t(2;11)(q37;q23) in AML

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t(2;11)(q37;q23) in AML

Identity

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 non lymphocytic leukemia (ANLL) and therapy-related ANLL.

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 MLL

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.

External links

Other database t(2;11)(q37;q23) in AML Mitelman database (CGAP - NCBI)

Other database t(2;11)(q37;q23) in AML CancerChromosomes (NCBI)

Other database	t(2;11)(q37;q23) in AML	Mitelman database (CGAP - NCBI)
Other database	t(2;11)(q37;q23) in AML	CancerChromosomes (NCBI)

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

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

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

Molecular cytogenetic delineation of deletions and translocations involving chromosome band 7q22 in myeloid leukemias.

Fischer K, Frˆhling S, Scherer SW, McAllister Brown J, Scholl C, Stilgenbauer S, Tsui LC, Lichter P, Dˆhner H

Blood. 1997 ; 89 (6) : 2036-2041.

PMID 9058725

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

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

Contributor(s)

Written 09-2007 Cecília Correia, Manuel R Teixeira

Department of Genetics, Portuguese Oncology Institute, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal.

Citation

This paper should be referenced as such :
Correia C, Teixeira MR . t(2;11)(q37;q23) in AML. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/t0211q37q23ANLLID1457.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Dec 6 18:02:17 2008

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Disease	Rare type of acute non lymphocytic leukemia (ANLL) and therapy-related ANLL.
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.

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	MLL
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.



Description	MLLSEPT2. MLL exon 6 or 7 fused with SEPT2 exon 3.



	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.

Written	09-2007	Cecília Correia, Manuel R Teixeira
		Department of Genetics, Portuguese Oncology Institute, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal.