SEPT6

Gene Summary

Gene:SEPT6; septin 6
Aliases: SEP2, SEPT2
Location:Xq24
Summary:This gene is a member of the septin family of GTPases. Members of this family are required for cytokinesis. One version of pediatric acute myeloid leukemia is the result of a reciprocal translocation between chromosomes 11 and X, with the breakpoint associated with the genes encoding the mixed-lineage leukemia and septin 2 proteins. This gene encodes four transcript variants encoding three distinct isoforms. An additional transcript variant has been identified, but its biological validity has not been determined. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:septin-6
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (14)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 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.

  • Gene Rearrangement
  • DNA-Binding Proteins
  • Acute Myeloid Leukaemia
  • Infant
  • Messenger RNA
  • Childhood Cancer
  • Septins
  • Chromosome 11
  • Neoplasm Proteins
  • Uniparental Disomy
  • Leukemia, Monocytic, Acute
  • Base Sequence
  • Leukemia, Myelomonocytic, Acute
  • Cloning, Molecular
  • Cancer DNA
  • Chromosome Breakage
  • Translocation
  • Myeloid Leukemia
  • Leukaemia
  • Cytoskeletal Proteins
  • RTPCR
  • GTP-Binding Proteins
  • Gene Expression
  • Histone-Lysine N-Methyltransferase
  • Transcription
  • Proto-Oncogenes
  • Oncogene Fusion Proteins
  • X Chromosome
  • Chromosome X
  • Up-Regulation
  • Young Adult
  • ras Guanine Nucleotide Exchange Factors
  • FISH
  • Adolescents
  • Zinc Fingers
  • Alternative Splicing
  • Transcription Factors
  • KMT2A
  • Cancer Gene Expression Regulation
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: SEPT6 (cancer-related)

Yu J, Zhang W, Tang H, et al.
Septin 2 accelerates the progression of biliary tract cancer and is negatively regulated by mir-140-5p.
Gene. 2016; 589(1):20-6 [PubMed] Related Publications
Aberrant expression of septin family members (SEPTs) has been noticed in various carcinomas; however, few studies have been conducted to determine their function in biliary tract cancer (BTC). In this study, we identified SEPT2 as a tumor-promoting gene that is regulated by miR-140-5p in BTC. Although miR-140-5p has been reported to be an anti-oncomiR for several types of cancer, this has not previously been shown for BTC. We found that the expression levels of SEPT2 and miR-140-5p were inversely correlated; SEPT2 was aberrantly upregulated in both primary tumor specimens and cell lines whereas miR-140-5p was significantly downregulated. Ectopic expression of miR-140-5p markedly decreased SEPT2 protein concentration in BTC cells and suppressed cell proliferation and colony formation in vitro. Interaction between miR-140-5p and the 3'UTR of SEPT2 was confirmed by luciferase assays and rescue experiments. Furthermore, overexpression of SEPT2 and low expression of miR-140-5p were associated with increased invasion of BTC as indicated by clinical parameters and confirmed by invasion assays in vitro. Xenografts formation assay also showed that SEPT2 overexpression significantly facilitated the growth of tumor in vivo. This finding may provide a novel therapeutic strategy for the treatment of biliary tract cancer.

Colombrita C, Onesto E, Buratti E, et al.
From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models.
Biochim Biophys Acta. 2015; 1849(12):1398-410 [PubMed] Related Publications
The full definition of the physiological RNA targets regulated by TDP-43 and FUS RNA-binding proteins (RBPs) represents an important issue in understanding the pathogenic mechanisms associated to these two proteins in amyotrophic lateral sclerosis and frontotemporal dementia. In the last few years several high-throughput screenings have generated a plethora of data, which are difficult to compare due to the different experimental designs and models explored. In this study by using the Affymetrix Exon Arrays, we were able to assess and compare the effects of both TDP-43 and FUS loss-of-function on the whole transcriptome using the same human neuronal SK-N-BE cell model. We showed that TDP-43 and FUS depletion induces splicing and gene expression changes mainly distinct for the two RBPs, although they may regulate common pathways, including neuron differentiation and cytoskeleton organization as evidenced by functional annotation analysis. In particular, TDP-43 and FUS were found to regulate splicing and expression of genes related to neuronal (SEPT6, SULT4A1, TNIK) and RNA metabolism (DICER, ELAVL3/HuC, POLDIP3). Our extended analysis at protein level revealed that these changes have also impact on the protein isoform ratio and content, not always in a direct correlation with transcriptomic data. Contrarily to a loss-of-function mechanism, we showed that mutant TDP-43 proteins maintained their splicing activity in human ALS fibroblasts and experimental cell lines. Our findings further contribute to define the biological functions of these two RBPs in physiological and disease state, strongly encouraging the evaluation of the identified transcriptomic changes at protein level in neuronal experimental models.

Wei Y, Yang J, Yi L, et al.
MiR-223-3p targeting SEPT6 promotes the biological behavior of prostate cancer.
Sci Rep. 2014; 4:7546 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) present frequently altered expression in urologic cancers including prostate, bladder, and kidney cancer. The altered expression of miR-223 has been reported in cancers and other diseases in recent researches. MiR-223 is up-regulated in systemic lupus erythematosus and rheumatoid arthritis. In neoplastic diseases, miR-223 is proved to be up-expressed in plasma or serum and cancer tissues compared with normal tissues in pancreatic cancer, gastric cancer, et al. However, whether altered expression of miR-223 is associated with prostate cancer (PCa) and what it is potential functions in PCa remained unveiled. In this study, we firstly found miR-223-3p were up-regulated in prostate cancer tissues and then we study functional role of miR-223-3p in PCa using DU145, PC3 and LNCaP cell lines. Our data suggested that miR-223-3p might target gene SEPT6 and promoted the biological behavior of prostate cancer. Notably, we found increasing SEPT6 expression might reverse the biological activity induced by miR-223-3p, which might be a potential therapeutic target for PCa.

Cerveira N, Lisboa S, Correia C, et al.
Genetic and clinical characterization of 45 acute leukemia patients with MLL gene rearrangements from a single institution.
Mol Oncol. 2012; 6(5):553-64 [PubMed] Related Publications
Chromosomal rearrangements affecting the MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemia. In this study, conventional cytogenetic, fluorescence in situ hybridization, and molecular genetic studies were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloid leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant.

Cerveira N, Bizarro S, Teixeira MR
MLL-SEPTIN gene fusions in hematological malignancies.
Biol Chem. 2011; 392(8-9):713-24 [PubMed] Related Publications
The mixed lineage leukemia (MLL) locus is involved in more than 60 different rearrangements with a remarkably diverse group of fusion partners in approximately 10% of human leukemias. MLL rearrangements include chromosomal translocations, gene internal duplications, chromosome 11q deletions or inversions and MLL gene insertions into other chromosomes, or vice versa. MLL fusion partners can be classified into four distinct categories: nuclear proteins, cytoplasmatic proteins, histone acetyltransferases and septins. Five different septin genes (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been identified as MLL fusion partners, giving rise to chimeric fusion proteins in which the N terminus of MLL is fused, in frame, to almost the entire open reading frame of the septin partner gene. The rearranged alleles result from heterogeneous breaks in distinct introns of both MLL and its septin fusion partner, originating distinct gene fusion variants. MLL-SEPTIN rearrangements have been repeatedly identified in de novo and therapy related myeloid neoplasia in both children and adults, and some clinicopathogenetic associations are being uncovered. The fundamental roles of septins in cytokinesis, membrane remodeling and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton and MLL deregulation could be involved in the pathogenesis of hematological malignancies.

Bielorai B, Meyer C, Trakhtenbrot L, et al.
Therapy-related acute myeloid leukemia with t(2;11)(q37;q23) after treatment for osteosarcoma.
Cancer Genet Cytogenet. 2010; 203(2):288-91 [PubMed] Related Publications
The survival rate for children with osteosarcoma (OS) has improved dramatically with the introduction of multiagent chemotherapy. As the number of pediatric cancer survivors increases, there is a concern about the development of secondary malignant neoplasms. Secondary acute myeloid leukemia (AML) has been rarely reported after treatment for OS. We describe a 14-year-old boy with OS of the left ileum who developed secondary AML 15 months after completion of treatment. Cytogenetic analysis of the leukemic cells demonstrated deletion 11q23, whereas fluorescence in situ hybridization revealed rearrangement of the MLL gene. Only the addition of the long-distance inverse polymerase chain reaction technique identified the SEPT2 as the MLL fusion partner resulting in t(2;11)(q37;q23) that was reported in a very few secondary AML cases. Because of the cryptic nature of MLL translocations that cannot be detected by conventional cytogenetics or may misinterpreted as deletion, additional molecular techniques are required to identify the precise translocation partner. Because long-distance inverse polymerase chain reaction is not available in most molecular laboratories, the true incidence of t(2;11)(q37;q23) and the involvement of SEPT2 as the MLL translocation partner could be more prevalent in secondary AML.

Xiangji L, Feng X, Qingbao C, et al.
Knockdown of HBV surface antigen gene expression by a lentiviral microRNA-based system inhibits HBV replication and HCC growth.
J Viral Hepat. 2011; 18(9):653-60 [PubMed] Related Publications
Current options for the treatment of hepatitis B virus (HBV) infections, a common liver cancer risk factor, are limited. While RNA interference (RNAi) technologies have been shown to inhibit HBV replication, the consequent effects on hepatocellular carcinoma (HCC) cell growth are not fully understood. The aim of this study was to evaluate the effect of RNAi-mediated decrease in the HBV surface antigen (HBsAg) gene on HBV replication and HCC growth. A lentiviral microRNA-based system expressing siRNAs targeting the HBsAg gene (LVshHBS) was developed and transfected into HepG2.2.15 cells (HBV stably expressing line). We found that LVshHBS significantly inhibited the HBsAg mRNA and protein levels in the HepG2.2.15 cells, while HBsAg secretion into the culture supernatant decreased by 70%. BALB/c (nu/nu) mice were injected with HepG2.2.15 cells transduced with LVshHBS or control vectors to investigate the effect of inhibiting the HBsAg on the development of tumour growth in a human HCC nude mice model. Compared with the control, the tumour growth in nude mice was significantly decreased after injection with LVshHBS. Microarray analysis of tumour-related genes in LVshHBS-transduced HepG2.2.15 cells showed that the expressions of genes involved in cell cycle, differentiation and oncogenesis such as ACP2, BHLHB2, CLK3, CTSC, FOS, NR1D1, PIM1 and SEPT6 genes were downregulated, while that of the E2F3 gene was upregulated. In conclusion, lentiviral microRNA-based RNAi against the HBsAg gene not only inhibits HBV replication but also inhibits the growth of HCC. Downregulation of growth-related genes is implicated in this mechanism of inhibition.

Liu M, Shen S, Chen F, et al.
Linking the septin expression with carcinogenesis.
Mol Biol Rep. 2010; 37(7):3601-8 [PubMed] Related Publications
The septin is a conserved GTP binding protein family which is involved in multiple cellular processes. Many evidences have indicated that some septins were abnormally expressed in certain kinds of tumors and the altered expressions were related to the process of carcinogenesis. To better understand the relationship between septins and cancer, we compared the expression of 14 human septin family members in 35 kinds of tumor types with their normal counterparts using the publicly available ONCOMINE microarray database. We found altered expression of most septin members in many kinds of tumors. Significantly, SEPT2, SEPT8, SEPT9, SEPT11 were consistently up-regulated, and SEPT4, SEPT10 were down-regulated in most cancer types investigated. Furthermore, the abnormal expressions were also in accordance with the tumor malignancies or prognosis of corresponding cancer patients. These findings have contributed to the view that septins may belong to a kind of cancer critical genes. More septins might act as potential oncogenes or tumor suppressor genes in cancer development.

Cerveira N, Santos J, Teixeira MR
Structural and expression changes of septins in myeloid neoplasia.
Crit Rev Oncog. 2009; 15(1-2):91-115 [PubMed] Related Publications
Septins are an evolutionarily conserved family of GTP-binding proteins that associate with cellular membranes and the actin and microtubule cytoskeletons. Fourteen septin genes have been characterized to date (SEPT1 to SEPT14) in humans. Septins have been reported to be misregulated in various human diseases, including neurological disorders, infection, and neoplasia. In this review, we describe what is known thus far about septin deregulation in myeloid neoplasia. Septin abnormalities in myeloid neoplasia can be divided into two major groups. First, some septins (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been repeatedly identified as in-frame fusion partners of the MLL gene in de novo and therapy-related myeloid neoplasia, in both children and adults. Second, deregulation of the expression of septin family genes in hematological cancers can be observed either with or without the concomitant presence of MLL gene fusions. Although current hypotheses regarding the roles of septins in oncogenesis remain speculative for the most part, the fundamental roles of septins in cytokinesis, membrane remodeling, and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton could be involved in neo-plastic disorders.

Santos J, Cerveira N, Bizarro S, et al.
Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes.
Leuk Res. 2010; 34(5):615-21 [PubMed] Related Publications
Septins are proteins associated with crucial steps in cell division and cellular integrity. In humans, 14 septin genes have been identified, of which five (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) are known to participate in reciprocal translocations with the MLL gene in myeloid neoplasias. We have recently shown a significant down-regulation of both SEPT2 and MLL in myeloid neoplasias with the MLL-SEPT2 fusion gene. In this study, we examined the expression pattern of the other 13 known septin genes in altogether 67 cases of myeloid neoplasia, including three patients with the MLL-SEPT2 fusion gene, four with MLL-SEPT6 fusion, and three patients with the MLL-SEPT9 fusion gene. When compared with normal controls, a statistically significant down-regulation was observed for the expression of both MLL (6.4-fold; p=0.008) and SEPT6 (1.7-fold; p=0.002) in MLL-SEPT6 leukemia. Significant down-regulation of MLL was also found in MLL-MLLT3 leukemias. In addition, there was a trend for SEPT9 down-regulation in MLL-SEPT9 leukemias (4.6-fold; p=0.077). Using hierarchical clustering analysis to compare acute myeloid leukemia genetic subgroups based on their similarity of septin expression changes, we found that MLL-SEPT2 and MLL-SEPT6 neoplasias cluster together apart from the remaining subgroups and that PML-RARA leukemia presents under-expression of most septin family genes.

Schwindt H, Vater I, Kreuz M, et al.
Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma.
Leukemia. 2009; 23(10):1875-84 [PubMed] Related Publications
To determine the pattern of genetic alterations in primary central nervous system lymphomas (PCNSL), 19 PCNSL were studied by high-density single-nucleotide polymorphism arrays. Recurrent losses involved 6p21.32, 6q21, 8q12-12.2, 9p21.3, 3p14.2, 4q35.2, 10q23.21 and 12p13.2, whereas gains involved 18q21-23, 19q13.31, 19q13.43 and the entire chromosomes X and 12. Partial uniparental disomies (pUPDs) were identified in 6p and 9p21.3. These genomic alterations affected the HLA locus, the CDKN2A/p16, CDKN2B/p15 and MTAP, as well as the PRDM1, FAS, MALT1, and BCL2 genes. Increased methylation values of the CDKN2A/p16 promoter region were detected in 75% (6/8) PCNSL. Gene expression profiling showed 4/21 (20%) minimal common regions of imbalances to be associated with a differential mRNA expression affecting the FAS, STAT6, CD27, ARHGEF6 and SEPT6 genes. Collectively, this study unraveled novel genomic imbalances and pUPD with a high resolution in PCNSL and identified target genes of potential relevance in the pathogenesis of this lymphoma entity.

Cerveira N, Santos J, Bizarro S, et al.
Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia.
BMC Cancer. 2009; 9:147 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature.
METHODS: Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1-RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL-SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.
RESULTS: When compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023)
CONCLUSION: We found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2.

Watanabe-Okochi N, Oki T, Komeno Y, et al.
Possible involvement of RasGRP4 in leukemogenesis.
Int J Hematol. 2009; 89(4):470-81 [PubMed] Related Publications
It is now conceivable that leukemogenesis requires two types of mutations, class I and class II mutations. We previously established a mouse bone marrow-derived HF6, an IL-3-dependent cell line, that was immortalized by a class II mutation MLL/SEPT6 and can be fully transformed by class I mutations such as FLT3 mutants. To understand the molecular mechanism of leukemogenesis, particularly progression of myelodysplastic syndrome (MDS) to acute leukemia, we made cDNA libraries from the samples of patients and screened them by expression-cloning to detect class I mutations that render HF6 cells factor-independent. We identified RasGRP4, an activator of Ras, as a candidate for class I mutation from three of six patients (MDS/MPD = 1, MDS-RA = 1, MDS/AML = 2, CMMoL/AML = 1 and AML-M2 = 1). To investigate the potential roles of RasGRP4 in leukemogenesis, we tested its in vivo effect in a mouse bone marrow transplantation (BMT) model. C57BL/6J mice transplanted with RasGRP4-transduced primary bone marrow cells died of T cell leukemia, myeloid leukemia, or myeloid leukemia with T cell leukemia. To further examine if the combination of class I and class II mutations accelerated leukemic transformation, we performed a mouse BMT model in which both AML1 mutant (S291fsX300) and RasGRP4 were transduced into bone marrow cells. The double transduction led to early onset of T cell leukemia but not of AML in the transplanted mice when compared to transduction of RasGRP4 alone. Thus, we have identified RasGRP4 as a gene potentially involved in leukemogenesis and suggest that RasGRP4 cooperates with AML1 mutations in T cell leukemogenesis as a class I mutation.

Meyer C, Kowarz E, Hofmann J, et al.
New insights to the MLL recombinome of acute leukemias.
Leukemia. 2009; 23(8):1490-9 [PubMed] Related Publications
Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.

Cerveira N, Micci F, Santos J, et al.
Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: identification of novel fusion transcripts and cloning of genomic breakpoint junctions.
Haematologica. 2008; 93(7):1076-80 [PubMed] Related Publications
One of the MLL fusion partners in leukemia is the SEPT6 gene, which belongs to the evolutionarily conserved family of genes of septins. In this work we aimed to characterize at both the RNA and DNA levels three acute myeloid leukemias with cytogenetic evidence of a rearrangement between 11q23 and Xq24. Molecular analysis led to the identification of several MLL-SEPT6 fusion transcripts in all cases, including a novel MLL-SEPT6 rearrangement (MLL exon 6 fused with SEPT6 exon 2). Genomic DNA breakpoints were found inside or near Alu or LINE repeats in the MLL breakpoint cluster region, whereas the breakpoint junctions in the SEPT6 intron 1 mapped to the vicinity of GC-rich low-complexity repeats, Alu repeats, and a topoisomerase II consensus cleavage site. These data suggest that a non-homologous end-joining repair mechanism may be involved in the generation of MLL-SEPT6 rearrangements in acute myeloid leukemia.

Snijder S, Mellink CH, van der Lelie H
Translocation (2;11)(q37;q23) in therapy-related myelodysplastic syndrome after treatment for acute promyelocytic leukemia.
Cancer Genet Cytogenet. 2008; 180(2):149-52 [PubMed] Related Publications
Treatment of acute promyelocytic leukemia (APL) with a combination of anthracycline-based chemotherapy and all-trans retinoic acid (ATRA) leads to very high rates of complete remission and survival. There are only a limited number of publications on the development of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia during follow-up of APL. Although drugs targeting at DNA-topoisomerase II characteristically induce translocations involving 11q23, this was seldom seen in patients treated for APL. We report on a patient initially diagnosed with APL. Response to therapy was monitored by fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction for the PML-RARalpha rearrangement. Consecutive samples showed a swift and complete reduction of PML-RARalpha rearranged cells. Twenty months after diagnosis, however, conventional cytogenetics revealed a complex karyotype with a translocation involving 11q23 and loss of chromosomes 7q and Xq. FISH analysis with the MLL probe identified 2q37 (harboring the SEPT2 gene) as the translocation partner of chromosome 11. We consider the rather unique t(2;11)(q37;q23) as the primary event causing therapy-related MDS in our patient. This case stresses the importance of conventional karyotyping to be performed on a regular basis in all treated APL patients for the early detection of chromosomal aberrations that indicate the development of therapy-related MDS or acute myeloid leukemia.

van Binsbergen E, de Weerdt O, Buijs A
A new subtype of MLL-SEPT2 fusion transcript in therapy-related acute myeloid leukemia with t(2;11)(q37;q23): a case report and literature review.
Cancer Genet Cytogenet. 2007; 176(1):72-5 [PubMed] Related Publications
The t(2;11)(q37;q23) is a rare recurrent cytogenetic abnormality associated with de novo and therapy-related acute myeloid leukemia, resulting in a MLL-SEPT2 fusion gene. We report on a case of therapy-related acute myeloid leukemia M2 showing a t(2;11)(q37;q23) and resulting in a new subtype of a MLL-SEPT2 chimeric transcript. The literature on this translocation is reviewed.

Strehl S, König M, Meyer C, et al.
Molecular dissection of t(11;17) in acute myeloid leukemia reveals a variety of gene fusions with heterogeneous fusion transcripts and multiple splice variants.
Genes Chromosomes Cancer. 2006; 45(11):1041-9 [PubMed] Related Publications
The majority of translocations that involve the long arms of chromosomes 11 and 17 in acute myeloid leukemia appear identical on the cytogenetic level. Nevertheless, they are diverse on the molecular level. At present, two genes are known in 11q23 and four in 17q12-25 that generate five distinct fusion genes: MLL-MLLT6/AF17, MLL-LASP1, MLL-ACACA or MLL-SEPT9/MSF, and ZBTB16/PLZF-RARA. We analyzed 14 cases with a t(11;17) by fluorescence in situ hybridization and molecular genetic techniques and determined the molecular characteristics of their fusion genes. We identified six different gene fusions that comprised seven cases with a MLL-MLLT6/AF17, three with a MLL-SEPT9/MSF, and one each with MLL-LASP1, MLL-ACACA, and ZBTB16/PLZF-RARA fusions. In the remaining case, a MLL-SEPT6/Xq24 fusion suggested a complex rearrangement. The MLL-MLLT6/AF17 transcripts were extremely heterogeneous and the detection of seven different in-frame transcript and splice variants enabled us to predict the protein domains relevant for leukemogenesis. The putative MLL-MLLT6 consensus chimeric protein consists of the AT-hook DNA-binding, the methyltransferase, and the CXXC zinc-finger domains of MLL and the highly conserved octapeptide and the leucine-zipper dimerization motifs of MLLT6. The MLL-SEPT9 transcripts showed a similar high degree of variability. These analyses prove that the diverse types of t(11;17)-associated fusion genes can be reliably identified and delineated with a proper combination of cytogenetic and molecular genetic techniques. The heterogeneity of transcripts encountered in cases with MLL-MLLT6/AF17 and MLL-SEPT9/MSF fusions clearly demonstrates that thorough attention has to be paid to the appropriate selection of primers to cover all these hitherto unrecognized fusion variants.

Kadkol SS, Bruno A, Oh S, et al.
MLL-SEPT6 fusion transcript with a novel sequence in an infant with acute myeloid leukemia.
Cancer Genet Cytogenet. 2006; 168(2):162-7 [PubMed] Related Publications
The MLL gene at 11q23 is a site of frequent rearrangement in acute leukemia with multiple fusion partners. A relatively uncommon rearrangement, associated with infant AML-M4, fuses the MLL and SEPT6 genes. SEPT6, located at Xq24, is a member of a family of mammalian septins involved in diverse functions such as cytokinesis, cell polarity, and oncogenesis. We describe the case of an infant with acute myelogenous leukemia who showed cytogenetic evidence of rearrangement between 11q23 and Xq24 regions. Fluorescence in situ hybridization analysis suggested a possible break in the MLL gene, and molecular analysis using reverse transcriptase-polymerase chain reaction followed by sequencing confirmed the expression of an MLL-SEPT6 fusion transcript with a novel sequence. The findings emphasize the importance of combined cytogenetic and molecular analyses in the workup of acute leukemia, especially in those leukemias that occur infrequently.

Cerveira N, Correia C, Bizarro S, et al.
SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23).
Oncogene. 2006; 25(45):6147-52 [PubMed] Related Publications
We have identified a new mixed lineage leukemia (MLL) gene fusion partner in a patient with treatment-related acute myeloid leukemia (AML) presenting a t(2;11)(q37;q23) as the only cytogenetic abnormality. Fluorescence in situ hybridization demonstrated a rearrangement of the MLL gene and molecular genetic analyses identified a septin family gene, SEPT2, located on chromosome 2q37, as the fusion partner of MLL. RNA and DNA analyses showed the existence of an in-frame fusion of MLL exon 7 with SEPT2 exon 3, with the genomic breakpoints located in intron 7 and 2 of MLL and SEPT2, respectively. Search for DNA sequence motifs revealed the existence of two sequences with 94.4% homology with the topoisomerase II consensus cleavage site in MLL intron 7 and SEPT2 intron 2. SEPT2 is the fifth septin family gene fused with MLL, making this gene family the most frequently involved in MLL-related AML (about 10% of all known fusion partners). The protein encoded by SEPT2 is highly homologous to septins 1, 4 and 5 and is involved in the coordination of several key steps of mitosis. Further studies are warranted to understand why the septin protein family is particularly involved in the pathogenesis of MLL-associated leukemia.

Shih LY, Liang DC, Fu JF, et al.
Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement.
Leukemia. 2006; 20(2):218-23 [PubMed] Related Publications
The fusion transcripts of MLL rearrangement [MLL(+)] in acute myeloid leukemia (AML) and their clinicohematologic correlation have not be well characterized in the previous studies. We used Southern blot analysis to screen MLL(+) in de novo AML. Reverse transcriptase-polymerase chain reaction was used to detect the common MLL fusion transcripts. cDNA panhandle PCR was used to identify infrequent or unknown MLL partner genes. MLL(+) was identified in 114 (98 adults) of 988 AML patients. MLL fusion transcripts comprised of 63 partial tandem duplication of MLL (MLL-PTD), 14 MLL-AF9, 9 MLL-AF10, 9 MLL-ELL, 8 MLL-AF6, 4 MLL-ENL and one each of MLL-AF1, MLL-AF4, MLL-MSF, MLL-LCX, MLL-LARG, MLL-SEPT6 and MLL-CBL. The frequency of MLL-PTD was 7.1% in adults and 0.9% in children (P<0.001). 11q23 abnormalities were detected in 64% of MLL/t11q23 and in none of MLL-PTD by conventional cytogenetics. There were no differences in remission rate, event-free survival and overall survival between adult MLL-PTD and MLL/t11q23 groups. Adult patients had a significantly poorer outcome than children. The present study showed that cDNA panhandle PCR can identify all rare or novel MLL partner genes. MLL-PTD was rare in childhood AML. MLL(+) adults had a poor outcome with no difference in survival between MLL-PTD and MLL/t11q23 groups.

Ono R, Nakajima H, Ozaki K, et al.
Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis.
J Clin Invest. 2005; 115(4):919-29 [PubMed] Free Access to Full Article Related Publications
The mechanisms by which mixed-lineage leukemia (MLL) fusion products resulting from in utero translocations in 11q23 contribute to leukemogenesis and infant acute leukemia remain elusive. It is still controversial whether the MLL fusion protein is sufficient to induce acute leukemia without additional genetic alterations, although carcinogenesis in general is known to result from more than 1 genetic disorder accumulating during a lifetime. Here we demonstrate that the fusion partner-mediated homo-oligomerization of MLL-SEPT6 is essential to immortalize hematopoietic progenitors in vitro. MLL-SEPT6 induced myeloproliferative disease with long latency in mice, but not acute leukemia, implying that secondary genotoxic events are required to develop leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3 (FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. In these systems, MLL-ENL, another type of the fusion product that seems to act as a monomer, also induced the transformation in vitro and leukemogenesis in vivo in concert with activated FLT3. These findings show direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.

Fu JF, Liang DC, Yang CP, et al.
Molecular analysis of t(X;11)(q24;q23) in an infant with AML-M4.
Genes Chromosomes Cancer. 2003; 38(3):253-9 [PubMed] Related Publications
t(X;11)(q24;q23) is a recurring chromosomal translocation in pediatric acute myeloid leukemia. The rearrangement results in fusion of MLL at 11q23 with SEPT6 at Xq24. Here, we report the identification of an MLL-SEPT6 fusion transcript in an infant with acute myeloid leukemia (AML)-M4. Reverse transcription-polymerase chain reaction confirmed the presence of an MLL-SEPT6 fusion transcript composed of exon 8 of MLL and exon 2 of SEPT6, but the absence of the reciprocal SEPT6-MLL fusion transcript. Sequence analysis of the genomic break junctions in MLL and SEPT6 suggested that the rearrangement in this case was the result of an insertion of the inverted Xq24 segment, which contained the 3' region of SEPT6 intron 1 and up to 950 kb centromeric to SEPT6, into MLL intron 8. This is a novel type of chromosomal rearrangement leading to the MLL-SEPT6 fusion. The presence of deletions, duplications, and non-template DNA sequence at the break junctions suggested that the DNA damage-repair machinery is likely to be involved in the translocation events.

Kim HJ, Ki CS, Park Q, et al.
MLL/SEPTIN6 chimeric transcript from inv ins(X;11)(q24;q23q13) in acute monocytic leukemia: report of a case and review of the literature.
Genes Chromosomes Cancer. 2003; 38(1):8-12 [PubMed] Related Publications
Rearrangements of the MLL gene on chromosome 11, band q23, are one of the most common genetic changes in acute leukemia. Reciprocal translocation is the most common form of MLL rearrangement, and the partner genes in MLL translocation are notably diverse. Involvement of the SEPTIN6 gene on Xq24 in MLL rearrangements occurs very rarely, with only six cases having been documented in the literature. Of note, the MLL/SEPTIN6 rearrangements in these cases were cryptic or complex, and it was shown that the 5'-MLL/SEPTIN6-3' transcript resides on the derivative X chromosome rather than on the derivative chromosome 11 as in the majority of cases of MLL translocations. These observations suggested that MLL and SEPTIN6 reside on their respective chromosome loci in reverse orientation, that is, centromere-to-telomere and telomere-to-centromere, respectively. We here report a case of acute monocytic leukemia with inv ins(X;11)(q24;q23q13) in a 29-month-old child. Fluorescence in situ hybridization study revealed the break-apart 5'-MLL segment to be translocated to the derivative X chromosome, and reverse transcriptase-polymerase chain reaction followed by sequencing analysis confirmed the 5'-MLL/SEPTIN6-3' chimeric transcript. This case is the first to provide direct cytogenetic evidence for the salient nature of the MLL/SEPTIN6 rearrangement. We reviewed clinical and cytogenetic features of all cases of 11q23 and Xq22-24 rearrangements reported up to now, including six cases where the involvement of the SEPTIN6 gene was confirmed by molecular techniques.

Slater DJ, Hilgenfeld E, Rappaport EF, et al.
MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site.
Oncogene. 2002; 21(30):4706-14 [PubMed] Related Publications
We examined the MLL translocation in two cases of infant AML with X chromosome disruption. The G-banded karyotype in the first case suggested t(X;3)(q22;p21)ins(X;11)(q22;q13q25). Southern blot analysis showed one MLL rearrangement. Panhandle PCR approaches were used to identify the MLL fusion transcript and MLL genomic breakpoint junction. SEPTIN6 from chromosome band Xq24 was the partner gene of MLL. MLL exon 7 was joined in-frame to SEPTIN6 exon 2 in the fusion transcript. The MLL genomic breakpoint was in intron 7; the SEPTIN6 genomic breakpoint was in intron 1. Spectral karyotyping revealed a complex rearrangement disrupting band 11q23. FISH with a probe for MLL confirmed MLL involvement and showed that the MLL-SEPTIN6 junction was on the der(X). The MLL genomic breakpoint was a functional DNA topoisomerase II cleavage site in an in vitro assay. In the second case, the karyotype revealed t(X;11)(q22;q23). Southern blot analysis showed two MLL rearrangements. cDNA panhandle PCR detected a transcript fusing MLL exon 8 in-frame to SEPTIN6 exon 2. MLL and SEPTIN6 are vulnerable to damage to form recurrent translocations in infant AML. Identification of SEPTIN6 and the SEPTIN family members hCDCrel and MSF as partner genes of MLL suggests a common pathway to leukaemogenesis.

Ono R, Taki T, Taketani T, et al.
SEPTIN6, a human homologue to mouse Septin6, is fused to MLL in infant acute myeloid leukemia with complex chromosomal abnormalities involving 11q23 and Xq24.
Cancer Res. 2002; 62(2):333-7 [PubMed] Related Publications
t(X;11) is a recurrent translocation in pediatric acute myeloid leukemia (AML). We showed that the MLL gene on 11q23 was fused to the SEPTIN6 gene on Xq24, a human homologue to mouse Septin6, in three de novo infant AML with complex chromosomal abnormalities involving 11q23 and Xq22-24. SEPTIN6 consisted of at least 12 exons and was predicted to encode at least two types of proteins by alternative splicing. Expression of approximately 2.3-, 3.1-, and 4.6-kb SEPTIN6 transcripts was simultaneously detected in fetal lung, liver, and brain, in all of the adult tissues except brain, and in acute lymphoblastic leukemia and AML cell lines. However, the expression of an approximately 2.7-kb transcript was detected alone in fetal heart and adult brain. The SEPTIN6 protein is homologous to septin family members including CDCREL1 and AF17q25/MSF, which generate fusion products with MLL. The MLL-SEPTIN6 fusion proteins contain almost the entire septin protein, similar to MLL-CDCREL1 and MLL-AF17q25/MSF. Notably, all three of the patients were diagnosed with M1 or M2. Combined present results and literatures suggest that AML with the MLL-SEPTIN6 fusion gene is a subset of infant AML, which differentiate into the myeloid lineage, although AML with other MLL fusion genes is capable of differentiating into the myelomonocytic or monocytic lineage.

Borkhardt A, Teigler-Schlegel A, Fuchs U, et al.
An ins(X;11)(q24;q23) fuses the MLL and the Septin 6/KIAA0128 gene in an infant with AML-M2.
Genes Chromosomes Cancer. 2001; 32(1):82-8 [PubMed] Related Publications
The MLL (HRX, ALL-1 HTRX) gene at chromosome band 11q23 frequently is rearranged in acute lymphoblastic and myeloblastic leukemia. To date, more than 40 different 11q23 abnormalities have been described on the cytogenetic level, and at least 25 of the respective fusion partner genes are cloned. The vast majority of the respective reciprocal translocations generate a chimeric 5'-MLL/partner-3' gene on the derivative 11q23. In this work, we report a unique ins(X;11)(q24;q23) in an infant with acute myeloid leukemia (AML-M2) that fuses the human KIAA0128 gene at Xq24 with MLL. In contrast to the typical reciprocal MLL translocations, however, we provide evidence that the 5'-MLL/KIAA0128-3' fusion resides on Xq24 rather than on 11q23. The KIAA0128 gene encodes the human Septin 6 protein, which contains an ATP-GTP binding motif and three nuclear targeting sequences in its carboxy terminus. The maintenance of the reading frame of the 5'-MLL/KIAA0128-3' mRNA fusion allows for the formation of a novel chimeric protein. Septin 6 is the third member of the Septins that is fused to the MLL protein; the other two are hCDCrel at 22q11 and MSF at 17q25.

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