol/pharmacology
Chemical Substances	Antigens, CD34 ; Antioxidants ; Basic Helix-Loop-Helix Transcription Factors ; Reactive Oxygen Species ; Vitamins ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; alpha-Tocopherol (H4N855PNZ1)
Language	English
Publishing date	2021-04-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11040558
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Article ; Online: Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in

Dumas, Pierre-Yves / Villacreces, Arnaud / Guitart, Amélie V / El-Habhab, Ali / Massara, Layal / Mansier, Olivier / Bidet, Audrey / Martineau, Delphine / Fernandez, Solene / Leguay, Thibaut / Pigneux, Arnaud / Vigon, Isabelle / Pasquet, Jean-Max / Desplat, Vanessa

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Volume 27, Issue 21, Page(s) 6012–6025

Abstract: Purpose: AXL has been shown to play a pivotal role in the selective response of : Experimental design: Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through : Results: We observed that gilteritinib maintained a ... ...

Abstract	Purpose: AXL has been shown to play a pivotal role in the selective response of Experimental design: Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through Results: We observed that gilteritinib maintained a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells compared with quizartinib, linked to a dose-dependent inhibition of AXL phosphorylation. Conclusions: Overall, these findings suggest that gilteritinib as a single agent, compared with quizartinib, is more likely to reach leukemic cells in their protective microenvironment, particularly AML clones highly dependent on
MeSH term(s)	Aniline Compounds/pharmacology ; Aniline Compounds/therapeutic use ; Benzothiazoles/pharmacology ; Benzothiazoles/therapeutic use ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Hematopoiesis ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Phenylurea Compounds/pharmacology ; Phenylurea Compounds/therapeutic use ; Proto-Oncogene Proteins/antagonists & inhibitors ; Pyrazines/pharmacology ; Pyrazines/therapeutic use ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; fms-Like Tyrosine Kinase 3/antagonists & inhibitors ; fms-Like Tyrosine Kinase 3/physiology
Chemical Substances	Aniline Compounds ; Benzothiazoles ; Phenylurea Compounds ; Proto-Oncogene Proteins ; Pyrazines ; gilteritinib ; quizartinib (7LA4O6Q0D3) ; FLT3 protein, human (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2021-08-16
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-3114
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Article ; Online: α-Tocopherol Acetate Attenuates Mitochondrial Oxygen Consumption and Maintains Primitive Cells within Mesenchymal Stromal Cell Population.

Loncaric, Darija / Rodriguez, Laura / Debeissat, Christelle / Touya, Nicolas / Labat, Veronique / Villacreces, Arnaud / Bouzier-Sore, Anne-Karine / Pasquet, Jean-Max / Brunet de la Grange, Philippe / Vlaski-Lafarge, Marija / Pavlovic, Sonja / Ivanovic, Zoran

Stem cell reviews and reports

2021 Volume 17, Issue 4, Page(s) 1390–1405

Abstract: We present here the data showing, in standard cultures exposed to atmospheric ... ...

Abstract	We present here the data showing, in standard cultures exposed to atmospheric O
MeSH term(s)	Cell Differentiation ; Humans ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mitochondria/metabolism ; Oxygen/metabolism ; alpha-Tocopherol/pharmacology
Chemical Substances	alpha-Tocopherol (H4N855PNZ1) ; Oxygen (S88TT14065)
Language	English
Publishing date	2021-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2495577-2
ISSN	2629-3277 ; 1558-6804 ; 1550-8943
ISSN (online)	2629-3277 ; 1558-6804
ISSN	1550-8943
DOI	10.1007/s12015-020-10111-9
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Article ; Online: Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Fernandez, Solène / Desplat, Vanessa / Villacreces, Arnaud / Guitart, Amélie V / Milpied, Noël / Pigneux, Arnaud / Vigon, Isabelle / Pasquet, Jean-Max / Dumas, Pierre-Yves

International journal of molecular sciences

2019 Volume 20, Issue 14

Abstract: Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical ...

Abstract	Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical "3 + 7" treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor ; Clinical Trials as Topic ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/etiology ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Molecular Targeted Therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Proteome ; Signal Transduction ; Transcriptome ; Treatment Outcome
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Protein Kinase Inhibitors ; Proteome ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2019-07-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20143429
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Article ; Online: Characteristics of cells with engraftment capacity within CD34+ cell population upon G-CSF and Plerixafor mobilization.

Mombled, Margaux / Rodriguez, Laura / Avalon, Maryse / Duchez, Pascale / Vlaski-Lafarge, Marija / Debeissat, Christelle / Pérard, Baptiste / Sawai, Katherine M / Pasquet, Jean Max / Bijou, Fontanet / Thévenot, Florian / Cabantous, Txomin / Ivanovic, Zoran / Brunet de la Grange, Philippe

Leukemia

2020 Volume 34, Issue 12, Page(s) 3370–3381

Abstract: In the context of hematopoietic cell transplantation, hematopoietic stem cells and progenitor cells (HSC and HPC) are usually collected by apheresis following their mobilization by G-CSF alone or in combination with Plerixafor® when patients fail to ... ...

Abstract	In the context of hematopoietic cell transplantation, hematopoietic stem cells and progenitor cells (HSC and HPC) are usually collected by apheresis following their mobilization by G-CSF alone or in combination with Plerixafor® when patients fail to respond to G-CSF alone. In medical practice, the quality of the hematopoietic graft is based on CD34
MeSH term(s)	Animals ; Antigens, CD34/metabolism ; Child ; Female ; Granulocyte Colony-Stimulating Factor/metabolism ; Hematopoietic Stem Cell Mobilization/methods ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Heterocyclic Compounds/therapeutic use ; Humans ; Lymphoma/drug therapy ; Lymphoma/metabolism ; Male ; Mice ; Middle Aged ; Multiple Myeloma/drug therapy ; Multiple Myeloma/metabolism ; Stem Cells/drug effects ; Stem Cells/metabolism
Chemical Substances	Antigens, CD34 ; Heterocyclic Compounds ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; plerixafor (S915P5499N)
Language	English
Publishing date	2020-07-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-020-0982-y
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Zs.A 2295: Show issues

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Article: The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation.

Mansier, Olivier / Prouzet-Mauléon, Valérie / Jégou, Gwénaële / Barroso, Kim / Raymundo, Diana Pelizzari / Chauveau, Aurélie / Dumas, Pierre-Yves / Lagarde, Valérie / Turcq, Béatrice / Pasquet, Jean-Max / Viallard, Jean-François / James, Chloé / Praloran, Vincent / Voutetakis, Konstantinos / Chatziioannou, Aristotelis / Mahon, François-Xavier / Chevet, Eric / Lippert, Eric

Cancers

2019 Volume 11, Issue 12

Abstract: Background: Mutations in : Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 ( ...

Abstract	Background: Mutations in Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.
Language	English
Publishing date	2019-12-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11121921
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Article ; Online: Killer immunoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment-free remission.

Dumas, Pierre-Yves / Bérard, Emilie / Bréal, Claire / Dulucq, Stéphanie / Réa, Delphine / Nicolini, Franck / Forcade, Edouard / Dufossée, Melody / Pasquet, Jean-Max / Turcq, Béatrice / Bidet, Audrey / Milpied, Noel / Déchanet-Merville, Julie / Lafarge, Xavier / Etienne, Gabriel / Mahon, François-Xavier

Cancer medicine

2019 Volume 8, Issue 11, Page(s) 4976–4985

Abstract: Background: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer ... ...

Abstract	Background: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates. Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse.
MeSH term(s)	Aged ; Antineoplastic Agents/therapeutic use ; Biomarkers ; Female ; Genetic Variation ; Genotype ; Haplotypes ; Humans ; Imatinib Mesylate/therapeutic use ; Immunophenotyping ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Male ; Middle Aged ; Protein Kinase Inhibitors/therapeutic use ; Receptors, KIR/genetics ; Receptors, KIR/metabolism ; Receptors, KIR2DL5/genetics ; Remission Induction ; Treatment Outcome ; Withholding Treatment
Chemical Substances	Antineoplastic Agents ; Biomarkers ; KIR2DL5B protein, human ; Protein Kinase Inhibitors ; Receptors, KIR ; Receptors, KIR2DL5 ; Imatinib Mesylate (8A1O1M485B)
Language	English
Publishing date	2019-07-09
Publishing country	United States
Document type	Journal Article
ISSN	2045-7634
ISSN (online)	2045-7634
DOI	10.1002/cam4.2371
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Article ; Online: MiR-10a and HOXB4 are overexpressed in atypical myeloproliferative neoplasms.

Dumas, Pierre-Yves / Mansier, Olivier / Prouzet-Mauleon, Valerie / Koya, Junji / Villacreces, Arnaud / Brunet de la Grange, Philippe / Luque Paz, Damien / Bidet, Audrey / Pasquet, Jean-Max / Praloran, Vincent / Salin, Franck / Kurokawa, Mineo / Mahon, François-Xavier / Cardinaud, Bruno / Lippert, Eric

BMC cancer

2018 Volume 18, Issue 1, Page(s) 1098

Abstract: Background: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since ... ...

Abstract	Background: Atypical Myeloproliferative Neoplasms (aMPN) share characteristics of MPN and Myelodysplastic Syndromes. Although abnormalities in cytokine signaling are common in MPN, the pathophysiology of atypical MPN still remains elusive. Since deregulation of microRNAs is involved in the biology of various cancers, we studied the miRNome of aMPN patients. Methods: MiRNome and mutations in epigenetic regulator genes ASXL1, TET2, DNMT3A, EZH2 and IDH1/2 were explored in aMPN patients. Epigenetic regulation of miR-10a and HOXB4 expression was investigated by treating hematopoietic cell lines with 5-aza-2'deoxycytidine, valproic acid and retinoic acid. Functional effects of miR-10a overexpression on cell proliferation, differentiation and self-renewal were studied by transducing CD34 Results: MiR-10a was identified as the most significantly up-regulated microRNA in aMPN. MiR-10a expression correlated with that of HOXB4, sitting in the same genomic locus. The transcription of these two genes was increased by DNA demethylation and histone acetylation, both necessary for optimal expression induction by retinoic acid. Moreover, miR-10a and HOXB4 overexpression seemed associated with DNMT3A mutation in hematological malignancies. However, overexpression of miR-10a had no effect on proliferation, differentiation or self-renewal of normal hematopoietic progenitors. Conclusions: MiR-10a and HOXB4 are overexpressed in aMPN. This overexpression seems to be the result of abnormalities in epigenetic regulation mechanisms. Our data suggest that miR-10a could represent a simple marker of transcription at this genomic locus including HOXB4, widely recognized as involved in stem cell expansion.
MeSH term(s)	Animals ; Biomarkers ; Case-Control Studies ; Cell Differentiation/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; DNA (Cytosine-5-)-Methyltransferases/genetics ; Epigenesis, Genetic ; Female ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Genotype ; Hematopoietic Stem Cells/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemoid Reaction/genetics ; Mice ; MicroRNAs/genetics ; Mutation ; Myeloproliferative Disorders/genetics ; Myeloproliferative Disorders/metabolism ; Myeloproliferative Disorders/pathology ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Biomarkers ; HOXB4 protein, human ; Homeodomain Proteins ; MIRN10 microRNA, human ; MicroRNAs ; Transcription Factors ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA methyltransferase 3A (EC 2.1.1.37)
Language	English
Publishing date	2018-11-12
Publishing country	England
Document type	Journal Article
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-018-4993-2
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