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t(2;11)(q37;q23) KMT2A/SEPT2

Written2007-09Cecília Correia, Manuel R Teixeira
Department of Genetics, Portuguese Oncology Institute, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal.

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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
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
Atlas_Id 1457
 
  t(2;11)(q37;q23) by G-banding and FISH with dual-color, break-apart MLL probe; Cecília, Manuel R Teixeira (left); partial GTG-banded karyotype of t(2;11)(q37;23) and FISH analysis using probe LSI MLL DCBA demonstrating a 11q23 MLL rearrangement with a fusion signal on the normal chromosome 11, a split 5'MLL signal on der(11) and a 3'MLL signal on der(2); courtesy Arjan Buijs and Ellen van Binsbergen (right).

Clinics and Pathology

Disease Rare type of acute myeloid leukemia (AML) and therapy-related AML.
Phenotype / cell stem origin No specific AML FAB sub-type (two cases M4, one M2, one M5a and one NOS).
Etiology Either de novo or therapy-related (prior cancer is variable: breast cancer, non-Hodgkin lymphoma and LLA).
Epidemiology Five cases known in the literature; four adults and one child, sex ratio 2M/3F; (age range 14.4-76).
 
Prognosis Two cases showed poor survival, 9 and 17 months respectively, one case achieved remission after stem cell transplantation. The prognosis may be likely to be comparable with that of other entities with 11q23/MLL involvement, and worse in therapy related leukemias.

Genes involved and Proteins

Gene Name SEPT2
Location 2q37
Dna / Rna The SEPT2 gene has 14 exons.
SEPT2 has four types of transcripts with 3.6 kb, 3.5 kb, 3.4 kb and 3.3 kb encoding the same protein, as a result of alternative splicing.
Protein SEPT2 belongs to an evolutionarily conserved family of genes that encode a P loop-based GTP-binding domain flanked by a polybasic domain and (usually) a coiled-coil region, and assemble into homo- and hetero-oligomers and filaments with key roles in cell division cytoskeletal dynamics and secretion. The SEPT2 gene codes for a protein with 361 amino acids and a molecular weight of 41.5 kDa.
SEPT2 was identified as a gene expressed in early embryonic mouse brain and down-regulated during development. It is ubiquitously expressed in cell lines and tissues with the highest protein levels found in brain tissue.
The SEPT2 protein, like other septin family members, is thought to be cytoplasmic. SEPT2 co-localises with actin filaments in interphase cells, and in dividing cells concentrates at the cleavage furrow.
SEPT2 is a multifunctional protein that was shown to be required for cytokinesis and to bind actin and associate with focal adhesions. Recent data support the idea that SEPT2 can have a role in chromosome congression and segregation. Additional functions have also been suggested; for instance, in rat brain lysates SEPT2 is part of a multi-septin complex that interacts with the exocyst complex, which plays a role in secretion and neurite outgrowth. SEPT2 has also been localised to senile plaques of brains in patients with Alzheimer¹s disease suggesting a role in neurodegeneration.
The SEPT2 protein belongs to an evolutionarily family of proteins with at least 14 members and shares a very high homology with septin 1, septin 4 and septin 5.
Gene Name KMT2A
Location 11q23
Dna / Rna 37 exons, spanning over 100 kb. In a centromeric to telomeric direction; 13 and 15 kb; coding sequence: 11.9 kb.
Protein 3969 amino acids; 431 KDa; contains from N-term to C-term 3 AT hooks homologous to high mobility group proteins HMGA1 and HMGA2, binding to the minor grove of DNA; 2 speckled nuclear localisation signals; 2 repression domains RD1 and RD2: RD1 or CXXC: cystein methyl transferase, binds CpG rich DNA, has a transcriptional repression activity; RD2 recruits histone desacetylases HDAC1 and HDAC2; 3 plant homeodomains (cystein rich zinc finger domains, with homodimerization properties), 1 bromodomain (may bind acetylated histones), and 1 plant homeodomain; these domains may be involved in protein-protein interaction; a FYRN and a FRYC domain; a transactivation domain which binds CBP ; may acetylates H3 and H4 in the HOX area; a SET domain: methyltransferase; methyltates H3, including histones in the HOX area for allowing chromatin to be open to transcription. MLL is cleaved by taspase 1 into 2 proteins before entering the nucleus: a p300/320 N-term protein called MLL-N, and a p180 C-term protein, called MLL-C. The FYRN and a FRYC domains of native MLL associate MLL-N and MLL-C in a stable complex; they form a multiprotein complex with transcription factor TFIID.

Result of the chromosomal anomaly

Hybrid gene
 
Description MLL­SEPT2. MLL exon 6 or 7 fused with SEPT2 exon 3.
  
Fusion Protein
 
  Structure of the normal MLL and SEPT2 proteins and the resulting MLL-SEPT2 fusion protein.
Description AT hook, SNL-1, SNL-2 and DNA methyltransferase domains from MLL fused to almost the entire open-reading frame of SEPT2, except for the first three aminoacids.
  

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

SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23).
Cerveira N, Correia C, Bizarro S, Pinto C, Lisboa S, Mariz JM, Marques M, Teixeira MR
Oncogene. 2006 ; 25 (45) : 6147-6152.
PMID 16682951
 
Translocation 2;11 and other significant chromosome changes in acute monoblastic leukemia (M5) with clonal evolution: sequential clinical and cytogenetic studies.
DeLozier-Blanchet CD, Cabrol C, Werner-Favre C, Beris P, Engel E
Cancer genetics and cytogenetics. 1985 ; 16 (2) : 95-102.
PMID 3855693
 
Molecular cytogenetic delineation of deletions and translocations involving chromosome band 7q22 in myeloid leukemias.
Fischer K, Fröhling S, Scherer SW, McAllister Brown J, Scholl C, Stilgenbauer S, Tsui LC, Lichter P, Döhner H
Blood. 1997 ; 89 (6) : 2036-2041.
PMID 9058725
 
Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide.
Winick NJ, McKenna RW, Shuster JJ, Schneider NR, Borowitz MJ, Bowman WP, Jacaruso D, Kamen BA, Buchanan GR
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1993 ; 11 (2) : 209-217.
PMID 8426196
 
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.
van Binsbergen E, de Weerdt O, Buijs A
Cancer genetics and cytogenetics. 2007 ; 176 (1) : 72-75.
PMID 17574968
 

Citation

This paper should be referenced as such :
Correia C, Teixeira MR
t(2;11)(q37;q23) KMT2A/SEPT2;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0211q37q23ANLLID1457.html


Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes SEPT2

Translocations implicated (Data extracted from papers in the Atlas)

 t(2;11)(q37;q23) KMT2A/SEPT2

External links

KMT2A (11q23.3) SEPT2 (2q37.3)

KMT2A (11q23.3) SEPT2 (2q37.3)

Mitelman databaset(2;11)(q37;q23) [Case List]    t(2;11)(q37;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]
arrayMapTopo ( C42) Morph ( 9920/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionKMT2A/SEPT2 KMT2A (11q23.3) SEPT2 (2q37.3)   [fusion1972]   [fusion1973]   [fusion1974]   [fusion1975]  
TICdbKMT2A/SEPT2  KMT2A (11q23.3) SEPT2 (2q37.3)
 
Disease databaset(2;11)(q37;q23) KMT2A/SEPT2
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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