Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets

Collins, Cailin; Hess, Jay L.

doi:10.1038/onc.2015.174

Cited by 152 publications

(150 citation statements)

References 167 publications

(164 reference statements)

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“…Our observations are in agreement with those shown in other models of epithelial malignancies; methylation and HOXA9 loss of expression have been reported in breast, ovarian, bladder, oral, and lung cancer (Rauch et al, 2007;Wu et al, 2007;Guerrero-Preston et al, 2011;Kim et al, 2013;Conway et al, 2014). All of these observations Indicate a possible role of HOXA9 as a tumor suppressor gene in epithelial cells; unlike its well described oncogenic potential in hematopoietic malignancies (Collins and Hess, 2015).…”

Section: Discussionsupporting

confidence: 92%

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

Alvarado-Ruíz¹,

Martínez-Silva²,

Torres-Reyes³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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HOX transcription factors are evolutionarily conserved in many different species and are involved in important cellular processes such as morphogenesis, differentiation, and proliferation. They have also recently been implicated in carcinogenesis, but their precise role in cancer, especially in cervical cancer (CC), remains unclear. In this work, using microarray assays followed by the quantitative polymerase chain reaction (qPCR), we found that the expression of 25 HOX genes was downregulated in CC derived cell lines compared with nontumorigenic keratinocytes. In particular, the expression of HOXA9 was observed as down-modulated in CCderived cell lines. The expression of HOXA9 has not been previously reported in CC, or in normal keratinocytes of the cervix. We found that normal CC from women without cervical lesions express HOXA9; in contrast, CC cell lines and samples of biopsies from women with CC showed significantly diminished HOXA9 expression. Furthermore, we found that methylation at the first exon of HOXA9 could play an important role in modulating the expression of this gene. Exogenous restoration of HOXA9 expression in CC cell lines decreased cell proliferation and migration, and induced an epithelial-like phenotype. Interestingly, the silencing of human papilloma virus (HPV) E6 and E7 oncogenes induced expression of HOXA9. In conclusion, controlling HOXA9 expression appears to be a necessary step during CC development. Further studies are needed to delineate the role of HOXA9 during malignant progression and to afford more insights into the relationship between downmodulation of HOXA9 and viral HPV oncoprotein expression during cercical cancer development.

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Section: Discussionsupporting

confidence: 92%

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

Alvarado-Ruíz¹,

Martínez-Silva²,

Torres-Reyes³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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“…Using this approach, we confirmed the requirement for the Hoxa9/10 functional gene network in Npm1c AML maintenance. Interestingly, although it is widely appreciated that overexpression of Hoxa9 stimulates leukemic transformation, 22,29,33 in our model, disruption of Hoxa10 had a more detrimental impact on AML cell survival, mirroring our recent genome-wide essentiality screen in the NPM1c-harboring OCI-AML3 cell line.…”

Section: Discussionmentioning

confidence: 98%

“…11,29,30 Notably, although Nkx2-3 overexpression enhanced colony-forming ability of wild-type and Other genes whose disruption reduced proliferation of Npm1cA-driven AMLs included the Mll (Kmt2a) gene, recently shown to be a therapeutic target in this AML type 31 ; Hoxa9/10 partners or cofactors including Meis1, Pbx1, and Pbx3; and the HOXA9 targets Bcl2 and Lmo2. [32][33][34] A number of genes with altered expression in mutant preleukemic MPP cells were not required for survival of AML cells in vitro ( Figure 6C). However, we cannot exclude a potential role for these in leukemia initiation.…”

Section: Hoxa Gene Expression Is Unaltered In Npm1-mutant Early Multimentioning

confidence: 99%

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

Dovey

Cooper

Mupo

et al. 2017

Blood

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Key Points• Npm1c and Nras-G12D comutation in mice leads to AML with a longer latency and a more mature phenotype than the Npm1c/Flt3-ITD combination.• Mutant Flt3 or Nras allele amplification is the dominant mode of progression in both Npm1c/Flt3-ITD and Npm1c/ Nras-G12D murine AML.NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. . During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1 cA/1 ;Nras G12D/1 mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that Hoxa genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRAS-G12D-mutant AML and functionally confirm the role of HOXA genes in

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“…Hoxa9 belongs to a family of homeodomain containing transcription factors (60). Hox family regulates genes which control the anterior-posterior body plan and assign tissue fate in human (61).…”

Section: Abnormally Spliced (As) Mrnas In Amlmentioning

confidence: 99%

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

Zhou

Chng

2017

Stem Cell Investig.

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The spliceosome, the cellular splicing machinery, regulates RNA splicing of messenger RNA precursors (pre-mRNAs) into maturation of protein coding RNAs. Recurrent mutations and copy number changes in genes encoding spliceosomal proteins and splicing regulatory factors have tumor promoting or suppressive functions in hematological malignancies, as well as some other cancers. Leukemia stem cell (LSC) populations, although rare, are essential contributors of treatment failure and relapse. Recent researches have provided the compelling evidence that link the erratic spicing activity to the LSC phenotype in acute myeloid leukemia (AML). In this article, we describe the diverse roles of aberrant splicing in hematological malignancies, particularly in AML and their contributions to the characteristics of LSC. We review these promising strategies to exploit the addiction of aberrant spliceosomal machinery for anti-leukemic therapy with aim to eradicate LSC. However, given the complexity and plasticity of spliceosome and not fully known functions of splicing in cancer, the challenges facing the development of the therapeutic strategies targeting RAN splicing are highlighted and future directions are discussed too.

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Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets

Cited by 152 publications

References 167 publications

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

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