scholarly journals Role of HOX Genes in Stem Cell Differentiation and Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Seema Bhatlekar ◽  
Jeremy Z. Fields ◽  
Bruce M. Boman
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Hox Genes ◽  
Stem Cell Differentiation ◽  
Gene Clusters ◽  
Bilateral Symmetry ◽  
The Cancer Genome Atlas ◽  
Cancer Development ◽  
Hox Gene

HOX genes encode an evolutionarily conserved set of transcription factors that control how the phenotype of an organism becomes organized during development based on its genetic makeup. For example, in bilaterian-type animals, HOX genes are organized in gene clusters that encode anatomic segment identity, that is, whether the embryo will form with bilateral symmetry with a head (anterior), tail (posterior), back (dorsal), and belly (ventral). Although HOX genes are known to regulate stem cell (SC) differentiation and HOX genes are dysregulated in cancer, the mechanisms by which dysregulation of HOX genes in SCs causes cancer development is not fully understood. Therefore, the purpose of this manuscript was (i) to review the role of HOX genes in SC differentiation, particularly in embryonic, adult tissue-specific, and induced pluripotent SC, and (ii) to investigate how dysregulated HOX genes in SCs are responsible for the development of colorectal cancer (CRC) and acute myeloid leukemia (AML). We analyzed HOX gene expression in CRC and AML using information from The Cancer Genome Atlas study. Finally, we reviewed the literature on HOX genes and related therapeutics that might help us understand ways to develop SC-specific therapies that target aberrant HOX gene expression that contributes to cancer development.

scholarly journals The Role of Histone Demethylases and DNA Methyltransferases in the Transcription Regulation of HOX Genes in PML-RARa+ AML Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3921-3921
Author(s):  
Katerina Rejlova ◽  
Alena Musilova ◽  
Martina Slamova ◽  
Karel Fiser ◽  
Karolina Skvarova Kramarzova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Fold Increase ◽  
Dna Methyltransferases ◽  
Histone Mark ◽  
Gene Promoters ◽  
Histone Demethylases ◽  
Atra Treatment ◽  
Hox Gene

Abstract Homeobox genes (HOX) encode transcription factors that are frequently deregulated in leukemias. Our previous results showed that HOX gene expression differs among genetically characterized subtypes of pediatric acute myeloid leukemia (AML). Specifically, PML-RARa positive AML patients have overall lowest HOX gene expression which positively correlates with expression of histone 3 lysine 27 (H3K27) demethylases - JMJD3 and UTX and negatively with the expression of DNA methyltransferases - DNMT3a and DNMT3b. Interestingly, JMJD3 was already shown to be a direct target of PML-RARa protein (Martens, JH et al, 2010, Cancer Cell). From these findings we postulated a hypothesis that reduced levels of HOX genes in PML-RARa positive AML are a consequence of suppressed expression of histone demethylases resulting in increased H3K27 methylation and/or of elevated levels of DNMTs leading to de novoDNA methylation. We studied the role of histone demethylases and DNMTs in the regulation of HOX gene expression and the effect of treatment in PML-RARa positive cell lines (NB4 and ATRA-resistant clones NB4-LR2 and NB4-MR2). We treated NB4 cell line by all-trans retinoic acid (ATRA; 1uM), which was described to release the differentiation block caused by the presence of PML-RARa and to degrade the fusion protein. We observed that expression of particular HOX genes (HOXA1, HOXA3, HOXA4, HOXA5, HOXA7, HOXB4, HOXB6) measured by qPCR was significantly increased after ATRA treatment. While the level of JMJD3 was significantly increased upon ATRA treatment as well, the expression of UTX did not change. Furthermore, we detected significantly reduced expression of DNMT3b gene. To exclude a non-specific effect of ATRA, independent of PML-RARa, we used resistant clones LR2 and MR2 bearing mutations in retinoic acid-binding domain. HOX gene expression together with JMJD3, UTX and DNMT3b expression did not change upon ATRA treatment. These results confirm the PML-RARa-dependent regulation of HOX genes. To test the role of JMJD3 in the HOX gene expression regulation, we cultured NB4 cells with a specific inhibitor of histone demethylases, GSK-J4 (1 uM, 10 uM), in the presence of ATRA. The co-treatment caused significant decrease in the expression of studied HOX genes (HOXA1, HOXA3, HOXA5, HOXA7, HOXA10, HOXB4, HOXB6) in comparison to ATRA alone which supports the role of JMJD3 in the transcription regulation. Further, we performed chromatin immunoprecipitation (ChIP) to investigate if the changes of HOX gene expression upon ATRA and GSK-J4 treatment would correspond with changes of histone code on HOX gene promoter regions. ATRA treatment caused reduction of repressive histone mark (H3K27me3) on particular HOX gene promoters (HOXA1, HOXA3, HOXA5, HOXA7), by contrast, combinational treatment of ATRA and GSK-J4 reversed this effect. Accordingly, we detected that ATRA/GSK-J4 co-treatment reduced active histone mark H3K4me2. Next we were interested if JMJD3 inhibition would interfere with the differentiation effect of ATRA. As shown previously, ATRA treatment alone caused differentiation of NB4 cell line whereas the combination with GSK-J4 did not reduce the effect. Interestingly, in addition to differentiation it led cells to apoptosis. Combination of drugs (ATRA - 1uM, GSK-J4 - 1, 2, 5uM) increased significantly the percentage of dead cells in comparison to ATRA or GSK treatment alone (GSK-J4 alone vs in combination with ATRA, 1uM - 1.8 fold, 2uM - 2.2 fold, 5 uM - 2.3 fold increase). Next we measured apoptosis in resistant clones LR2 and MR2. In both cases the highest concentration used of GSK-J4 (5uM) in combination with ATRA caused significant increase of dead cells as well (LR2 - 2.1 fold, MR2 - 2.0 fold increase). Our results indicate that JMJD3 is responsible for the regulation of HOX gene expression in PML-RARa positive leukemia since changes of HOX gene expression correspond with histone modifications on the regions of HOX gene promoters. We assume that DNA methylation driven by DNMT3b can also participate in this process. Moreover, our findings demonstrate potential therapeutic implications of GSK-J4 inhibitor in combination with ATRA in patients with acute promyelocytic leukemia who are not responsive to ATRA monotherapy. Supported by P304/12/2214 and GAUK 196616 Disclosures No relevant conflicts of interest to declare.

The Role of Histone Demethylases in the Transcription Regulation of HOX Genes in PML-RARa+ AML Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 876-876
Author(s):  
Katerina Rejlova ◽  
Karolina Kramarzova ◽  
Meritxell Alberich-Jorda ◽  
Karel Fiser ◽  
Marketa Zaliova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Methylation ◽  
Hox Genes ◽  
Histone Demethylases ◽  
Atra Treatment ◽  
Hox Gene ◽  
Genes Expression ◽  
Methylation Mark

Abstract Homeobox genes (HOX) encode transcription factors that are frequently deregulated in leukemias. Our previous findings described that HOX gene expression differs among genetically characterized subtypes of pediatric AML with PML-RARa+ patients having the lowest overall HOX gene expression. We observed that HOX gene expression positively correlated with expression of histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX and negatively with DNA methyltransferase DNMT3b. Interestingly, it has been shown that JMJD3 is a direct target of PML-RARa protein (Martens, JH et al, 2010, Cancer Cell). These findings led us to postulate the hypothesis that reduced levels of HOX genes in PML-RARa+ AML can be caused by the suppressed expression of histone demethylases, such as JMJD3 and UTX, resulting in increased H3K27 methylation and transcription inhibition. We chose PML-RARa+ NB4 cell line to study the role of PML-RARa fusion gene in the regulation of HOX gene expression. To inhibit the effect of PML-RARa we used all-trans retinoic acid (ATRA; 1 uM, 10 uM) which was described to release the block caused by this fusion protein. Expression of particular HOX genes (e.g., HOXA1, HOXA3, HOXA5, HOXA7) together with that of JMJD3 and UTX assessed by qPCR was significantly elevated after ATRA treatment, while gene expression of DNMT3b was decreased. To test whether the reduction in HOX gene expression is directly related to the levels of JMJD3 and UTX, we cultured NB4 cells with a specific inhibitor of these histone demethylases, GSK-J4 (1 uM, 10 uM), in combination with ATRA. This co-treatment led to inhibition of JMJD3 and UTX proteins, followed by significant reduction of HOX genes expression (e.g., HOXA1, HOXA3, HOXA5, HOXA7). This result supports our hypothesis that HOX genes expression is directly related to JMJD3/UTX activity. To determine the effect of ATRA and GSK-J4 on histone marks we have isolated histones by acid extraction and detected the levels of histones by western blot in NB4 ATRA or GSK-J4/ATRA treated cells. We observed that the level of repressive histone methylation mark (trimethylated H3K27; H3K27me3) was decreased after ATRA treatment (activation of JMJD3/UTX) and increased after GSK-J4/ATRA co-treatment (inhibition of JMJD3/UTX). The opposite effect was observed in active histone methylation marks where di- and tri-methylated H3K4 (H3K4me2, H3K4me3) increased after ATRA treatment and decreased after GSK-J4/ATRA co-treatment. H3K9 dimethylated (another repressive histone methylation mark) levels did not change. Next, to investigate the histone code directly in particular HOX genes regions we performed chromatin immunoprecipitation (ChIP) assays. We studied the presence of H3K27me3 and H3K4me2 in 5´UTR genomic region of particular HOX genes (HOXA1, HOXA2, HOXA3, HOXA5, HOXA7) in cells treated with ATRA alone or in the combination with GSK-J4. Preliminary results showed reduction in repressive marks (H3K27me3) upon ATRA treatment, whereas addition of GSK-J4 prevented this decrease. Accordingly, we observed that ATRA/GSK-J4 co-treatment reduced active histone mark H3K4me2. To evaluate the role of DNA methylation in observed expression changes after ATRA treatment we performed bisulfite sequencing of particular promoter sites of HOX genes (e.g., HOXA7, HOXA5). Although we detected decreased DNMT3b gene expression after ATRA treatment there was no change in DNA methylation of CpGs in studied regions. Our results demonstrate that changes in chromatin activity correspond with changes in HOX gene expression. Moreover, ChIP data show direct binding of the modified histones and HOX 5´UTR sites. Our data implicate histone demethylases in regulation of HOX gene expression in PML-RARa+ leukemic blasts. DNA methylation in these particular HOX genes is not involved in the regulation. Elucidating the mechanism of regulation of HOX genes expression can help to understand their role in the leukemogenic process. Supported by GACR P304/12/2214 and GAUK 568213. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mammalian Homeobox B6 Expression Can Be Correlated With Erythropoietin Production Sites and Erythropoiesis During Development, But Not With Hematopoietic or Nonhematopoietic Stem Cell Populations

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2723-2735 ◽  
Author(s):  
Frank Zimmermann ◽  
Ivan N. Rich
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Hox Genes ◽  
Fetal Liver ◽  
Single Gene ◽  
Lymphoid Cells ◽  
Cell Populations ◽  
Hematopoietic Stem ◽  
Hox Gene ◽  
Stem Cell Populations

Abstract There has been increasing interest in the involvement of mammalian homeobox (HOX) genes in hematopoietic regulation. The HOX genes are clustered in 4 chromosomes in mice and humans. In general, 5′ end HOX gene expression is predominant in hematopoietic stem cell populations, whereas 3′ end HOX gene expression are primarily found in committed progenitor cells. Furthermore, HOX genes of the A cluster are generally found in myelomonocytic cells, B cluster genes in erythropoietic cells, and C cluster genes in lymphoid cells. The results presented here concentrate on a single gene, namely HOX B6. Preliminary observations using whole mount in situ hybridization showed that both HOX B6 and erythropoietin (EPO) gene expression occurred in exactly the same areas of the 8.5-day mouse embryo. As a consequence, we studied the expression of HOX B6 and EPO gene expression from 6.5 to 19.5 days of gestation, in the neonate, and in the adult. It was found that the sequential transfer of erythropoiesis in different organs during development was followed by a similar transfer of HOX B6 and EPO gene expression. Between days 16.5 and 17.5, both HOX B6 and EPO gene expression decrease in the fetal liver, even though hepatic erythropoiesis continues to decline and is transferred to the fetal spleen. Precisely at this time point, HOX B6 and EPO gene expression are transferred to both the fetal spleen and fetal kidney. However, surprisingly, expression of both genes increases again in the fetal liver just before birth. HOX B6 is expressed in cells from in vitro erythropoietic colonies (colony-forming unit-erythroid and burst-forming unit-erythroid) and TER-119+ erythroid cells but not in hematopoietic or nonhematopoietic stem cell populations. When the latter two populations are allowed to differentiate into erythropoietic cells, HOX B6 and erythroid-relevant markers are expressed. The results indicate that HOX B6 is intimately involved in the regulation of the erythropoietic system and could be a marker for this lineage.

The CALM/AF10 Fusion: Molecular Analysis of the Fusion Transcripts in 13 Cases of AML and ALL; Gene Expression Profiling Reveals HOX Gene Deregulation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2895-2895 ◽  
Author(s):  
Alexandre Krause ◽  
Alexander Kohlmann ◽  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fusion Protein ◽  
Hox Genes ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Gene Clusters ◽  
Dominant Negative ◽  
Nucleotide Position ◽  
Gamma Delta ◽  
Hox Gene

Abstract The t(10;11)(p13;q14) is a recurring translocation associated with the CALM/AF10 fusion gene which is found in undifferentiated leukemia, acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma with poor prognosis. The CALM/AF10 fusion protein was reported to be the most common fusion protein in T-ALL with TCR gamma delta rearrangement. We have analyzed samples from 9 patients with different types of leukemia: case 1 (AML M2), case 2 (AML M0), case 3 (Pre T-ALL), case 4 (Acute Undifferentiated Leukemia), case 5 (PreT-ALL), case 6 and 7 (ProT-ALL), case 8 (T-ALL), case 9 (AML), with a t(10;11) translocation suggesting a CALM/AF10-rearrangement. The samples were analyzed for the presence of the CALM/AF10 and AF10/CALM mRNA by RT-PCR and sequence analysis. All these patients were found positive for the CALM/AF10 fusion. In addition, we analyzed a series of twenty-nine patients with T-ALL with gamma delta rearrangement. Among these patients, four were positive for CALM/AF10 transcripts, indicating a high incidence of CALM/AF10 fusions in this group of leukemia. We found three different breakpoints in CALM at nucleotide 1926, 2091 and a new exon, with 106 bases inserted after nt 2064 of CALM in patient 4. In AF10 four breakpoints were identified: at nucleotide position 424, 589, 883 and 979. In seven patients it was also possible to amplify the reciprocal AF10/CALM fusion transcript (case 1, 3, 4, 8, 9, 10 and 11). There was no correlation between disease phenotype and breakpoint location. The patients were 5 to 46 years old (median 25). Ten CALM/AF10 positive patients were further analyzed using oligonucleotide microarrays representing 33,000 different genes (U133 set, Affymetrix). Analysis of microarray gene expression signatures of these patients revealed high expression levels of the homeobox gene MEIS1 and the HOXA cluster genes HOXA1, HOXA4, HOXA5, HOXA7, HOXA9, and HOXA10. The overexpression of HOX genes seen in these CALM/AF10 positive leukemias is reminiscent of the pattern seen in leukemias with rearrangements of the MLL gene, and complex aberrant karyotypes suggesting a common effector pathway (i.e. HOX gene deregulation) for these diverse leukemias. It is known that alhambra, the Drosophila homologue of AF10 can act on polycomb group responsive elements, which play a critical role in the regulation of the HOX gene clusters. It is thus conceivable that the CALM/AF10 fusion proteins acts in a dominant negative fashion on wild type AF10 function relieving the repression that is presumably normally exerted by AF10 on the expression of HOX genes.

scholarly journals Quantitative Analysis of Differential Expression of HOX Genes in Multiple Cancers

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1572
Author(s):  
Orit Adato ◽  
Yaron Orenstein ◽  
Juri Kopolovic ◽  
Tamar Juven-Gershon ◽  
Ron Unger
Keyword(s):  
Gene Expression ◽  
Quantitative Analysis ◽  
Differential Expression ◽  
Survival Data ◽  
Hox Genes ◽  
Expression Patterns ◽  
The Cancer Genome Atlas ◽  
Tumor Type ◽  
Hox Gene ◽  
Cancer Types

Transcription factors encoded by Homeobox (HOX) genes play numerous key functions during early embryonic development and differentiation. Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers. Their expression levels in cancers tend to differ based on tissue and tumor type. Here, we performed a comprehensive analysis comparing HOX gene expression in different cancer types, obtained from The Cancer Genome Atlas (TCGA), with matched healthy tissues, obtained from Genotype-Tissue Expression (GTEx). We identified and quantified differential expression patterns that confirmed previously identified expression changes and highlighted new differential expression signatures. We discovered differential expression patterns that are in line with patient survival data. This comprehensive and quantitative analysis provides a global picture of HOX genes’ differential expression patterns in different cancer types.

scholarly journals A Case of Identity: HOX Genes in Normal and Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 512 ◽  
Author(s):  
Smith ◽  
Zyoud ◽  
Allegrucci
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Cancer Stem Cells ◽  
Adult Stem Cells ◽  
Hox Genes ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Hox Gene

Stem cells are undifferentiated cells that have the unique ability to self-renew and differentiate into many different cell types. Their function is controlled by core gene networks whose misregulation can result in aberrant stem cell function and defects of regeneration or neoplasia. HOX genes are master regulators of cell identity and cell fate during embryonic development. They play a crucial role in embryonic stem cell differentiation into specific lineages and their expression is maintained in adult stem cells along differentiation hierarchies. Aberrant HOX gene expression is found in several cancers where they can function as either oncogenes by sustaining cell proliferation or tumor-suppressor genes by controlling cell differentiation. Emerging evidence shows that abnormal expression of HOX genes is involved in the transformation of adult stem cells into cancer stem cells. Cancer stem cells have been identified in most malignancies and proved to be responsible for cancer initiation, recurrence, and metastasis. In this review, we consider the role of HOX genes in normal and cancer stem cells and discuss how the modulation of HOX gene function could lead to the development of novel therapeutic strategies that target cancer stem cells to halt tumor initiation, progression, and resistance to treatment.

scholarly journals Time-Space Translation: A Developmental Principle

2010 ◽  
Vol 10 ◽  
pp. 2207-2214 ◽  
Author(s):  
A. J. Durston ◽  
H. J. Jansen ◽  
S. A. Wacker
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Positional Information ◽  
Hox Gene ◽  
Morphogenetic Movements ◽  
Spemann Organizer ◽  
Stable Pattern ◽  
Time Space ◽  
Anterior Posterior

We review a recently discovered developmental mechanism. Anterior-posterior positional information for the vertebrate trunk is generated by sequential interactions between a timer in the early nonorganizer mesoderm (NOM) and the Spemann organizer (SO). The timer is characterized by temporally collinear activation of a series of Hox genes in the early ventral and lateral mesoderm (i.e., the NOM) of the Xenopus gastrula. This early Hox gene expression is transient, unless it is stabilized by signals from the SO. The NOM and the SO undergo timed interactions due to morphogenetic movements during gastrulation, which lead to the formation of an anterior-posterior axial pattern and stable Hox gene expression. When separated from each other, neither the NOM nor the SO is able to induce anterior-posterior pattern formation of the trunk. We present a model describing that the NOM acquires transiently stable hox codes and spatial collinearity, and that morphogenetic movements then continually bring new cells from the NOM within the range of SO signals that cause transfer of the mesodermal pattern to a stable pattern in neurectoderm and, thereby, create patterned axial structures. In doing so, the age of the NOM, but not the age of the SO, defines positional values along the anterior-posterior axis. We postulate that the temporal information from the NOM is linked to mesodermal Hox expression. The role of the SO for trunk patterning turns out to be the induction of neural tissue as prerequisite for neural hox patterning. Apparently, development of a stable anterior-posterior pattern requires neural hox patterning. We believe that this mechanism represents a developmental principle.

scholarly journals Organ- and Site-Specific HOX Gene Expression in Stromal Cells

2021 ◽  
Author(s):  
Masoumeh Mirrahimi ◽  
Caroline Ospelt
Keyword(s):  
Gene Expression ◽  
Stromal Cells ◽  
Hox Genes ◽  
Specific Pattern ◽  
Body Plan ◽  
The Body ◽  
Site Specific ◽  
Hox Gene ◽  
Conserved Genes

HOX genes are a group of evolutionarily conserved genes that encode a family of transcription factors that regulate early developmental morphogenetic processes and continue to be expressed into adulthood. These highly conserved HOX factors play an unquestioned crucial role as master regulators during embryonic vertebrate development and morphogenesis by controlling the three dimensional body plan organization. HOX genes specify regions of the body plan of an embryo along the head-tail axis. They encode proteins that specify the characteristics of ‘position’, ensuring that the correct structures form in the correct places of the body. Expression of HOX is known to persist in many tissues in the postnatal period suggesting the role of these genes not only during development but also for the functioning of tissues throughout life. The tissue-specific pattern of HOX gene expression is inherent in stromal/stem cells of mesenchymal origin, such as mesenchymal stromal cells, fibroblasts, smooth muscle cells, and preadipocytes, enabling them to memorize their topographic location in the form of their HOX code and to fulfill their location-specific functions. In this chapter, we focus on the expression and potential role of HOX genes in adult tissues. We review evidence that site-specific expression of HOX genes is connected to location-specific disease susceptibility and review studies showing that dysregulated expression of HOX genes can be associated with various diseases. By recognizing the importance of site-specific molecular mechanisms in the organ stroma, we gain new insights into the processes underlying the site-specific manifestation of disease.

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