Gene Summary

Gene:HOXA9; homeobox A9
Aliases: HOX1, ABD-B, HOX1G, HOX1.7
Summary:In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. This gene is highly similar to the abdominal-B (Abd-B) gene of Drosophila. A specific translocation event which causes a fusion between this gene and the NUP98 gene has been associated with myeloid leukemogenesis. Read-through transcription exists between this gene and the upstream homeobox A10 (HOXA10) gene.[provided by RefSeq, Mar 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Hox-A9
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • HOXA9
  • Mutation
  • Up-Regulation
  • DNA-Binding Proteins
  • Chromosome 7
  • Homeodomain Proteins
  • Biomarkers, Tumor
  • Chromosome 11
  • Recombinant Fusion Proteins
  • Molecular Sequence Data
  • RUNX1 Translocation Partner 1 Protein
  • Validation Studies as Topic
  • Leukemic Gene Expression Regulation
  • Messenger RNA
  • Histone-Lysine N-Methyltransferase
  • Homeobox Genes
  • Oncogene Fusion Proteins
  • Transcriptional Elongation Factors
  • Transduction
  • Tumor Stem Cell Assay
  • Cancer Gene Expression Regulation
  • Oligonucleotide Array Sequence Analysis
  • Disease Models, Animal
  • Myeloid Leukemia
  • Proto-Oncogenes
  • Cell Differentiation
  • Leukaemia
  • CpG Islands
  • KMT2A
  • myeloid ecotropic viral integration site 1 protein
  • Autologous Transplantat
  • Transcriptome
  • Base Sequence
  • Chronic Myelogenous Leukemia
  • Sulfites
  • DNA Methylation
  • Epigenetics
  • Cell Proliferation
  • Gene Expression Profiling
  • NUP98
  • Neoplastic Cell Transformation
  • Acute Myeloid Leukaemia
  • Nuclear Proteins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HOXA9 (cancer-related)

Kelly MJ, So J, Rogers AJ, et al.
Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis.
Nat Commun. 2019; 10(1):1347 [PubMed] Free Access to Full Article Related Publications
The BCL6 Corepressor (BCOR) is a component of a variant Polycomb repressive complex 1 (PRC1) that is essential for normal development. Recurrent mutations in the BCOR gene have been identified in acute myeloid leukaemia and myelodysplastic syndrome among other cancers; however, its function remains poorly understood. Here we examine the role of BCOR in haematopoiesis in vivo using a conditional mouse model that mimics the mutations observed in haematological malignancies. Inactivation of Bcor in haematopoietic stem cells (HSCs) results in expansion of myeloid progenitors and co-operates with oncogenic Kras

Zhang X, Zhou M, Chao H, et al.
[Characteristics of a patient with myeloid neoplasm and co-existence of t(7;11)(p15;p15) and t(5;12)(q33;p13) translocations].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019; 36(3):249-252 [PubMed] Related Publications
OBJECTIVE: To delineate the clinical and molecular characteristics of a patient with myeloid neoplasm and co-existence of t(7;11)(p15;p15) and t(5;12)(q33;p13) translocations.
METHODS: Clinical data of the patient was collected. Conventional karyotyping, reverse transcriptase (RT)-PCR and next generation sequencing (NGS) were carried out to delineate its genetic features.
RESULTS: The patient has featured recurrent rash, fatigue, loss of appetite and splenomegaly. Laboratory test suggested hyperleukocytosis of FAB-M2-subtype. Neither eosinophilia nor basophilia was presented. NUP98/HOXA9 and ETV6/PDGFRB fusion genes were detected by RT-PCR. NGS and DNA-PCR showed the co-existence of WT1 p.C423Y, KRAS p.G12D and DNMT3A p.R882C mutations. The patient achieved morphological remission after imatinib plus coventional chemotherapy (standard IAC regimen). However, the disease has relapsed shortly after. Treatment was switched to HHT-Ara-C-Acla regimen, no hematological response was observed. The ETV6/PDGFRB fusion gene was undetectable in bone marrow sample, though strong expression of NUP98/HOXA9 was detectable throughout the whole course.
CONCLUSION: Acute myeloid leukemia in association with the co-existence of NUP98/HOXA9 and ETV6/PDGFRB fusion genes have unique clinical and genetic features. Imatinib seems to have no impact on the overall survival in such cases.

Liu Y, Wang Y, Yang H, et al.
MicroRNA‑873 targets HOXA9 to inhibit the aggressive phenotype of osteosarcoma by deactivating the Wnt/β‑catenin pathway.
Int J Oncol. 2019; 54(5):1809-1820 [PubMed] Related Publications
Several microRNAs (miRNAs or miRs) that regulate a variety of cancer‑related events are dysregulated in osteosarcoma (OS). An exploration of the specific roles of miRNAs in OS is crucial for the identification of suitable therapeutic targets. Previous studies have shown that miR‑873 plays tumor suppressive or oncogenic roles in different types of cancer. However, whether miR‑873 is implicated in OS carcinogenesis and cancer progression remains poorly understood. In the present study, we demonstrated that the miR‑873 levels were decreased in OS tissues and cell lines. The decreased expression of miR‑873 was related to tumor size, clinical stage and distant metastasis in patients with OS. The introduction of miR‑873 significantly inhibited tumor cell proliferation, migration and invasion in vitro, promoted apoptosis in vitro and restricted tumor growth in vivo. Furthermore, homeobox A9 (HOXA9) was validated as a direct target gene of miR‑873 in OS cells. HOXA9 was markedly expressed in OS tissues, and its upregulation inversely correlated with the miR‑873 levels. Moreover, HOXA9 silencing produced similar effects as observed with miR‑873 overexpression in OS cells. Consistently, the exogenous expression of HOXA9 partially reversed the suppression of the aggressive phenotype induced by miR‑873 overexpression in OS cells. Notably, miR‑873 was able to deactivate the Wnt/β‑catenin pathway in OS cells by regulating HOXA9, both in vitro and in vivo. On the whole, the present study demonstrates that miR‑873 suppresses the development of OS by directly targeting HOXA9 and inhibiting the Wnt/β‑catenin pathway, and suggests that miR‑873 may prove to be useful as a diagnostic biomarker of OS, as well as in the development of novel therapies.

Kawahara M, Teramoto Y, Asai A, et al.
[Significance of monitoring cerebrospinal fluid leukocyte counts in managing central nervous system disease of acute myeloid leukemia in patients presenting with intracerebral hemorrhage upon initial examination].
Rinsho Ketsueki. 2018; 59(12):2578-2582 [PubMed] Related Publications
A 17-year-old woman was urgently transported to our hospital due to consciousness disturbance. A blood examination revealed intracerebral hemorrhage, WBC 233,800/l, blasts 93%, and disseminated intravascular coagulation. The results of bone-marrow aspiration indicated acute myeloid leukemia (M2 in FAB classification) with t (7;11) (p15;p15) and the resulting chimeric gene NUP98-HOXA9 and with FLT3-ITD. Following hematoma evacuation, induction therapy was initiated and the leukocytes in the cerebrospinal fluid observed in the spinal drainage were monitored. Because they increased on days 5 and 9 after the completion of induction therapy, intrathecal chemotherapy (IT) was performed; this finally contributed to controlling AML in the central nervous system (CNS), together with the restoration of normal hematopoiesis. Subsequently, after complete molecular remission with consolidation therapies containing high-dose cytarabine, a bone-marrow transplantation with a myeloablative regimen was conducted from a 1-allele mismatched sibling donor. Finally, the patient was discharged without major sequela on day 228 after the first visit. The management of CNS disease in AML with intracerebral hemorrhage remains unclear. Our case suggests that IT at the appropriate time based on the monitored number of cerebrospinal fluid leukocytes could be useful in controlling AML in the CNS after intracerebral hemorrhage.

Yang Z, Qi W, Sun L, et al.
DNA methylation analysis of selected genes for the detection of early-stage lung cancer using circulating cell-free DNA.
Adv Clin Exp Med. 2019; 28(3):361-366 [PubMed] Related Publications
BACKGROUND: Lung cancer is still the deadliest cancer in the world, but early diagnosis cannot be achieved because of the limitations of diagnostic methods. DNA methylation has been proven to be a potentially powerful tool for cancer detection and diagnosis over the past decade.
OBJECTIVES: We explored whether free DNA methylation in plasma can be a reliable biomarker for noninvasive lung cancer detection.
MATERIAL AND METHODS: We detected the methylation of 8 genes in plasma-free DNA of patients with pulmonary space-occupying lesions using real-time quantitative methylation-specific polymerase chain reaction (QMSP). Among the 50 selected patients, 39 were confirmed using pathological analysis as having early lung cancer and 11 had an inflammatory pseudotumor.
RESULTS: The QMSP detection showed that the methylation levels of 8 genes in the patients were significantly higher than in the non-lung cancer group. The methylation level of CALCA was the highest and the methylation level of HOXA9 was the lowest. Methylation of RASSF1A, CDKN2A and DLEC1 occured only in lung cancer patients, while methylation of CALCA, CDH13, PITX2, HOXA9, and WT1 occured not only in lung cancer patients, but also in non-lung cancers. The specificity reached 95~100%, whether for a single gene or overall, but the sensitivity was relatively low for each gene. The sensitivity can reach 72% if the methylation of any of the 8 genes is positive and the overall specificity was 91%. The positive and negative predictive values were 96% and 60%, respectively.
CONCLUSIONS: Quantitative detection of DNA methylation in plasma is a potential method for early diagnosis of lung cancer.

Costa AL, Moreira-Barbosa C, Lobo J, et al.
DNA methylation profiling as a tool for testicular germ cell tumors subtyping.
Epigenomics. 2018; 10(12):1511-1523 [PubMed] Related Publications
AIM: Assess differential patterns of selected five genes' promoter methylation among testicular germ cell tumors (TGCT) subtypes.
MATERIALS & METHODS:  CRIPTO, HOXA9, MGMT, RASSF1A and SCGB3A1 promoter methylation levels were evaluated by quantitative methylation-specific PCR in 161 TGCT and 16 controls. Associations between clinicopathological parameters and promoter methylation levels were assessed, and receiver operating characteristics curve analysis was performed.
RESULTS: Promoter methylation of CRIPTO/HOXA9/SCGB3A1 panel and RASSF1A best discriminated between controls and nonseminomatous tumors or seminomas, respectively, whereas HOXA9/RASSF1A panel displayed the best discriminative performance between nonseminomatous tumor and seminomas. Significant differences in CRIPTO, MGMT and RASSF1A methylation levels were depicted between pure forms and matched mixed components of seminomas and embryonal carcinoma. HOXA9, RASSF1A and SCGB3A1 promoter methylation significantly associated with tumor stage.
CONCLUSION: Different combinations of five genes' promoter methylation levels discriminate among TGCT subtypes. Methylation patterns may also assist in identification of more clinically aggressive tumors.

Arabanian LS, Johansson P, Staffas A, et al.
The endothelin receptor type A is a downstream target of Hoxa9 and Meis1 in acute myeloid leukemia.
Leuk Res. 2018; 75:61-68 [PubMed] Related Publications
Endothelin receptor type A (EDNRA) is known as a mediator of cell proliferation and survival. Aberrant regulation of EDNRA has been shown to play a role in tumor growth and metastasis. Using a global gene expression screen, we found that expression of Ednra was upregulated in murine leukemia inducing cells co-expressing Hoxa9 and Meis1 compared to cells only expressing Hoxa9. The aim of this study was to explore the role of Ednra in leukemogenesis further. In a murine bone marrow transplantation model, mice transplanted with cells overexpressing Ednra and Hoxa9 succumbed to leukemia significantly earlier than mice transplanted with cells overexpressing Hoxa9 only. Furthermore, overexpression of Ednra led to increased proliferation and resistance to apoptosis of bone marrow cells in vitro. We could also show that Meis1 binds to the Ednra promoter region, suggesting a regulatory role for Meis1 in Ednra expression. Taken together, our results suggest a role for Ednra in Hoxa9/Meis1-driven leukemogenesis.

Lun Y, Huang JC, Long D, et al.
[Molecular Characteristics and Clinical Features of Adults with
Sichuan Da Xue Xue Bao Yi Xue Ban. 2018; 49(4):575-581 [PubMed] Related Publications
OBJECTIVE: To determine the molecular characteristics and clinical features of patients with nucleoporin 98 (NUP98) fusion gene positive acute myeloid leukemia (AML) and the impact of coexistence of
METHODS: Samples of bone marrow or peripheral blood were collected from the adult patients with de novo AML and myelodysplastic syndrome (MDS) in our hospital from July 1st, 2014 to March 1st, 2017.
RESULTS: A total of 197 AML patients participated in this study, including 16 (8.1%) having

Sun Y, Zhou B, Mao F, et al.
HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis.
Cancer Cell. 2018; 34(4):643-658.e5 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.

Zhang L, Chen Y, Liu N, et al.
Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors.
Bioorg Chem. 2018; 80:649-654 [PubMed] Related Publications
A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC

Lissa D, Ishigame T, Noro R, et al.
HOXA9 methylation and blood vessel invasion in FFPE tissues for prognostic stratification of stage I lung adenocarcinoma patients.
Lung Cancer. 2018; 122:151-159 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
OBJECTIVES: Surgery with curative intent is the standard treatment for stage I lung adenocarcinoma. However, disease recurrence occurs in a third of patients. Prognostic biomarkers are needed to improve postoperative management. Here, we evaluate the utility of Homeobox A9 (HOXA9) promoter methylation, alone or in combination with Blood Vessel Invasion (BVI) assessment, for prognostic stratification of stage I lung adenocarcinoma patients.
MATERIALS AND METHODS: We developed a Droplet Digital PCR (ddPCR) assay to measure HOXA9 promoter methylation in formalin-fixed paraffin-embedded (FFPE) biospecimens generated during routine pathology. The prognostic value of HOXA9 promoter methylation and BVI, alone and in combination, was evaluated by Kaplan-Meier survival and Cox regression analyses in a cohort of 177 stage I lung adenocarcinoma patients from the NCI-MD study.
RESULTS: The ddPCR assay showed linearity, sensitivity and specificity for measuring HOXA9 promoter methylation down to 0.1% methylated DNA input. The HOXA9 promoter was methylated de novo in FFPE tumors (P < 0.0001). High methylation was independently associated with worse cancer-specific survival (Hazard Ratio [HR], 3.37; P = 0.0002) and identified high-risk stage IA and IB patients. Addition of this molecular marker improved a risk model comprised of clinical and pathologic parameters (age, gender, race, stage, and smoking history; nested likelihood ratio test; P = 0.0004) and increased the C-index from 0.60 (95% CI 0.51-0.69) to 0.68 (0.60-0.76). High methylation tumors displayed high frequency of TP53 mutations and other molecular characteristics associated with aggressiveness. BVI was independently associated with poor outcome (HR, 2.62; P = 0.054). A score that combined BVI with HOXA9 promoter methylation further stratified high-risk patients (trend P = 0.0001 comparing 0, 1 or 2 positive markers).
CONCLUSIONS: ddPCR can be used to quantify HOXA9 promoter methylation in FFPE samples. Alone or combined with BVI in a prognostic classifier, HOXA9 promoter methylation could potentially inform the clinical management of patients with early-stage lung adenocarcinoma.

Kim KT, Lee CH, Chung CK, Kim JH
Is NF2 a Key Player of the Differentially Expressed Gene Between Spinal Cord Ependymoma and Intracranial Ependymoma?
World Neurosurg. 2018; 118:e906-e917 [PubMed] Related Publications
BACKGROUND: Although intracranial and spinal ependymomas are histopathologically similar, the molecular landscape is heterogeneous. An urgent need exists to identify differences in the genomic profiles to tailor treatment strategies. In the present study, we delineated differential gene expression patterns between intracranial and spinal ependymomas.
METHODS: We searched the Gene Expression Omnibus database using the term "ependymoma" and analyzed the raw gene expression profiles of 292 ependymomas (31 spinal and 261 intracranial). The gene expression data were analyzed to find differentially expressed genes (DEGs) between 2 regions. The fold change (FC) and false discovery rate (FDR) were used to assess DEGs after gene integration (|log
RESULTS: A total of 201 genes (105 upregulated and 96 downregulated) were significant DEGs in the data sets. The underexpression of NF2 in spinal ependymomas was statistically significant (FDR P = 7.91 × 10
CONCLUSIONS: The most substantial magnitude of DEGs in ependymoma might be HOX genes. However, whether the differential expression of these genes is the cause or consequence of the disease remains to be elucidated in a larger prospective study.

Lillico R, Lawrence CK, Lakowski TM
Selective DOT1L, LSD1, and HDAC Class I Inhibitors Reduce HOXA9 Expression in MLL-AF9 Rearranged Leukemia Cells, But Dysregulate the Expression of Many Histone-Modifying Enzymes.
J Proteome Res. 2018; 17(8):2657-2667 [PubMed] Related Publications
Mixed lineage leukemia results from chromosomal rearrangements of the gene mixed lineage leukemia (MLL). MLL-AF9 is one such rearrangement that recruits the lysine methyltransferase, human disruptor of telomere silencing 1-like (DOT1L) and lysine specific demethylase 1 (LSD1), resulting in elevated expression of the Homeobox protein A9 (HOXA9), and leukemia. Inhibitors of LSD1 or DOT1L reduce HOXA9 expression, kill MLL-rearranged cells, and may treat leukemia. To quantify their effects on histone modifying enzyme activity and expression in MLL-rearranged leukemia, we tested inhibitors of DOT1L (EPZ-5676), LSD1 (GSK2879552), and HDAC (mocetinostat), in the MLL-AF9 cell line MOLM-13. All inhibitors reduced MOLM-13 viability but only mocetinostat induced apoptosis. EPZ-5676 increased total histone lysine dimethylation, which was attributed to a reduction in LSD1 expression, and was indistinguishable from direct LSD1 inhibition by GSK2879552. All compounds directly inhibit, or reduce the expression of, HOXA9, DOT1L and LSD1 by qPCR, increase total histone lysine methylation and acetylation by LC-MS/MS, and specifically reduce H3K79Me2 and increase H3K14Ac. Each inhibitor altered the expression of many histone modifying enzymes which may precipitate additional changes in expression. To the extent that this decreases HOXA9 expression it benefits mixed lineage leukemia treatment, all other expression changes are off-target effects.

Zhou C, Ye M, Ni S, et al.
DNA methylation biomarkers for head and neck squamous cell carcinoma.
Epigenetics. 2018; 13(4):398-409 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
DNA methylation plays an important role in the etiology and pathogenesis of head and neck squamous cell carcinoma (HNSCC). The current study aimed to identify aberrantly methylated-differentially expressed genes (DEGs) by a comprehensive bioinformatics analysis. In addition, we screened for DEGs affected by DNA methylation modification and further investigated their prognostic values for HNSCC. We included microarray data of DNA methylation (GSE25093 and GSE33202) and gene expression (GSE23036 and GSE58911) from Gene Expression Omnibus. Aberrantly methylated-DEGs were analyzed with R software. The Cancer Genome Atlas (TCGA) RNA sequencing and DNA methylation (Illumina HumanMethylation450) databases were utilized for validation. In total, 27 aberrantly methylated genes accompanied by altered expression were identified. After confirmation by The Cancer Genome Atlas (TCGA) database, 2 hypermethylated-low-expression genes (FAM135B and ZNF610) and 2 hypomethylated-high-expression genes (HOXA9 and DCC) were identified. A receiver operating characteristic (ROC) curve confirmed the diagnostic value of these four methylated genes for HNSCC. Multivariate Cox proportional hazards analysis showed that FAM135B methylation was a favorable independent prognostic biomarker for overall survival of HNSCC patients.

Hass HG, Vogel U, Scheurlen M, Jobst J
Use of Gene Expression Analysis for Discrimination of Primary and Secondary Adenocarcinoma of the Liver.
Oncology. 2018; 95(4):211-219 [PubMed] Related Publications
BACKGROUND: Due to late diagnosis and resistance to chemotherapy, most patients with cholangiocarcinoma have an unfavorable prognosis. Despite the use of immunohistochemistry (IHC) in clinical routine, differentiation between intrahepatic cholangiocarcinoma (ICC) and secondary adenocarcinomas of the liver is frequently not clear, leading to false diagnosis and treatment decisions.
METHODS: Oligonucleotide microarrays (Affymetrix Hu133A©) were used for gene expression analysis of ICC (n = 11) and secondary adenocarcinomas (colorectal metastases; n = 6). By two-dimensional cluster analysis a specific gene expression profile of these tumors was established and confirmed by real-time polymerase chain reaction and IHC.
RESULTS: A total of 338 genes were significantly dysregulated (gene expression/fc ≥2; dysregulation in ≥60%) in both tumor groups. Using two-dimensional cluster analysis a fast, clear, and reproducible differentiation between ICC and colorectal metastases was possible in all cases. As potential biomarkers for differentiation, twelve genes (ICC: KRT7, DBN1, LCTB, LIF, STK17A, PIGF; metastases: TDGF1, HOXA9, TFF3, MYB, ABP1, BCL11A) were detected and will be used for further investigations.
CONCLUSIONS: A specific gene expression profile for discrimination of primary and secondary adenocarcinoma of the liver could be established. In addition, marker genes for both cancers and their potential use as discrimination markers in clinical routine were also described partially for the first time.

Skucha A, Ebner J, Schmöllerl J, et al.
MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity.
Nat Commun. 2018; 9(1):1983 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins. Functional investigation of 128 conserved MLL-fusion-interactors identifies a specific role for the lysine methyltransferase SETD2 in MLL-leukemia. SETD2 loss causes growth arrest and differentiation of AML cells, and leads to increased DNA damage. In addition to its role in H3K36 tri-methylation, SETD2 is required to maintain high H3K79 di-methylation and MLL-AF9-binding to critical target genes, such as Hoxa9. SETD2 loss synergizes with pharmacologic inhibition of the H3K79 methyltransferase DOT1L to induce DNA damage, growth arrest, differentiation, and apoptosis. These results uncover a dependency for SETD2 during MLL-leukemogenesis, revealing a novel actionable vulnerability in this disease.

Luo H, Wang F, Zha J, et al.
CTCF boundary remodels chromatin domain and drives aberrant
Blood. 2018; 132(8):837-848 [PubMed] Article available free on PMC after 08/10/2019 Related Publications

Trissal MC, Wong TN, Yao JC, et al.
Cancer Res. 2018; 78(13):3510-3521 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression.

Zhou L, Wang Y, Zhou M, et al.
HOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development.
Nat Commun. 2018; 9(1):1480 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Glycolytic reprogramming is a typical feature of many cancers; however, key regulators of glucose metabolism reengineering are poorly understood, especially in cutaneous squamous cell carcinoma (cSCC). Here, Homeobox A9 (HOXA9), a direct target of onco-miR-365, is identified to be significantly downregulated in cSCC tumors and cell lines. HOXA9 acts as a tumor suppressor and inhibits glycolysis in cSCC in vitro and in vivo by negatively regulating HIF-1α and its downstream glycolytic regulators, HK2, GLUT1 and PDK1. Mechanistic studies show that HOXA9-CRIP2 interaction at glycolytic gene promoters impeds HIF-1α binding, repressing gene expression in trans. Our results reveal a miR-365-HOXA9-HIF-1α regulatory axis that contributes to the enhanced glycolysis in cSCC development and may represent an intervention target for cSCC therapy.

Mahotka C, Bhatia S, Kollet J, Grinstein E
Nucleolin promotes execution of the hematopoietic stem cell gene expression program.
Leukemia. 2018; 32(8):1865-1868 [PubMed] Related Publications

Wang H, Bei L, Shah CA, et al.
The E3 ubiquitin ligase Triad1 influences development of Mll-Ell-induced acute myeloid leukemia.
Oncogene. 2018; 37(19):2532-2544 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Chromosomal translocations involving the MLL1 gene characterize a poor prognosis subset of acute myeloid leukemia (AML), referred to as 11q23-AML. Transcription of the HOXA9 and HOXA10 genes is enhanced in hematopoietic stem and progenitor cells in these leukemias. We previously found the ARIH2 gene was repressed by HoxA9 in myeloid progenitors, but activated by HoxA10 during granulopoiesis. ARIH2 encodes the Triad1 protein, an anti-proliferative E3 ubiquitin ligase. In the current study, we investigate the role of Triad1 in leukemogenesis induced by an MLL1 fusion protein (Mll-Ell). We found Mll-Ell increased expression of HoxA9, HoxA10, and Triad1 because HoxA9 represses only one of two ARIH2 cis elements that are activated by HoxA10. Although Triad1 antagonized the generally pro-proliferative effects of the Mll-Ell oncoprotein, we found blocking HoxA9 and HoxA10 phosphorylation shifted the balance to ARIH2 repression in Mll-Ell

Bhayadia R, Krowiorz K, Haetscher N, et al.
Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia.
J Clin Oncol. 2018; 36(10):1007-1016 [PubMed] Related Publications
Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio ± standard error, -0.56 ± 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms.

Tan L, Xu H, Chen G, et al.
Silencing of HMGA2 reverses retardance of cell differentiation in human myeloid leukaemia.
Br J Cancer. 2018; 118(3):405-415 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
BACKGROUND: High-mobility group AT-hook 2 (HMGA2) may serve as an architectural transcription factor, and it can regulate a range of normal biological processes including proliferation and differentiation. Upregulation of HMGA2 expression is correlated to the undifferentiated phenotype of immature leukaemic cells. However, the underlying mechanism of HMGA2-dependent myeloid differentiation blockage in leukaemia is unknown.
METHODS: To reveal the role and mechanism of HMGA2 in differentiation arrest of myeloid leukaemia cells, the quantitative expression of HMGA2 and homeobox A9 (HOXA9) was analysed by real-time PCR (qRT-PCR). The regulatory function of HMGA2 in blockage of differentiation in human myeloid leukaemia was investigated through in vitro assays (XTT assay, May-Grünwald-Giemsa, flow cytometry analysis and western blot).
RESULTS: We found that the expression of HMGA2 and HOXA9 was reduced during the process of granulo-monocytic maturation of acute myeloid leukaemia (AML) cells, knockdown of HMGA2 promotes terminal (granulocytic and monocytic) differentiation of myeloid leukaemia primary blasts and cell lines, and HOXA9 was significantly downregulated in leukaemic cells with knockdown of HMGA2. Downregulation of HOXA9 in myeloid leukaemia cells led to increased differentiation capacity in vitro.
CONCLUSIONS: Our data suggest that increased expression of HMGA2 represents a possible new mechanism of myeloid differentiation blockage of leukaemia. Aberrant expression of HMGA2 may enhance HOXA9-dependent leukaemogenesis and myeloid leukaemia phenotype. Disturbance of the HMGA2-HOXA9 pathway is probably a therapeutic strategy in myeloid leukaemia.

Somerville TDD, Simeoni F, Chadwick JA, et al.
Derepression of the Iroquois Homeodomain Transcription Factor Gene IRX3 Confers Differentiation Block in Acute Leukemia.
Cell Rep. 2018; 22(3):638-652 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
The Iroquois homeodomain transcription factor gene IRX3 is expressed in the developing nervous system, limb buds, and heart, and transcript levels specify obesity risk in humans. We now report a functional role for IRX3 in human acute leukemia. Although transcript levels are very low in normal human bone marrow cells, high IRX3 expression is found in ∼30% of patients with acute myeloid leukemia (AML), ∼50% with T-acute lymphoblastic leukemia, and ∼20% with B-acute lymphoblastic leukemia, frequently in association with high-level HOXA gene expression. Expression of IRX3 alone was sufficient to immortalize hematopoietic stem and progenitor cells (HSPCs) in myeloid culture and induce lymphoid leukemias in vivo. IRX3 knockdown induced terminal differentiation of AML cells. Combined IRX3 and Hoxa9 expression in murine HSPCs impeded normal T-progenitor differentiation in lymphoid culture and substantially enhanced the morphologic and phenotypic differentiation block of AML in myeloid leukemia transplantation experiments through suppression of a terminal myelomonocytic program. Likewise, in cases of primary human AML, high IRX3 expression is strongly associated with reduced myelomonocytic differentiation. Thus, tissue-inappropriate derepression of IRX3 contributes significantly to the block in differentiation, which is the pathognomonic feature of human acute leukemias.

Johansen S, Brenner AK, Bartaula-Brevik S, et al.
The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia.
Int J Mol Sci. 2018; 19(1) [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two β3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and β3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, β3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The β3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased β3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of β2 integrins. Finally, high integrin αV/β3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of β3 integrins for leukemogenesis and chemosensitivity in AML.

Um SW, Kim HK, Kim Y, et al.
Bronchial biopsy specimen as a surrogate for DNA methylation analysis in inoperable lung cancer.
Clin Epigenetics. 2017; 9:131 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer.
Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data.
Results: Four thousand seven hundred and twenty-six CpGs (
Conclusions: The present study suggests that bronchial biopsy specimen may be used as a surrogate for DNA methylation analysis in patient with inoperable lung cancer.

Schneider E, Staffas A, Röhner L, et al.
Micro-ribonucleic acid-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia.
Haematologica. 2018; 103(2):246-255 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Micro-ribonucleic acid-155 (miR-155) is one of the first described oncogenic miRNAs. Although multiple direct targets of miR-155 have been identified, it is not clear how it contributes to the pathogenesis of acute myeloid leukemia. We found miR-155 to be a direct target of Meis1 in murine Hoxa9/Meis1 induced acute myeloid leukemia. The additional overexpression of miR-155 accelerated the formation of acute myeloid leukemia in Hoxa9 as well as in Hoxa9/Meis1 cells

Hetzner K, Garcia-Cuellar MP, Büttner C, Slany RK
The interaction of ENL with PAF1 mitigates polycomb silencing and facilitates murine leukemogenesis.
Blood. 2018; 131(6):662-673 [PubMed] Related Publications
Eleven-nineteen leukemia (ENL) is a chromatin reader present in complexes stimulating transcriptional elongation. It is fused to mixed-lineage leukemia (MLL) in leukemia, and missense mutations have been identified in Wilms tumor and acute myeloid leukemia. Here we demonstrate that ENL overcomes polycomb silencing through recruitment of PAF1 via the conserved YEATS domain, which recognizes acetylated histone H3. PAF1 was responsible for antirepressive activities of ENL in vitro, and it determined the transforming potential of MLL-ENL. MLL-ENL target loci showed supraphysiological PAF1 binding, hyperubiquitination of histone H2B and hypomodification with H2AUb, resulting in accelerated transcription rates. YEATS mutations induced a gain of function, transforming primary hematopoietic cells in vitro and in transplantation assays through aberrant transcription and H2B ubiquitination of

Nair RM, Balla MM, Khan I, et al.
In vitro characterization of CD133
BMC Cancer. 2017; 17(1):779 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
BACKGROUND: Retinoblastoma (Rb), the most common childhood intraocular malignant tumor, is reported to have cancer stem cells (CSCs) similar to other tumors. Our previous investigation in primary tumors identified the small sized cells with low CD133 (Prominin-1) and high CD44 (Hyaluronic acid receptor) expression to be putative Rb CSCs using flow cytometry (FSC
METHODS: The cultured Rb Y79 cells were evaluated for surface markers by flow cytometry and CD133 sorted cells (CD133
RESULTS: Rb Y79 cell line shared the profile (CD133, CD90, CXCR4 and ABCB1) of primary tumors except for CD44 expression. The CD133
CONCLUSIONS: This study validates the observation from our earlier primary tumor study that CSC properties in Rb Y79 cell line are endowed within the CD133

Iijima-Yamashita Y, Matsuo H, Yamada M, et al.
Multiplex fusion gene testing in pediatric acute myeloid leukemia.
Pediatr Int. 2018; 60(1):47-51 [PubMed] Related Publications
BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required.
METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation. Multiplex quantitative RT-PCR was performed to detect eight important fusion genes: AML1(RUNX1)-ETO(RUNX1T1), CBFB-MYH11, MLL(KMT2A)-AF9(MLLT3), MLL-ELL, MLL-AF6(MLLT4), FUS(TLS)-ERG, NUP98-HOXA9, and PML-RARA.
RESULTS: Fusion genes were detected in 207 (46.2%) of the 448 AML-05 patient samples. After exclusion of two samples with PML-RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT-PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML-P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML-RARA positive on FISH.
CONCLUSIONS: Multiplex quantitative RT-PCR-based fusion gene screening may be effective for diagnosis of pediatric AML.

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