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13 pages, 3061 KiB

Open AccessArticle

Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

by Laura M. Kettyle, Charles-Étienne Lebert-Ghali, Ivan V. Grishagin, Glenda J. Dickson, Paul G. O’Reilly, David A. Simpson, Janet J. Bijl, Ken I. Mills, Guy Sauvageau and Alexander Thompson

Cancers 2019, 11(12), 2036; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11122036 - 17 Dec 2019

Cited by 4 | Viewed by 2758

Abstract

High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA [...] Read more.

High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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15 pages, 3166 KiB

Open AccessArticle

Anatomic Origin of Osteochondrogenic Progenitors Impacts Sensitivity to EWS-FLI1-Induced Transformation

by Elise R. Pfaltzgraff, April Apfelbaum, Andrew P. Kassa, Jane Y. Song, Wei Jiang, Tahra K. Suhan, Deneen M. Wellik and Elizabeth R. Lawlor

Cancers 2019, 11(3), 313; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030313 - 06 Mar 2019

Cited by 6 | Viewed by 3632

Abstract

Ewing sarcomas predominantly arise in pelvic and stylopod bones (i.e., femur and humerus), likely as a consequence of EWS-FLI1 oncogene-induced transformation of mesenchymal stem/progenitor cells (MSCs). MSCs located in the embryonic superficial zone cells (eSZ) of limbs express anatomically distinct posterior Hox genes. [...] Read more.

Ewing sarcomas predominantly arise in pelvic and stylopod bones (i.e., femur and humerus), likely as a consequence of EWS-FLI1 oncogene-induced transformation of mesenchymal stem/progenitor cells (MSCs). MSCs located in the embryonic superficial zone cells (eSZ) of limbs express anatomically distinct posterior Hox genes. Significantly, high expression of posterior HOXD genes, especially HOXD13, is a hallmark of Ewing sarcoma. These data drove our hypothesis that Hox genes in posterior skeleton MSCs contribute to Ewing sarcoma tumorigenesis. We isolated eSZ cells from stylopod and zeugopod (i.e., tibia/fibula, radius/ulna) bones, from wild-type and Hoxd13 mutant embryos, and tested the impact of EWS-FLI1 transduction on cell proliferation, gene expression, and tumorigenicity. Our data demonstrate that both stylopod and zeugopod eSZ cells tolerate EWS-FLI1 but that stylopod eSZ cells are relatively more susceptible, demonstrating changes in proliferation and gene expression consistent with initiation of malignant transformation. Significantly, loss of Hoxd13 had no impact, showing that it is dispensable for the initiation of EWS-FLI1-induced transformation in mouse MSCs. These findings show that MSCs from anatomically distinct sites are differentially susceptible to EWS-FLI1-induced transformation, supporting the premise that the dominant presentation of Ewing sarcoma in pelvic and stylopod bones is attributable to anatomically-defined differences in MSCs. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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Review

Jump to: Research

11 pages, 441 KiB

Open AccessReview

PBX3 in Cancer

by Richard Morgan and Hardev S Pandha

Cancers 2020, 12(2), 431; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020431 - 13 Feb 2020

Cited by 26 | Viewed by 2970

Abstract

PBX3 is a homeodomain-containing transcription factor of the pre-B cell leukemia (PBX) family, members of which have extensive roles in early development and some adult processes. A number of features distinguish PBX3 from other PBX proteins, including the ability to form specific and [...] Read more.

PBX3 is a homeodomain-containing transcription factor of the pre-B cell leukemia (PBX) family, members of which have extensive roles in early development and some adult processes. A number of features distinguish PBX3 from other PBX proteins, including the ability to form specific and stable interactions with DNA in the absence of cofactors. PBX3 has frequently been reported as having a role in the development and maintenance of a malignant phenotype, and high levels of PBX3 tumor expression have been linked to shorter overall survival in cancer. In this review we consider the similarities and differences in the function of PBX3 in different cancer types and draw together the core signaling pathways involved to help provide a better insight into its potential as a therapeutic target. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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10 pages, 370 KiB

Open AccessReview

HOX Genes in High Grade Ovarian Cancer

by Praveena Idaikkadar, Richard Morgan and Agnieszka Michael

Cancers 2019, 11(8), 1107; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081107 - 03 Aug 2019

Cited by 12 | Viewed by 3809

Abstract

HOX genes are highly conserved members of the homeobox superfamily that have a crucial role in determining cellular identity. High grade ovarian cancer is the most lethal gynaecological malignancy. Our understanding of the role of HOX genes in the oncogenesis of ovarian cancer [...] Read more.

HOX genes are highly conserved members of the homeobox superfamily that have a crucial role in determining cellular identity. High grade ovarian cancer is the most lethal gynaecological malignancy. Our understanding of the role of HOX genes in the oncogenesis of ovarian cancer is evolving, and here we review their dysregulated expression patterns, their function in cell survival and invasion, their potential uses as biomarkers, and ways in which HOX genes are being targeted with new and existing drugs. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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38 pages, 2734 KiB

Open AccessReview

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

by Mélanie Lambert, Meryem Alioui, Samy Jambon, Sabine Depauw, Isabelle Van Seuningen and Marie-Hélène David-Cordonnier

Cancers 2019, 11(6), 837; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060837 - 17 Jun 2019

Cited by 33 | Viewed by 6805

Abstract

HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with [...] Read more.

HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an “undruggable” target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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10 pages, 6047 KiB

Open AccessReview

Deciphering The Potential Role of Hox Genes in Pancreatic Cancer

by Tzu-Lei Kuo, Kuang-Hung Cheng, Li-Tzong Chen and Wen-Chun Hung

Cancers 2019, 11(5), 734; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050734 - 27 May 2019

Cited by 18 | Viewed by 4303

Abstract

The Hox gene family plays an important role in organogenesis and animal development. Currently, 39 Hox genes that are clustered in four chromosome regions have been identified in humans. Emerging evidence suggests that Hox genes are involved in the development of the pancreas. [...] Read more.

The Hox gene family plays an important role in organogenesis and animal development. Currently, 39 Hox genes that are clustered in four chromosome regions have been identified in humans. Emerging evidence suggests that Hox genes are involved in the development of the pancreas. However, the expression of Hox genes in pancreatic tumor tissues has been investigated in only a few studies. In addition, whether specific Hox genes can promote or suppress cancer metastasis is not clear. In this article, we first review the recent progress in studies on the role of Hox genes in pancreatic cancer. By comparing the expression profiles of pancreatic cancer cells isolated from genetically engineered mice established in our laboratory with three different proliferative and metastatic abilities, we identified novel Hox genes that exhibited tumor-promoting activity in pancreatic cancer. Finally, a potential oncogenic mechanism of the Hox genes was hypothesized. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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20 pages, 632 KiB

Open AccessReview

Paralogous HOX13 Genes in Human Cancers

by Gerardo Botti, Clemente Cillo, Rossella De Cecio, Maria Gabriella Malzone and Monica Cantile

Cancers 2019, 11(5), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050699 - 20 May 2019

Cited by 9 | Viewed by 3763

Abstract

Hox genes (HOX in humans), an evolutionary preserved gene family, are key determinants of embryonic development and cell memory gene program. Hox genes are organized in four clusters on four chromosomal loci aligned in 13 paralogous groups based on sequence homology (Hox gene [...] Read more.

Hox genes (HOX in humans), an evolutionary preserved gene family, are key determinants of embryonic development and cell memory gene program. Hox genes are organized in four clusters on four chromosomal loci aligned in 13 paralogous groups based on sequence homology (Hox gene network). During development Hox genes are transcribed, according to the rule of “spatio-temporal collinearity”, with early regulators of anterior body regions located at the 3’ end of each Hox cluster and the later regulators of posterior body regions placed at the distal 5’ end. The onset of 3’ Hox gene activation is determined by Wingless-type MMTV integration site family (Wnt) signaling, whereas 5’ Hox activation is due to paralogous group 13 genes, which act as posterior-inhibitors of more anterior Hox proteins (posterior prevalence). Deregulation of HOX genes is associated with developmental abnormalities and different human diseases. Paralogous HOX13 genes (HOX A13, HOX B13, HOX C13 and HOX D13) also play a relevant role in tumor development and progression. In this review, we will discuss the role of paralogous HOX13 genes regarding their regulatory mechanisms during carcinogenesis and tumor progression and their use as biomarkers for cancer diagnosis and treatment. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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25 pages, 857 KiB

Open AccessReview

The Role of HOX Transcription Factors in Cancer Predisposition and Progression

by Bo Li, Qilai Huang and Gong-Hong Wei

Cancers 2019, 11(4), 528; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040528 - 12 Apr 2019

Cited by 84 | Viewed by 7504

Abstract

Homeobox (HOX) transcription factors, encoded by a subset of homeodomain superfamily genes, play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. Findings over the past decade have revealed that mutations in HOX genes can lead to increased cancer [...] Read more.

Homeobox (HOX) transcription factors, encoded by a subset of homeodomain superfamily genes, play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. Findings over the past decade have revealed that mutations in HOX genes can lead to increased cancer predisposition, and HOX genes might mediate the effect of many other cancer susceptibility factors by recognizing or executing altered genetic information. Remarkably, several lines of evidence highlight the interplays between HOX transcription factors and cancer risk loci discovered by genome-wide association studies, thereby gaining molecular and biological insight into cancer etiology. In addition, deregulated HOX gene expression impacts various aspects of cancer progression, including tumor angiogenesis, cell autophagy, proliferation, apoptosis, tumor cell migration, and metabolism. In this review, we will discuss the fundamental roles of HOX genes in cancer susceptibility and progression, highlighting multiple molecular mechanisms of HOX involved gene misregulation, as well as their potential implications in clinical practice. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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13 pages, 682 KiB

Open AccessReview

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

by Jessica Smith, Ahmad Zyoud and Cinzia Allegrucci

Cancers 2019, 11(4), 512; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040512 - 10 Apr 2019

Cited by 33 | Viewed by 6343

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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9 pages, 662 KiB

Open AccessReview

Kinase Regulation of HOX Transcription Factors

by Monika Primon, Keith D. Hunter, Hardev S. Pandha and Richard Morgan

Cancers 2019, 11(4), 508; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040508 - 10 Apr 2019

Cited by 19 | Viewed by 3882

Abstract

The HOX genes are a group of homeodomain-containing transcription factors that play important regulatory roles in early development, including the establishment of cell and tissue identity. HOX expression is generally reduced in adult cells but is frequently re-established as an early event in [...] Read more.

The HOX genes are a group of homeodomain-containing transcription factors that play important regulatory roles in early development, including the establishment of cell and tissue identity. HOX expression is generally reduced in adult cells but is frequently re-established as an early event in tumour formation and supports an oncogenic phenotype. HOX transcription factors are also involved in cell cycle regulation and DNA repair, along with normal adult physiological process including stem cell renewal. There have been extensive studies on the mechanism by which HOX proteins regulate transcription, with particular emphasis on their interaction with cofactors such as Pre-B-cell Leukaemia Homeobox (PBX) and Myeloid Ecotropic Viral Integration Site 1 (MEIS). However, significantly less is known of how the activity of HOX proteins is regulated. There is growing evidence that phosphorylation may play an important role in this context, and in this review, we draw together a number of important studies published over the last 20 years, and discuss the relevance of phosphorylation in the regulation and function of HOX proteins in development, evolution, cell cycle regulation, and cancer. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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14 pages, 1537 KiB

Open AccessReview

The Enigmatic HOX Genes: Can We Crack Their Code?

by Zhifei Luo, Suhn K. Rhie and Peggy J. Farnham

Cancers 2019, 11(3), 323; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030323 - 07 Mar 2019

Cited by 38 | Viewed by 12391

Abstract

Homeobox genes (HOX) are a large family of transcription factors that direct the formation of many body structures during early embryonic development. There are 39 genes in the subgroup of homeobox genes that constitute the human HOX gene family. Correct embryonic development of [...] Read more.

Homeobox genes (HOX) are a large family of transcription factors that direct the formation of many body structures during early embryonic development. There are 39 genes in the subgroup of homeobox genes that constitute the human HOX gene family. Correct embryonic development of flies and vertebrates is, in part, mediated by the unique and highly regulated expression pattern of the HOX genes. Disruptions in these fine-tuned regulatory mechanisms can lead to developmental problems and to human diseases such as cancer. Unfortunately, the molecular mechanisms of action of the HOX family of transcription factors are severely under-studied, likely due to idiosyncratic details of their structure, expression, and function. We suggest that a concerted and collaborative effort to identify interacting protein partners, produce genome-wide binding profiles, and develop HOX network inhibitors in a variety of human cell types will lead to a deeper understanding of human development and disease. Within, we review the technological challenges and possible approaches needed to achieve this goal. Full article

(This article belongs to the Special Issue HOX Genes in Cancer)

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