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t(X;11)(q24;q23) KMT2A/SEPT6

Written2011-02Adriana Zamecnikova
Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653 Kuwait

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9807/3 Mixed phenotype acute leukaemia with t(v;11q23); MLL rearranged
ICD-Morpho 9813/3 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL rearranged
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1219

Clinics and Pathology

Disease All the described cases were diagnosed as having acute myeloid leukemia (AML), classified as FAB- M2 (5 cases), M4 (4 cases), M1 (1 case) and M5 (1 case), indicating that AML with the MLL-SEPTIN6 fusion gene have a tendency to differentiate into the myeloid lineage. All the patients were infants and young children aged 0 to 29 months, suggesting that AML with t(X;11)(q24;q23) is a subgroup of infant leukemia.
Phenotype / cell stem origin Suggested involvement of a pluripotent stem cell or a myeloid progenitor cell.
Etiology No known prior exposure; putative association with in utero exposure to recurrent genetic insults.
Epidemiology Involvement of the SEPTIN6 gene on Xq24 in MLL rearrangements occurs very rarely, with only 13 cases (7 males, 6 females) having been documented in the literature. In addition, 3 AML cases with chromosomal translocation t(X;11)(q24;q23) (3 males aged 0 to 6 years), which also potentially could be found to involve MLL and SEPTIN6 genes have been described confirming the recurrent nature of this translocation.
Clinics Hepatosplenomegaly (3 cases), massive and diffuse adenopathy (2 cases), lympadenophaty (2 cases), CNS involvement in 2 cases as well as chloroma, scalp nodules, mucosal and cutaneous pallor, bluish cutaneous nodules and petecchiae were described. Notably, in 2 of the patients bilateral and right exophthalmus was described. Peripheral blood leukocytosis (WBC 13.4x109/L to 608x109/L; mean 223x109/L), anemia and thrombocytopenia were reported in the majority of patients.
Prognosis From the 4 patients treated with chemotherapy one is alive (13+ months), 3 patients died 1 to 8 months from diagnosis; 8 patients received bone marrow transplantation, among them 2 of the patients died after 9 and 11 months, 6 patients are alive (one months to 7 years) indicating the prognosis is rather poor.

Cytogenetics

Cytogenetics Morphological Chromosomal rearrangements of 11q23 and Xq24 resulting in MLL-SEPT6 fusions are often complex and sometimes cryptic associated with 11q insertions. In addition, molecular detection of MLL-SEPTIN6 transcripts in cases with normal cytogenetics and in patients with chromosomal Xq22 breakpoints indicates the difficulty in precise chromosomal breakpoint definition.
Additional anomalies +6 (2 cases), del(11)(q13), i(10)(q10), add(X)(p11) described in single cases.
Variants At least four different types of chromosomal rearrangements have been described that can generate the MLL-SEPT6 fusion.

Genes involved and Proteins

Note MLL and SEPTIN6 reside on their respective chromosome loci in reverse orientation, that is, the orientation of the MLL gene is centromere-to-telomere and the orientation of the SEPTIN6 gene is reversed, telomere to centromere at Xq24. This may explain why the MLL/SEPTIN6/Xq24 rearrangement is often associated with complex translocations and with 11q insertions.
Gene NameKMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location 11q23.3
Dna / Rna The MLL genomic structure consists of at least 36 exons spanning a region of ~89 kb. The mRNA of ~11.9 kb encodes a massive nuclear protein of 3969 amino acids with a molecular weight of nearly 430 kDa.
Protein Multi-domain protein characteristic of several domains with assigned activities including an N terminus with DNA binding motifs; AT-hook motifs, 4 cysteine-rich zinc fingers, a transactivation domain, and a highly conserved C-terminal domain with histone methyltransferase activity. Nuclear protein; a major regulator of class I homeobox (HOX) gene expression; functions as a positive regulator of gene expression in early embryonic development and hematopoiesis regulation.
Gene NameSEPT6 (septin 6)
Location Xq24
Dna / Rna The SEPT6 gene, belongs to the evolutionarily conserved family of genes of septins consisting of 12 exons. Four types of transcripts: 2.3 kb, 2.7 kb, 3.1 kb and 4.6 kb coding for three isoforms. SEPT6 is ubiquitously expressed in tissues; in the human, several alternatively spliced SEPTIN6 transcripts are differentially expressed in adult and fetal tissues.
Protein 434 amino acids; 49717 Da.
SEPT6 is a GTP-binding protein with a central conserved ATP-GTP binding motif, a lysin rich region, a variable N-terminal extension domain and a C-terminal coiled coil. May function in heteropolymeric complexes; roles in GTPase signaling, cell division, cytokinesis, cytoskeletal filament formation, cell polarity, and oncogenesis.
Septins, a family of conserved GTP-binding proteins, are characteristically found in the heteropolymeric filaments and associate with cellular membranes, microtubules and actin filaments which are assembled from asymmetrical heterotrimers, composed of SEPT2, SEPT6 and SEPT7 that associate head-to-head to form a hexameric unit. Mammalian septins localize in the cytoplasm and assemble into heteromeric complexes composed of three or more septin subunits.

Result of the chromosomal anomaly

Hybrid gene
Note 5' MLL - SEPTIN6 3'
The MLL genomic breakpoints in MLL-SEPT6 AML patients in all cases occurred in the MLL 8.3 kb breakpoint cluster region (BCR) and seem to occur preferentially in the telomeric half (between introns 7 and 11) of the MLL BCR. In the majority of reported cases 5' MLL sequences joined in-frame with SEPTIN6 downstream of SEPT6 exon 1. In rare cases, out-of-frame fusion between MLL exon 7 and SEPT6 exon 2, with splicing of MLL exon 6 have been described.
The breakpoint junctions in the SEPT6 intron 1 mapped to the vicinity of GC-rich low-complexity repeats, Alu repeats, and a topoisomerase II recognition sequence raising the possibility that the non-homologous DNA end-joining pathway may be involved in the in the generation of MLL-SEPT6 rearrangements in infant acute myeloid leukemia and a putative association with in utero exposure to topoisomerase II inhibitors has been hypothesized.
  Schematic representation of MLL-SEPTIN6 fusion protein.
 
Transcript 5'-MLL/SEPTIN6-3' chimeric transcript.
  
Fusion Protein
Note The MLL-SEPT6 chimeric protein consists of the AT-hook DNA-binding, the DNA methyltransferase, the and repression domains of MLL and almost the entire open reading frame of SEPT6 including the central conserved ATP-GTP binding motif.
Expression Localisation MLL fusion genes express in- frame chimeric proteins residing in the nucleus.
Oncogenesis MLL is fused with a partner gene in MLL-related leukemias leading to the aberrant activation of target genes, including HOX genes. The phenotype depends on the fusion partner, indicating that each fusion partner is critical for the leukemogenesis. Among partner genes, septins are the protein family most frequently involved in rearrangements with MLL, suggesting that SEPTIN family members are particularly vulnerable to form MLL translocations. MLL fusions with several different SEPTIN family members (SEPT2, SEPT5, SEPT9, and SEPT11) are preferentially associated with myeoloblastic rather than lymphoblastic leukemogenesis suggesting an important common pathway to leukaemogenesis in AML with these translocations.
The observation that overexpression of SEPT6 itself does not lead to the myeloid immortalization of murine hematopoietic progenitors in vitro, whereas the overexpression of MLL-SEPT6 does indicate that the fusion partner-mediated homooligomerization of MLL-SEPT6 through its intact GTP-binding domain and coiled-coil region in the nucleus is essential to immortalize hematopoietic progenitors. However, MLL-SEPT6 rearrangment induced lethal myeloproliferative disease with long latency in mice, but not acute leukemia in experimental models. These findings suggest that secondary genotoxic effects on DNA repair and/or cell-cycle regulation are required for oncogenesis in MLL-SEPT6 associated leukemias.
  

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Bibliography

An ins(X;11)(q24;q23) fuses the MLL and the Septin 6/KIAA0128 gene in an infant with AML-M2.
Borkhardt A, Teigler-Schlegel A, Fuchs U, Keller C, Konig M, Harbott J, Haas OA.
Genes Chromosomes Cancer. 2001 Sep;32(1):82-8.
PMID 11477664
 
Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: identification of novel fusion transcripts and cloning of genomic breakpoint junctions.
Cerveira N, Micci F, Santos J, Pinheiro M, Correia C, Lisboa S, Bizarro S, Norton L, Glomstein A, Asberg AE, Heim S, Teixeira MR.
Haematologica. 2008 Jul;93(7):1076-80. Epub 2008 May 19.
PMID 18492691
 
Molecular analysis of t(X;11)(q24;q23) in an infant with AML-M4.
Fu JF, Liang DC, Yang CP, Hsu JJ, Shih LY.
Genes Chromosomes Cancer. 2003 Nov;38(3):253-9.
PMID 14506700
 
Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants.
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Leukemia. 1998 May;12(5):811-22.
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MLL-SEPT6 fusion transcript with a novel sequence in an infant with acute myeloid leukemia.
Kadkol SS, Bruno A, Oh S, Schmidt ML, Lindgren V.
Cancer Genet Cytogenet. 2006 Jul 15;168(2):162-7.
PMID 16843108
 
MLL/SEPTIN6 chimeric transcript from inv ins(X;11)(q24;q23q13) in acute monocytic leukemia: report of a case and review of the literature.
Kim HJ, Ki CS, Park Q, Koo HH, Yoo KH, Kim EJ, Kim SH.
Genes Chromosomes Cancer. 2003 Sep;38(1):8-12. (REVIEW)
PMID 12874781
 
Phenotypic and genotypic heterogeneity in infant acute leukemia. II. Acute nonlymphoblastic leukemia.
Koller U, Haas OA, Ludwig WD, Bartram CR, Harbott J, Panzer-Grumayer R, Hansen-Hagge T, Ritter J, Creutzig U, Knapp W, et al.
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Acute myeloid leukemia with hypergranular cytoplasm accompanied by t(X;11)(q24;q23) and rearrangement of the MLL gene.
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Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis.
Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T, Kitamura T, Hayashi Y, Nosaka T.
J Clin Invest. 2005 Apr;115(4):919-29. Epub 2005 Mar 10.
PMID 15761502
 
SEPTIN6, a human homologue to mouse Septin6, is fused to MLL in infant acute myeloid leukemia with complex chromosomal abnormalities involving 11q23 and Xq24.
Ono R, Taki T, Taketani T, Kawaguchi H, Taniwaki M, Okamura T, Kawa K, Hanada R, Kobayashi M, Hayashi Y.
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PMID 11809673
 
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.
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Citation

This paper should be referenced as such :
Zamecnikova, A
t(X;11)(q24;q23) MLL-SEPTIN6
Atlas Genet Cytogenet Oncol Haematol. 2011;15(9):765-767.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0X11q24q23ID1219.html


Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes SEPT6 TPM4

Translocations implicated (Data extracted from papers in the Atlas)

 t(X;11)(q24;q23) KMT2A/SEPT6

External links

KMT2A (11q23.3) SEPT6 (Xq24)

KMT2A (11q23.3) SEPT6 (Xq24)

Mitelman databaset(X;11)(q24;q23) [Case List]    t(X;11)(q24;q23) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9807/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9813/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionKMT2A/SEPT6 KMT2A (11q23.3) SEPT6 (Xq24)   [fusion1916]   [fusion1917]   [fusion1918]   [fusion1919]   [fusion1922]   [fusion1923]   [fusion1924]   [fusion1925]   [fusion1926]   [fusion2069]  
TICdbKMT2A/SEPT6  KMT2A (11q23.3) SEPT6 (Xq24)
 
Disease databaset(X;11)(q24;q23) KMT2A/SEPT6
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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