The molecular pathogenesis of the NUP98-HOXA9 fusion protein in acute myeloid leukemia

Río-Machín, Ana; Gómez‐López, Gonzalo; Muñoz, Jimmy; García, Fernando; Maiques-Díaz, Alba; Álvarez, Sara; Salgado, Rocío; Shrestha, Mahesh; Torres-Ruíz, Raúl; Haferlach, Claudia; Larráyoz, María José; Calasanz, Marı́a José; Fitzgibbon, Jude; Cigudosa, Juan C.

doi:10.1038/leu.2017.194

Cited by 28 publications

(20 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…), available online ( ) using the default parameters: Fisher’s exact test, with the Benjamini–Hochberg FDR correction for multiple testing and the background reference list: Homo sapiens whole genome [ 38 , 39 , 40 ]. Clustered enrichment analysis was performed with the Cytoscape software (v3.7.1) plugin ClueGO (v2.5.5), to calculate enrichment of terms as right-sided tests based on the hypergeometric distribution [ 41 ]. ClueGO uses Cohen’s kappa statistics to link the terms in the network and to determine the association strength between the terms, which is an indication of term overlapping to define functional clusters [ 41 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

“…Clustered enrichment analysis was performed with the Cytoscape software (v3.7.1) plugin ClueGO (v2.5.5), to calculate enrichment of terms as right-sided tests based on the hypergeometric distribution [41]. ClueGO uses Cohen's kappa statistics to link the terms in the network and to determine the association strength between the terms, which is an indication of term overlapping to define functional clusters [41,42]. For the analysis of proximal interactors of NUP98-HOXA9 and SET-NUP214, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and REACTOME Pathways together with GO vocabularies (GO Biological Processes (GOBP), GO Molecular Function (GOMF), and GO Cellular Compartments (GOCC)) were used, and functional representations of non-redundant and over-represented terms within the input protein sets were generated.…”

Section: Gene Ontology and Pathway Analysismentioning

confidence: 99%

See 1 more Smart Citation

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Mendes

Jühlen

Bousbata

et al. 2020

Cells

View full text Add to dashboard Cite

The interaction of oncogenes with cellular proteins is a major determinant of cellular transformation. The NUP98-HOXA9 and SET-NUP214 chimeras result from recurrent chromosomal translocations in acute leukemia. Functionally, the two fusion proteins inhibit nuclear export and interact with epigenetic regulators. The full interactome of NUP98-HOXA9 and SET-NUP214 is currently unknown. We used proximity-dependent biotin identification (BioID) to study the landscape of the NUP98-HOXA9 and SET-NUP214 environments. Our results suggest that both fusion proteins interact with major regulators of RNA processing, with translation-associated proteins, and that both chimeras perturb the transcriptional program of the tumor suppressor p53. Other cellular processes appear to be distinctively affected by the particular fusion protein. NUP98-HOXA9 likely perturbs Wnt, MAPK, and estrogen receptor (ER) signaling pathways, as well as the cytoskeleton, the latter likely due to its interaction with the nuclear export receptor CRM1. Conversely, mitochondrial proteins and metabolic regulators are significantly overrepresented in the SET-NUP214 proximal interactome. Our study provides new clues on the mechanistic actions of nucleoporin fusion proteins and might be of particular relevance in the search for new druggable targets for the treatment of nucleoporin-related leukemia.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Gene Ontology and Pathway Analysismentioning

confidence: 99%

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Mendes

Jühlen

Bousbata

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…Several studies also showed that HOX genes promote AML development by forming chimeric fusions with other genes. Fusion of the nucleoprotein NUP98 with HOXA9 via chromosome translocation t(7;11) (p15s;p15) causes development of AML [ 78 ]. Mice overexpressing Hoxa9 and Meis1a induced growth factor-dependent AML in less than 3 months.…”

Section: Hox Genes and Cancermentioning

confidence: 99%

Role of HOX Genes in Stem Cell Differentiation and Cancer

Bhatlekar

Fields²,

Boman

2018

Stem Cells International

144

125

View full text Add to dashboard Cite

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.

show abstract

“…In human leukemia, the first implication of HOXA9 was highlighted by the discovery of the NUP98-HOXA9 fusion protein resulting from t(7;11)(p15;p15) translocation [30,32], a rare (1%–3%) AML subtype associated with poor prognosis [33,34]. NUP98, a nucleoporin of 98 kDa, is a chaperone protein associated with the nuclear pore.…”

Section: Hoxa9: a Leukemic Driver In Amlmentioning

confidence: 99%

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

Lambert

Alioui

Jambon

et al. 2019

Cancers

View full text Add to dashboard Cite

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.

show abstract

The molecular pathogenesis of the NUP98-HOXA9 fusion protein in acute myeloid leukemia

Cited by 28 publications

References 18 publications

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Role of HOX Genes in Stem Cell Differentiation and Cancer

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

Contact Info

Product

Resources

About