MNX1

Gene Summary

Gene:MNX1; motor neuron and pancreas homeobox 1
Aliases: HB9, HLXB9, SCRA1, HOXHB9
Location:7q36
Summary:This gene encodes a nuclear protein, which contains a homeobox domain and is a transcription factor. Mutations in this gene result in Currarino syndrome, an autosomic dominant congenital malformation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:motor neuron and pancreas homeobox protein 1
HPRD
Source:NCBIAccessed: 27 February, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 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.

  • Syringomyelia
  • Repressor Proteins
  • RTPCR
  • Transcription Factors
  • Young Adult
  • FISH
  • Newborns
  • Uterus
  • Cancer Gene Expression Regulation
  • Rectum
  • Sacrum
  • Chromosome 7
  • Chromosome 12
  • Leukaemia
  • Cancer RNA
  • Wilms Tumour
  • Pedigree
  • Cell Nucleus
  • Multiple Abnormalities
  • Fatal Outcome
  • Proto-Oncogene Proteins c-ets
  • U937 Cells
  • Oncogene Fusion Proteins
  • Homeodomain Proteins
  • Acute Myeloid Leukaemia
  • Translocation
  • Teratoma
  • Pelvic Neoplasms
  • Digestive System Abnormalities
  • Anal Canal
  • Cell Differentiation
  • Molecular Sequence Data
  • Sacrococcygeal Region
  • Infant
  • Base Sequence
  • Childhood Cancer
  • Polymerase Chain Reaction
  • Karyotyping
  • Acute Lymphocytic Leukaemia
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: MNX1 (cancer-related)

Kole MJ, Fridley JS, Jea A, Bollo RJ
Currarino syndrome and spinal dysraphism.
J Neurosurg Pediatr. 2014; 13(6):685-9 [PubMed] Related Publications
Currarino syndrome is a rare constellation of congenital anomalies characterized by the triad of sacral dysgenesis, presacral mass, and anorectal malformation. It is frequently associated with other congenital anomalies, often including occult spinal dysraphism. Mutations in the MNX1 gene are identified in the majority of cases. The authors report a rare case of Currarino syndrome in an infant with tethered cord syndrome and a dorsal lipomyelomeningocele continuous with a presacral intradural spinal lipoma, in addition to an imperforate anus and a scimitar sacrum. They review the literature to highlight patterns of occult spinal dysraphism in patients with Currarino syndrome and their relationship to tethered cord syndrome. Approximately 60% of the patients with Currarino syndrome reported in the literature have an occult spinal dysraphism. Published studies suggest that the risk of tethered cord syndrome may be higher among patients with a lipoma and lower among those with a teratoma or anterior meningocele.

Desai SS, Modali SD, Parekh VI, et al.
GSK-3β protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation.
J Biol Chem. 2014; 289(9):5386-98 [PubMed] Article available free on PMC after 28/02/2015 Related Publications
Insulinomas (pancreatic islet β cell tumors) are the most common type of functioning pancreatic neuroendocrine tumors that occur sporadically or as a part of the MEN1 syndrome that is caused by germ line mutations in MEN1. Tissue-specific tumor predisposition from germ line mutations in ubiquitously expressed genes such as MEN1 could occur because of functional consequences on tissue-specific factors. We previously reported the proapoptotic β cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3β inactivates the proapoptotic activity of HLXB9 by phosphorylating HLXB9 at Ser-78/Ser-80 (pHLXB9). Although HLXB9 is found in the nucleus and cytoplasm, pHLXB9 is predominantly nuclear. Both pHLXB9 and active GSK-3β are elevated in β cells with menin knockdown, in MEN1-associated β cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3β blocked cell proliferation in three different rodent insulinoma cell lines by arresting the cells in G2/M phase and caused apoptosis. Taken together, these data suggest that the combination of GSK-3β and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3β and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with β cell proliferation.

Shi K, Parekh VI, Roy S, et al.
The embryonic transcription factor Hlxb9 is a menin interacting partner that controls pancreatic β-cell proliferation and the expression of insulin regulators.
Endocr Relat Cancer. 2013; 20(1):111-22 [PubMed] Related Publications
The multiple endocrine neoplasia type 1 (MEN1) syndrome is caused by germline mutations in the MEN1 gene encoding menin, with tissue-specific tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Also, 30-40% of sporadic pancreatic endocrine tumors show somatic MEN1 gene inactivation. Although menin is expressed in all cell types of the pancreas, mouse models with loss of menin in either pancreatic α-cells, or β-cells, or total pancreas develop β-cell-specific endocrine tumors (insulinomas). Loss of widely expressed tumor suppressor genes may produce tissue-specific tumors by reactivating one or more embryonic-specific differentiation factors. Therefore, we determined the effect of menin overexpression or knockdown on the expression of β-cell differentiation factors in a mouse β-cell line (MIN6). We show that the β-cell differentiation factor Hlxb9 is posttranscriptionally upregulated upon menin knockdown, and it interacts with menin. Hlxb9 reduces cell proliferation and causes apoptosis in the presence of menin, and it regulates genes that modulate insulin level. Thus, upon menin loss or from other causes, dysregulation of Hlxb9 predicts a possible combined mechanism for β-cell proliferation and insulin production in insulinomas. These observations help to understand how a ubiquitously expressed protein such as menin might control tissue-specific tumorigenesis. Also, our findings identify Hlxb9 as an important factor for β-cell proliferation and insulin regulation.

Wildenhain S, Ingenhag D, Ruckert C, et al.
Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.
J Biol Chem. 2012; 287(48):40703-12 [PubMed] Article available free on PMC after 28/02/2015 Related Publications
BACKGROUND: HB9 is highly expressed in translocation t(7;12) positive infant AML.
RESULTS: HB9 binds to the PTGER2 promoter, down-regulates PTGER2 gene expression and subsequently represses cAMP synthesis in hematopoietic cells.
CONCLUSION: Expression of HLXB9 represses PTGER2 mediated signaling.
SIGNIFICANCE: First molecular report of HB9-dependent target gene regulation in hematopoietic cells. The transcription factor HB9, encoded by the homeobox gene B9 (HLXB9), is involved in the development of pancreatic beta- and motor neuronal cells. In addition, HLXB9 is recurrently rearranged in young children with acute myeloid leukemia characterized by a chromosomal translocation t(7;12)-HLXB9/TEL and concomitant high expression of the unrearranged, wild-type HLXB9 allele. However, target genes of HB9 in hematopoietic cells are not known to date. In this study, we used ChIP-on-chip analysis together with expression profiling and identified PTGER2 (prostaglandin E receptor 2) as a target gene of HB9 in a hematopoietic cell line. The functional HB9 homeodomain as well as the HB9 binding domain within the PTGER2 promoter are essential for binding of HB9 to the PTGER2 promoter region and down-regulation of PTGER2 expression. Functionally, HB9 conducted down-regulation of PTGER2 results in a reduced content of intracellular cAMP mobilization and furthermore the decreased PTGER2 gene expression is valid in bone marrow cells from translocation t(7;12) positive patients. Among the primary and secondary target genes of HB9 in the myeloid cell line HL60, 78% of significantly regulated genes are down-regulated, indicating an overall repressive function of HB9. Differentially regulated genes were preferentially confined to pathways involved in cell-adhesion and cell-cell interactions, similar to the gene expression footprint of HLXB9-expressing cells from t(7;12) positive patients.

Halldórsdóttir AM, Kanduri M, Marincevic M, et al.
Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.
Am J Hematol. 2012; 87(4):361-7 [PubMed] Related Publications
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.

Lin YH, Huang RL, Lai HC
Presacral teratoma in a Curarrino syndrome woman with an unreported insertion in MNX1 gene.
Taiwan J Obstet Gynecol. 2011; 50(4):512-4 [PubMed] Related Publications
OBJECTIVE: Currarino syndrome (CS) comprises a presacral mass, anorectal malformation, and a sacral bony defect. It is rarely reported in the gynecological field.
CASE REPORT: We describe here the case of a 26-year-old married woman with Currarino syndrome who presented with a presacral teratoma and a previously unreported insertion in MNX1 gene. She had had a pelvic teratoma diagnosed by laparoscopy 8 years previously. She was referred to our clinic because of the increasing size of the teratoma and associated compression symptoms. Computed tomography demonstrated a heterogeneous 12 cm mass in the presacral region. Spina bifida at S2eS5 was also noted. Laparotomy confirmed the diagnosis of presacral teratoma. Genetic analysis disclosed a triple CGC repeat insertion in exon 1 of MNX1, resulting in three in-frame shifts encoding for the amino acid alanine. No siblings had known similar symptoms.
CONCLUSION: Currarino syndrome is known to be an autosomal dominant disorder. The presence of constipation can lead to a diagnosis of the syndrome early in childhood. In sporadic cases diagnosis is late because of atypical symptoms. Delayed treatment of a presacral tumor may cause serious complications such as central nervous system infection or subsequent neurological dysfunction. In clinical practice, a presacral tumor with a sacral bony defect may indicate Currarino syndrome. Genetic analysis of the family may provide information on the hereditary traits of specific MNX1 mutation.

Ciotti P, Mandich P, Bellone E, et al.
Currarino syndrome with pelvic neuroendocrine tumor diagnosed by post-mortem genetic analysis of tissue specimens.
Am J Med Genet A. 2011; 155A(11):2750-3 [PubMed] Related Publications
Currarino syndrome (CS) is an autosomal dominant disorder of embryonic development characterized by the triad of anorectal abnormalities, partial sacral agenesis, and presacral mass. Mutations of the HLXB9 gene have been identified in most CS cases, but a precise genotype-phenotype correlation has not been described so far. We report the clinical case of a 44-year-old Caucasian woman with malignant neuroendocrine transformation of a pre-sacrococcygeal mass combined with bicornuate uterus, dermoid cyst of the ovaries, and chronic constipation. After the patient died, a sacrococcygeal malformation and anterior meningocele were diagnosed in her 22-year-old son. CS diagnosis was then retrospectively confirmed by molecular analysis of normal and pathological tissue specimens of the mother, with identification of a HLXB9 mutation (c.727C>T; p.R243W). CS should be considered, and genetic counseling recommended, to all patients with presacral masses. Since malignant neuroendocrine transformation of presacral mass in CS is a possible complication, even thought rare, close follow up in these patients is advisable.

Zu S, Winberg J, Arnberg F, et al.
Mutation analysis of the motor neuron and pancreas homeobox 1 (MNX1, former HLXB9) gene in Swedish patients with Currarino syndrome.
J Pediatr Surg. 2011; 46(7):1390-5 [PubMed] Related Publications
BACKGROUND: Currarino syndrome (CS) is a triad consisting of partial sacral agenesis, presacral mass, and anorectal malformations, typically anal stenosis but the phenotype varies. The main cause of this monogenic disorder is mutations in the motor neuron and pancreas homeobox 1 gene. We describe the clinical and genetic findings in 4 unrelated Swedish cases with CS and their relatives.
METHODS: We performed mutation analysis of the motor neuron and pancreas homeobox 1 gene in 4 cases with CS by DNA sequence analysis as well as multiplex ligation-dependent probe amplification. In addition, array comparative genome hybridization was performed in 2 cases. Including relatives, totally, 14 individuals were analyzed.
RESULTS: We found 2 previously described mutations, 1 de novo nonsense mutation (p.Gln212X) and 1 maternally inherited frameshift mutation (p.Pro18ProfsX38). In the family with the frameshift mutation, we also detected the same maternally inherited mutation in 3 of the proband's 4 brothers, who displayed varying symptoms. All mutation carriers had presacral tumors, although 2 were asymptomatic.
CONCLUSION: Our findings emphasize the need for genetic counseling and mutation analysis in patients with CS to detect tumors early. It shows the importance of evaluation of the sacrum and the presacral region in patients with anal stenosis with or without funnel anus. Family members of index cases should be considered for evaluation even if they are asymptomatic.

Wilkens L, Jaggi R, Hammer C, et al.
The homeobox gene HLXB9 is upregulated in a morphological subset of poorly differentiated hepatocellular carcinoma.
Virchows Arch. 2011; 458(6):697-708 [PubMed] Related Publications
The prognostic outcome for hepatocellular carcinoma (HCC) remains poor. Disease progression is accompanied by dedifferentiation of the carcinoma, a process that is not well understood. The aim of this study was to get more insight into the molecular characteristics of dedifferentiated carcinomas using high throughput techniques. Microarray-based global gene expression analysis was performed on five poorly differentiated HCC cell lines compared with non-neoplastic hepatic controls and a set of three cholangiolar carcinoma (CC) cell lines. The gene with the highest upregulation was HLXB9. HLXB9 is a gene of the homeobox genfamily important for the development of the pancreas. RT-PCR confirmed the upregulation of HLXB9 in surgical specimens of carcinoma tissue, suggesting its biological significance. Interestingly, HLXB9 upregulation was primary observed in poorly differentiated HCC with a pseudoglandular pattern compared with a solid pattern HCC or in moderate or well-differentiated HCC. Additional the expression of translated HLXB9, the protein HB9 (NCBI: NP_001158727), was analyzed by western blotting. Expression of HB9 was only detected in the cytoplasm but not in the nuclei of the HCC cells. For validation CC were also investigated. Again, we found an upregulation of HLXB9 in CC cells accompanied by an expression of HB9 in the cytoplasms of these tumor cells, respectively. In conclusion, homeobox HLXB9 is upregulated in poorly differentiated HCC with a pseudoglandular pattern. The translated HB9 protein is found in the cytoplasm of these HCC and CC. We therefore assume HLXB9 as a possible link in the understanding of the development of HCC and CC, respectively.

Ferguson S, Gautrey HE, Strathdee G
The dual role of HLXB9 in leukemia.
Pediatr Blood Cancer. 2011; 56(3):349-52 [PubMed] Related Publications
BACKGROUND: The HLXB9 gene encodes a homeodomain containing transcription factor which has been implicated in the development of both solid and hematological malignancies. In leukemia it is one of the two fused genes, along with ETV6, in a recurrent translocation frequently observed in infant AML.
PROCEDURE: Here we investigate the role of epigenetic inactivation of the HLXB9 gene in leukemia. Quantitative DNA methylation analysis was performed using the COBRA assay, and qRT-PCR was used to assess the effects of methylation on expression in hematological cell lines and primary ALL samples.
RESULTS: Hypermethylation of the HLXB9 gene was found to be a frequent event in childhood ALL, occurring in 33% of cases. However, it was rarely or never observed in other types of leukemia, including AML, CML, and CLL, with the exception of adult ALL, in which 39% of cases were hypermethylated. Furthermore, hypermethylation of HLXB9 results in loss of expression in hematological cell lines and primary ALL samples.
CONCLUSION: These results suggest that HLXB9 may have a dual role in childhood leukemia, as an oncogene in infant AML but as a tumor suppressor in childhood ALL.

Bartels SA, van Koperen PJ, van der Steeg AF, et al.
Presacral masses in children: presentation, aetiology and risk of malignancy.
Colorectal Dis. 2011; 13(8):930-4 [PubMed] Related Publications
AIM: The risk of malignant changes in presacral tumours in children was investigated in relation to age at diagnosis, type of presentation and origin of the tumour.
METHOD: A retrospective review was carried out in 17 patients surgically treated for congenital presacral masses over a 22-year period.
RESULTS: Constipation was the main symptom in 14 (82%) of 17 patients. The lesions were evident on digital examination in 14 patients. Mature teratoma (n = 9, 64%) was the most common lesion, including three malignancies. Currarino syndrome was diagnosed in 10 (71%) patients. Two unclassified variant HLXB9 gene mutations were found in five (29%) patients who underwent genetic testing.
CONCLUSION: Congenital presacral tumours in children were mostly mature teratomas, either as sacrococcygeal teratomas or as part of the Currarino syndrome. The risk of malignancy in patients older than 1 year necessitates early surgical resection.

Park J, Kim M, Lim J, et al.
Three-way complex translocations in infant acute myeloid leukemia with t(7;12)(q36;p13): the incidence and correlation of a HLXB9 overexpression.
Cancer Genet Cytogenet. 2009; 191(2):102-5 [PubMed] Related Publications
The t(7;12)(q36;p13) is one of the recurrent cytogenetic abnormalities that involves the ETV6 gene. It is found in patients suffering with infantile acute myeloid leukemia (AML). We reviewed the cytogenetic and clinical findings of 215 pediatric patients (ages

Taketani T, Taki T, Sako M, et al.
MNX1-ETV6 fusion gene in an acute megakaryoblastic leukemia and expression of the MNX1 gene in leukemia and normal B cell lines.
Cancer Genet Cytogenet. 2008; 186(2):115-9 [PubMed] Related Publications
Patients with infant acute myeloid leukemia (AML) who carry a t(7;12)(q36;p13) translocation have been reported to have a poor clinical outcome. MNX1-ETV6 fusion transcripts (previously HLXB9-ETV6) were rarely detected in AML patients having t(7;12)(q36;p13). A 23-month-old girl with acute megakaryoblastic leukemia (AMKL) exhibited chromosome abnormalities, including add(7)(q22), and del(12)(p12p13). Southern blot analysis of bone marrow cells showed an ETV6 gene rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) followed by sequence analysis revealed the presence of an MNX1-ETV6 fusion gene. The patient responded well to chemotherapy, achieved complete remission, and at writing had been in complete remission for 60 months. The MNX1 expression by RT-PCR was significantly more frequent in Epstein-Barr virus-transformed B-cell lines derived from normal adult lymphocytes than in leukemic cell lines. This represents a novel case of an AMKL patient with MNX1-ETV6 fusion transcripts who had a good prognosis.

Novotny GW, Nielsen JE, Sonne SB, et al.
Analysis of gene expression in normal and neoplastic human testis: new roles of RNA.
Int J Androl. 2007; 30(4):316-26; discussion 326-7 [PubMed] Related Publications
Large-scale methods for analysing gene expression, such as microarrays, have yielded a wealth of information about gene expression at the mRNA level. However, expression of alternative transcripts, together with the presence of a wide range of largely undescribed RNA transcripts combined with regulation from the RNA interference pathway, may cause misinterpretations when trying to base conclusions from expression data derived from studies at the mRNA level. With HLXB9, PRM1, DICER and E2F1 as examples, we here show a range of situations that can occur when investigating gene expression, and give recommendations for the complementary methods that can verify gene expression data from large-scale studies, as well as give new information regarding the regulation of specific genes. Especially, we show that the absence of a protein despite high expression of the corresponding mRNA can be caused by expression of miRNAs targeting the mRNA. Additionally, we show through cloning the presence of both known and new miRNAs in the testis emphasizing the necessity for following up mRNA expression data by investigating expression at the protein level.

Almstrup K, Leffers H, Lothe RA, et al.
Improved gene expression signature of testicular carcinoma in situ.
Int J Androl. 2007; 30(4):292-302; discussion 303 [PubMed] Related Publications
The carcinoma in situ (CIS) stage is the common precursor of testicular germ cell tumours (TGCTs) that arise in young adults. Within the past decade genome wide gene expression tools have been developed and have greatly advanced the insight into the biology of TGCTs. Two independent data sets on global gene expression in testicular CIS have been previously published. We have merged the two data sets on CIS samples (n = 6) and identified the shared gene expression signature in relation to expression in normal testis. Among the top-20 highest expressed genes, one-third was transcription factors and the list included some 'novel' CIS markers (i.e. DOCK11 and ANXA3). Genes related to biological terms 'nucleic acid binding' and 'translational activity' (e.g. transcription factors and ribosomal proteins, respectively) were consistently and significantly over-represented. Some of the significantly over-expressed genes in CIS cells were selected for validation by RT-PCR (IFI16, DOCK11, and ANXA3), immunohistochemistry (HLXB9), or in situ hybridization (IFI16). High-level analysis utilizing the Ingenuity pathway analysis tool indicated that networks relating to 'gene expression in cancer' and 'embryonic development' were significantly altered and could collectively affect cellular pathways like the WNT signalling cascade, which thus may be disrupted in testicular CIS. The merged CIS data from two different microarray platforms, to our knowledge, provide the most precise CIS gene expression signature to date.

von Bergh AR, van Drunen E, van Wering ER, et al.
High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9.
Genes Chromosomes Cancer. 2006; 45(8):731-9 [PubMed] Related Publications
The t(7;12)(q36;p13) is a recurrent translocation involving the ETV6/TEL gene (12p13) and a heterogeneous breakpoint at 7q36. A fusion transcript between HLXB9 and ETV6 in AML with t(7;12) is occasionally found. To study the incidence of t(7;12) in infant and childhood acute leukemia, we screened 320 cases <36 months using FISH. Additionally, 28 pediatric cases >36 months with cytogenetic breakpoints at 12p and 7q were investigated. We studied the presence of an HXLB9-ETV6 fusion transcript and quantified the expression of various genes located in the 7q36 breakpoint region. In total, six AML patients carried the t(7;12) of which five were infants and one child of 18 months. Only one out of 99 infant ALL patients harbored the t(7;12). No t(7;12) was found in older children with AML or ALL. AML patients carrying a t(7;12) had a poor outcome with a 3-year EFS of 0%. A fusion of HLXB9 to ETV6 was found in four AML cases with t(7;12). The 7q36 genes NOM1, LMBR1, RNF32, and SHH were equally expressed among t(7;12)-positive AML versus t(7;12)-negative AML, t(7;12)-negative ALL, or normal bone marrow. However, the HLXB9 expression was highly increased in t(7;12)-positive cases, including those with an HLXB9-ETV6 fusion. We conclude that the t(7;12) is almost exclusively present in infant AML and covers 30% of infant AML, while it is extremely rare in infant ALL and older children. The t(7;12) is associated with a poor outcome and an ectopic expression of HLXB9 is commonly involved in this genetic subtype of leukemia.

Nagel S, Scherr M, Quentmeier H, et al.
HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3.
Leukemia. 2005; 19(5):841-6 [PubMed] Related Publications
Multiple cytokines are secreted by Hodgkin lymphoma (HL) cells, notably interleukin-6 (IL6), which is believed to play a significant pathobiological role in this and certain other tumors. Previous work on prostate carcinoma cells has shown that IL6 expression is activated therein by the homeodomain protein GBX2, which we found to be absent in HL cells. Instead, we observed expression of a closely related gene, HLXB9, albeit restricted to HL cells coexpressing IL6. Treatment of HL cell lines with antisense-oligonucleotides directed against HLXB9, forced expression of recombinant HLXB9, and analysis of reporter gene constructs containing IL6 promoter sequences all confirmed the potential of HLXB9 to drive expression of IL6. Chromosomal rearrangements of the HLXB9 locus at 7q36 were not detected in HL cells unlike AML subsets expressing HLXB9. However, inhibition of certain signal transduction pathways revealed that the phosphatidylinositol 3 kinase (PI3K) pathway contributes to HLXB9 expression. AKT/phospho-AKT analysis revealed constitutively active PI3K signalling in HL cell lines. Downstream analysis of PI3K revealed that E2F3 may mediate activation of HLXB9. Taken together, our data show that the PI3K signalling pathway in HL cells is constitutively activated and promotes HLXB9 expression, probably via E2F3, thereby enhancing malignant expression of IL6.

Nagel S, Kaufmann M, Scherr M, et al.
Activation of HLXB9 by juxtaposition with MYB via formation of t(6;7)(q23;q36) in an AML-M4 cell line (GDM-1).
Genes Chromosomes Cancer. 2005; 42(2):170-8 [PubMed] Related Publications
Mutation or dysregulation of related homeobox genes occurs in leukemia. Using RT-PCR, we screened members of the EHG family of homeobox genes, comprising EN1 (at 2q14), GBX2 (at 2q36), and EN2, GBX1, and HLXB9 (at 7q36), for dysregulation in acute myeloid leukemia (AML) cell lines indicated by chromosomal breakpoints at these sites. Only one EHG-family gene was expressed, HLXB9, in cell line GDM-1 (AML-M4). Karyotypic analysis of GDM-1 revealed a unique t(6;7)(q23;q35), also present in the patient. Fluorescence in situ hybridization analysis showed chromosomal breakpoints close to the region upstream of HLXB9, at 7q36, a region rearranged in certain AML patients, and at 6q23 upstream of MYB, a gene activated in leukemia. Detailed expression analysis suggested ectopic activation of HLXB9 occurred via juxtaposition with regions upstream of MYB, which was highly expressed in GDM-1. Our data identified a cell line model for a novel leukemic translocation involving MYB with HLXB9, further implicating HLXB9 in leukemogenesis.

Martucciello G, Torre M, Belloni E, et al.
Currarino syndrome: proposal of a diagnostic and therapeutic protocol.
J Pediatr Surg. 2004; 39(9):1305-11 [PubMed] Related Publications
BACKGROUND/PURPOSE: The Currarino syndrome (CS) is a peculiar form of caudal regression syndrome (CRS) characterized by the association of hemisacrum, anorectal malformation (ARM), and presacral mass. The authors analyzed retrospectively their series, and they propose a multidisciplinary diagnostic and therapuetic protocol that until now has not been introduced.
METHODS: A series of 6 patients with CS is presented. Five of them were treated initially in other centers. None of them had an early diagnosis. All presented associated anomalies; in 50%, Hirschsprung's disease (HD) and other dysganglionoses were present. One patient died of a presacral ectopic nephroblastoma.
RESULTS: Depending on the expressivity, 3 types of CS can be identified, complete, mild, and minimal. Dysganglionoses and HD can be considered part of CS. A multidisciplinary diagnostic and therapeutic protocol is presented. Main points are sacrum x-Ray, molecular genetic diagnosis, radiologic evaluation of every member of CS families, magnetic resonance (MR) evaluation of patient spine and pelvis, suction rectal biopsies, and search for associated anomalies.
CONCLUSIONS: This protocol could give a valid contribution to the treatment of CS, allowing an early diagnosis and proposing a rational timing of multidisciplinary surgical procedures. Early diagnosis and treatment are essential to avoid morbidity and mortality from an undiagnosed presacral mass.

Hollington P, Neufing P, Kalionis B, et al.
Expression and localization of homeodomain proteins DLX4, HB9 and HB24 in malignant and benign human colorectal tissues.
Anticancer Res. 2004 Mar-Apr; 24(2B):955-62 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to identify homeobox genes expressed in the human colon and to determine whether their expression levels were altered between matched non-malignant and malignant colon tissues.
MATERIALS AND METHODS: Homeobox genes expressed in colon tissue were identified by reverse transcription polymerase chain reaction (RT-PCR). Antibodies were raised to the homeodomain proteins DLX4, HB9 and HB24 and immunohistochemistry was performed on 3 moderately-differentiated tumors and their corresponding non-malignant colon tissue samples.
RESULTS: The RT-PCR screen identified expression of DLX4, HB9, HB24 and MSX2 in the normal colon. Immunoaffinity purified polyclonal antisera raised against DLX4, HB9 and HB24 detect specific immunoreactivity in glandular epithelial cells, stromal cells of the lamina propria but not in the submucosa. Nuclear epithelial immunoreactivity of all three antibodies decreased in moderately-differentiated tumors compared to the corresponding matched non-malignant mucosa. These data suggest that differential expression of HB9, HB24 and DLX4 may be associated with colorectal carcinogenesis.

Le Caignec C, Winer N, Boceno M, et al.
Prenatal diagnosis of sacrococcygeal teratoma with constitutional partial monosomy 7q/trisomy 2p.
Prenat Diagn. 2003; 23(12):981-4 [PubMed] Related Publications
We report the prenatal diagnosis of a fetus with sacrococcygeal teratoma and facial dysmorphism attributed to a constitutional terminal deletion of chromosome 7q and partial trisomy of chromosome 2p likely resulting from a de novo balanced translocation. The cytogenetic abnormality was diagnosed prenatally after sonographic detection of teratoma and confirmed on peripheral blood cells at birth. The newborn died of post-operative complications at seven days of age. FISH analysis demonstrated haploinsufficiency of HLXB9, a gene identified in the triad of a presacral mass (teratoma or anterior meningocele), sacral agenesis, and anorectal malformation, which constitutes the Currarino syndrome. Despite the absence of other features of the triad, the teratoma observed in the fetus we describe might represent a partial form of Currarino syndrome.

Tosi S, Hughes J, Scherer SW, et al.
Heterogeneity of the 7q36 breakpoints in the t(7;12) involving ETV6 in infant leukemia.
Genes Chromosomes Cancer. 2003; 38(2):191-200 [PubMed] Related Publications
The t(7;12)(q36;p13) is a recurrent chromosome abnormality in infant leukemia. In these cases, the involvement of ETV6, with disruption of the gene consistently at its 5' end, has been reported by several groups. A fusion transcript between ETV6 and HLXB9 has been detected in some, but not all, reported cases of t(7;12). We report here a study based on fluorescence in situ hybridization (FISH) mapping of the translocation breakpoints in seven patients and detailed molecular studies using Southern blotting on two of these patients. The FISH studies have shown a cluster of breakpoints within a cosmid contig proximal to the HLXB9 gene. Southern blotting analysis enabled us to define two distinct breakpoints within the area covered by the cosmid contig in two patients. The analysis of an unusual case of t(7;12)(q22;p13) [full karyotype: 46,XX,der(7)t(7;12)(q22;p13)del(7)(q22q36)] also revealed a break in 7q36, although in a region proximal to the overlapping cosmids. 5' RACE PCR in one patient has shown a rearrangement involving the ETV6 allele not involved in the t(7;12), suggesting that no functional ETV6 allele might be present in this case. These data show some heterogeneity in the distribution of breakpoints in 7q36, indicating that the generation of a fusion gene might not be the mechanism responsible for leukemogenesis in the t(7;12), at least in some cases.

Neufing PJ, Kalionis B, Horsfall DJ, et al.
Expression and localization of homeodomain proteins DLX4/HB9 in normal and malignant human breast tissues.
Anticancer Res. 2003 Mar-Apr; 23(2B):1479-88 [PubMed] Related Publications
BACKGROUND: Alterations in the control of gene expression is a key event in neoplastic transformation. Investigating the expression of transcription factors such as homeodomain proteins may therefore allow better characterization of molecular mechanisms underlying the transformation process.
MATERIALS AND METHODS: Expression of homeodomain proteins DLX4 and HB9 was detected by RT-PCR and immunohistochemically in 24 breast tumors and their corresponding non-malignant tissue.
RESULTS: Although the percentage of nuclei expressing both DLX4 (p = 0.001) and HB9 (p = 0.0001) is increased in breast carcinoma, their intensity of nuclear staining is decreased compared to non-malignant nuclei. Furthermore HB9 nuclear immunoreactivity decreased progressively with increasing tumor grade (p = 0.001).
CONCLUSION: These data suggest that the reduction in malignant nuclear DLX4 immunoreactivity is an earlier event in breast carcinogenesis than the progressive loss of HB9 expression observed with increasing tumor grade. With further study and in conjunction with standard criterion of pathology, these findings may help to predict the malignant behaviour of some breast cancers.

Simmons HM, Oseth L, Nguyen P, et al.
Cytogenetic and molecular heterogeneity of 7q36/12p13 rearrangements in childhood AML.
Leukemia. 2002; 16(12):2408-16 [PubMed] Related Publications
The t(7;12)(q36;p13) is a recurrent abnormality in acute myeloid leukemia (AML) of childhood. The involved gene on chromosome 12 is TEL; the 7q36 partner gene has not been identified. We describe morphologic, molecular and cytogenetic characterization of two cases of 7q36/12p13-associated AML that provide important insights regarding the consequences of this rearrangement. First, the molecular organization of the breakpoint regions differ significantly: one case is a reciprocal 7;12 translocation (RTR); the other has an insertion of 7q into 12p (INS). While 12p13 breakpoints in both patients interrupt TEL intron 1, the centromere to telomere orientation of the 7q36 sequences relative to the TEL sequences are inverted in INS compared to RTR. This difference makes it difficult to postulate a mechanism whereby both patients could produce a common fusion transcript. Further, no evidence was obtained for any TEL-containing fusion transcripts. Finally, we report the first cloning of a 7;12 genomic breakpoint (from RTR) and find that it maps to a site 30 kbp proximal to the HLXB9 gene in 7q36. Together, these data suggest that, unlike most leukemia-associated chromosomal rearrangements, the important consequence of the t(7;12) is likely not the generation of a novel fusion transcript, but instead the inactivation of TEL and/or a gene at 7q36.

Beverloo HB, Panagopoulos I, Isaksson M, et al.
Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13).
Cancer Res. 2001; 61(14):5374-7 [PubMed] Related Publications
Recently, we and others reported a recurrent t(7;12)(q36;p13) found in myeloid malignancies in children < or =18 months of age and associated with a poor prognosis. Fluorescence in situ hybridization studies mapped the 12p13 breakpoint to the first intron of ETV6 and narrowed down the region of 7q36 involved. By using the sequences made public recently by the Human Genome Project, two candidate genes in 7q36 were identified: the homeobox gene HLXB9 and c7orf3, a gene with unknown function. Reverse transcription-PCR of two cases with t(7;12), using primers for c7orf3 and ETV6, was negative. However, reverse transcription-PCR for HLXB9-ETV6 demonstrated alternative splicing; the two major bands corresponded to fusion of exon 1 of HLXB9 to exons 2 and 3, respectively, of ETV6. The reciprocal ETV6-HLXB9 transcript was not detected. It remains to be elucidated if the leukemic phenotype is attributable to the formation of the HLXB9-ETV6 fusion protein, which includes the helix-loop-helix and E26 transformation-specific DNA binding domains of ETV6 or to the disruption of the normal ETV6 protein.

Kehrl JH, Deguchi Y
Potential roles for two human homeodomain containing proteins in the proliferation and differentiation of human hematopoietic progenitors.
Leuk Lymphoma. 1993; 10(3):173-6 [PubMed] Related Publications
Two human homeobox genes, HB9 and HLX, are expressed in hematopoietic progenitors and activated lymphocytes. They are implicated in the proliferation of hematopoietic progenitors in response to growth factors and the differentiation of hematopoietic progenitors to mature cell lineages. RNAs from bone marrow cells of patients with acute myeloid or lymphocytic leukemia have high levels of these two genes while similar RNAs from patients with chronic lymphocytic or myeloid leukemias have nearly normal levels. While the significance of these two genes in leukemogenesis is unknown, they are likely to regulate gene transcription during hematopoiesis and their dysregulation may have dire consequences for hematopoietic cells.

Deguchi Y, Yamanaka Y, Theodossiou C, et al.
High expression of two diverged homeobox genes, HB24 and HB9, in acute leukemias: molecular markers of hematopoietic cell immaturity.
Leukemia. 1993; 7(3):446-51 [PubMed] Related Publications
Homeobox genes encode for sequence-specific DNA-binding proteins which have been implicated in the control of gene expression during development and in certain adult tissues. Two recently characterized human homeobox-containing genes, HB9 and HB24, are known to be expressed in hematopoietic progenitors and to be involved in the regulation of growth and differentiation of progenitor cells to mature hematopoietic cell types. In this study, elevated levels of HB24 and HB9 mRNA expression were detected in bone marrow and peripheral blood mononuclear cells (PBMC) isolated from patients with acute myelogenous or acute lymphocytic leukemia. While the levels of both mRNAs were elevated in all the patients with acute leukemias, the levels of HB9 mRNA were more variable than those of HB24. Immunohistochemical analysis utilizing an HB24 polyclonal antiserum demonstrated elevated levels of HB24 protein in cytopreparations of acute leukemic cells. Nuclear run-on experiments showed that the increases of HB9 and HB24 mRNA transcripts in patients' cells were, at least in part, secondary to increased transcription. The expression of HB9 and HB24 correlated with the clinical status of the patient. No significant level of expression of either HB9 or HB24 was detected in PBMC isolated from patients in remission. In contrast to the findings with cells isolated from patients with acute leukemias, no significant increase in either HB9 or HB24 transcript levels were found in cells from patients with chronic lymphocytic or chronic myelogenous leukemia when compared to normal controls. These findings demonstrate that high levels of HB9 and HB24 expression are common features of acute leukemia and suggest the possibility that the dysregulated expression of these two genes may contribute to leukemogenesis. However, since these two genes are markers of immature hematopoietic cells they may not have an etiologic role in leukemogenesis.

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