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del(11)(q23q23) KMT2A/ARHGEF12

Written2011-09Jean-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 1420

Clinics and Pathology

Disease Acute myeloid leukemia (AML)
Epidemiology Two cases so far: a 38-year-old male patient with a history of occupational exposure to herbicides and a M4-AML, and a 77-year-old female patient with a M5a-AML (Kourlas et al., 2000; Shih el al., 2006).
Evolution The M4-AML patient underwent complete remission, but died 6 months later from an unrelated cause.

Cytogenetics

Cytogenetics Morphological The del(11)(q23q23) has been missed by cytogenetic analysis; both cases were hyperploid with +8 and other abnormalities.

Genes involved and Proteins

Gene Name KMT2A
Location 11q23.3
Protein A major transcript of 14982 bp produces a 3969 amino acids protein from 36 of the 37 exons. Contains from N-term to C-term a binding site for MEN1, 3 AT hooks (binds 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; methylates 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. General transcription factor; maintains HOX genes expression in undifferentiated cells. Major regulator of hematopoiesis and embryonic development; role in cell cycle regulation.
Gene Name ARHGEF12
Location 11q23.3
Protein Better known as LARG, ARHGEF12 contains a PDZ (postsynaptic density protein, Drosophila disc large tumor suppressor, and zonula occludens-1 protein) domain, which localize ARHGEF12 to the membrane, a regulator of G protein signalling-like domain (RGSL or RH), which binds to activated heterotrimeric G protein alpha12/13 subunits, a Dbl homology (DH) domain, responsible for exchange activity, and a pleckstrin homology (PH) domain, involved in the regulation of the process. Regulatory protein involved in the GDP/GTP exchange reaction of the Rho proteins; activates a Rho-GTPase-dependent signaling pathway; activated by FYN.

Result of the chromosomal anomaly

Hybrid gene
Description 5' MLL - 3' ARHGEF12
  
Fusion Protein
 
Description Joins amino acid 1362 from MLL to amino acid 309 from ARHGEF12. The fusion protein comprises the Ala/Gly/Ser-rich region, poly-Gly stretch, three AT hooks domains, poly-Pro stretches, and Zinc finger CXXC-type domain from MLL fused to the RGSL, DH, PH domains of ARHGEF12.
  

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

Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia.
Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, Krahe R, Ruutu T, Knuutila S, Bloomfield CD, Caligiuri MA.
Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2145-50.
PMID 10681437
 
Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement.
Shih LY, Liang DC, Fu JF, Wu JH, Wang PN, Lin TL, Dunn P, Kuo MC, Tang TC, Lin TH, Lai CL.
Leukemia. 2006 Feb;20(2):218-23.
PMID 16341046
 

Citation

This paper should be referenced as such :
Huret, JL
t(14;20)(q11;q13)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(6):437-438.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/del11q23q23ID1420.html


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

Genes KMT2A

Translocations implicated (Data extracted from papers in the Atlas)

 del(11)(q23q23) KMT2A/ARHGEF12

External links

KMT2A (11q23.3) ARHGEF12 (11q23.3)

KMT2A (11q23.3) ARHGEF12 (11q23.3)

Mitelman databasedel(11)(q23q23) [Case List]    del(11)(q23q23) [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/ARHGEF12 KMT2A (11q23.3) ARHGEF12 (11q23.3)   [fusion1846]   [fusion1847]  
TICdbKMT2A/ARHGEF12  KMT2A (11q23.3) ARHGEF12 (11q23.3)
 
Disease databasedel(11)(q23q23) KMT2A/ARHGEF12
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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indexed on : Tue Mar 14 13:53:39 CET 2017


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