del(11)(q23q23) KMT2A/ARHGEF12

2011-09-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology

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.

Genes Involved and Proteins

Gene name
KMT2A (myeloid/lymphoid or mixed lineage leukemia)
Location
11q23.3
Protein description
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 (Rho guanine nucleotide exchange factor (GEF) 12)
Location
11q23.3
Protein description
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

Description

5 MLL - 3 ARHGEF12
Atlas Image

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.

Bibliography

Pubmed IDLast YearTitleAuthors
106814372000Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia.Kourlas PJ et al
163410462006Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement.Shih LY et al

Summary

Fusion gene

KMT2A/ARHGEF12 KMT2A (11q23.3) ARHGEF12 (11q23.3) COF 1846 1847|KMT2A/ARHGEF12 KMT2A (11q23.3) ARHGEF12 (11q23.3) TIC

Citation

Jean-Loup Huret

del(11)(q23q23) KMT2A/ARHGEF12

Atlas Genet Cytogenet Oncol Haematol. 2011-09-01

Online version: http://atlasgeneticsoncology.org/haematological/1420/del(11)(q23q23)

External Links