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t(11;19)(q23;p13) KMT2A/SH3GL1

Written2014-11Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

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 1194
Note At least three other translocation t(11;19) involve KMT2A: the t(11;19)(q23;p13.1) KMT2A/ELL, the t(11;19)(q23;p13.3) KMT2A/MLLT1, and the t(11;19)(q23;p13.3) KMT2A/ACER1.

Clinics and Pathology

Epidemiology Only one case to date, a 22-month-old girl with a diagnosis of acute myeloid leukemia not otherwise specified (So et al., 1997).

Genes involved and Proteins

Gene Name KMT2A
Location 11q23
Protein KMT2A is better known as MLL. MLL is a transcriptional regulatory factor. MLL regulates chromatin-mediated transcription. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression. Translocations involving MLL are associated with high-risk de novo or treatment-related acute myeloid leukemias and myelodysplastic syndromes and acute lymphoblastic leukemias (review in Huret, 2006). Mutations in MLL cause Wiedemann-Steiner syndrome (Jones et al., 2012).
Gene Name SH3GL1
Location 19p13.3
Note The gene has previously been named EEN.
Protein The protein, named endophilin-A2, is made of 368 amino acids (aa) in isoform 1. From N-term to C-term, it contains a Bin/Amphiphysin/Rvs (BAR) domain (aa 18-249), involved in curvature of the cell membrane, a coiled-coil domain (protein-protein interactions, aa 119-227), and a SH3 domain (protein-protein interactions, aa 306-365). Endophilin-A2 is involved in clathrin-mediated endocytosis. Endophilin-A2 facilitates G1/S cell cycle transition of multiple myeloma cells (Huang et al., 2014).

Result of the chromosomal anomaly

Hybrid gene
Description 5' KMT2A - 3' SH3GL1. KMT2A exon 6 was fused to SH3GL1 exon 2.
  
Fusion Protein
Description 1564 amino acids (1212 from KMT2A, and 352 from SH3GL1). The fusion protein retains the AT hooks (DNA binding) and the Zinc finger CXXC-type from KMT2A fused to most of SH3GL1, including the BAR domain and the SH3 domain.
Oncogenesis KMT2A/SH3GL1 is localized in the nucleus, while SH3GL1 is located in the cytoplasm. KMT2A/SH3GL1 may drive to aberrant transcriptional regulation. KMT2A/SH3GL1 increases HOXA7 promoter activity (Liu et al., 2004).
  

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

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion.
Huang EW, Xue SJ, Li XY, Xu SW, Cheng JD, Zheng JX, Shi H, Lv GL, Li ZG, Li Y, Liu CH, Chen XH, Liu H, Li J, Liu C.
Biochem Biophys Res Commun. 2014 May 2;447(2):271-7.
PMID 24704450
 
MLL (myeloid/lymphoid or mixed lineage leukemia).
Huret JL.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):83-87. http://atlasgeneticsoncology.org/Genes/MLLID13.html.
 
De novo mutations in MLL cause Wiedemann-Steiner syndrome.
Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA.
Am J Hum Genet. 2012 Aug 10;91(2):358-64.
PMID 22795537
 
Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein.
Liu H, Chen B, Xiong H, Huang QH, Zhang QH, Wang ZG, Li BL, Chen Z, Chen SJ.
Oncogene. 2004 Apr 22;23(19):3385-94.
PMID 15077184
 
EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia.
So CW, Caldas C, Liu MM, Chen SJ, Huang QH, Gu LJ, Sham MH, Wiedemann LM, Chan LC.
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2563-8.
PMID 9122235
 

Citation

This paper should be referenced as such :
Huret JL
t(11;19)(q23;p13) KMT2A/SH3GL1;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t1119q23p13ID1194.html


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

Genes KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 t(11;19)(q23;p13) KMT2A/SH3GL1

External links

KMT2A (11q23.3) SH3GL1 (19p13.3)

KMT2A (11q23.3) SH3GL1 (19p13.3)

Mitelman databaset(11;19)(q23;p13) [Case List]    t(11;19)(q23;p13) [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/SH3GL1 KMT2A (11q23.3) SH3GL1 (19p13.3)   [fusion1914]   [fusion1915]  
TICdbKMT2A/SH3GL1  KMT2A (11q23.3) SH3GL1 (19p13.3)
 
Disease databaset(11;19)(q23;p13) KMT2A/SH3GL1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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