Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: Evidence for its fusion with MLL in acute myeloid leukemia

Abstract

We have identified a gene at 11q23, telomeric to MLL, that encodes a guanine nucleotide exchange factor (GEF). This gene is transcribed into a 9.5-kb mRNA containing a 4.6-kb ORF. By Northern analysis, it was found to be expressed in all human tissues examined including peripheral blood leukocytes, spleen, prostate, testis, ovary, small intestine, colon, and minimally in thymus. Analysis of the predicted protein sequence indicates that it has strong homology to several members of the family of Rho GEFs that includes such oncogenes as Dbl, Vav, Tiam, and Bcr. A patient with primary acute myeloid leukemia (AML) and a karyotype of 51,XY,؉8,؉19,؉3mar was found to have the 5 end of MLL at exon 6 fused in-frame with the 3 end of almost the entire ORF of this gene, which we named LARG for leukemia-associated Rho GEF. Transcriptional orientation of both genes at 11q23 is from centromere to telomere, consistent with other data that suggest the MLL-LARG fusion resulted from an interstitial deletion rather than a balanced translocation. LARG does not appear to have any homology with other MLL partner genes reported thus far. Thus, LARG represents an additional member of the GEF family and a novel MLL fusion partner in acute myeloid leukemia.LARG ͉ Dbl protein ͉ gene rearrangements

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

“…RhoA activation and PLCε-Ca 2+ signaling-Another RhoAspecific GEF, the LARG molecule containing several functional domains (e.g., an aminoterminal PDZ domain, RGS domain, a DH domain and a PH domain) has been identified recently [78]. In particular, the DH domain of LARG by itself exhibits GDP/GTP exchange activity on RhoA, and plays an important role in RhoGTPase signaling [79].…”

“…Thus, LARG appears to be selectively involved in certain signaling pathways initiated by G-protein coupled receptors (GPCRs) that are linked to different Gα subunits. Furthermore, overexpression of LARG in acute myeloid leukemia (AML) has been shown to exhibit growth-promoting activity [78]. A number of studies show that LARG and its transforming potential can be activated by focal adhesion kinase (FAK) phosphorylation [80] and/or hetero-oligomerization through LARG's inhibitory C-terminal region [81].…”

Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract

“…RhoA regulates smooth muscle contraction by cycling between a GDP-bound inactive form (coupled to a guanine dissociation inhibitor, RhoGDI) and a GTP-bound active form [16][17][18]. Upstream activation of heterotrimeric G proteins lead to the exchange of GDP for GTP, an event carried out by the guanine exchange factors (GEFs) p115RhoGEF [19], PDZ-RhoGEF [20] and LARG (Leukemia-associated RhoGEF) [21], which are able to transduce signals from G protein-coupled receptors to RhoA [22][23][24]. Rhokinase is activated by RhoA and inhibits myosin phosphatase through the phosphorylation of its myosin binding subunit, leading to an increase in Ca 2+ sensitivity.…”

Rho/Rhotekin-mediated NF-κB activation confers resistance to apoptosis

“…Members of the diffuse B cell lymphoma-derived (Dbl) family of Rho GEFs have transforming activity. Naturally occurring mutations resulting in constitutive activation of Rho GEFs have been described in Dbl, LARG, and Tiam (Srivastava et al, 1986;Engers et al, 2000;Kourlas et al, 2000). Overexpression or activation of Rho GTPase downstream effector proteins ROCK and protein kinase C-related kinase (PRK1) have recently been described in several human cancers (Kaneko et al, 2002;Ikeda et al, 2003;Kamai et al, 2003;Metzger et al, 2003;Zhou et al, 2003).…”