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Identification of a novel RAS GTPase‐activating protein ( RASGAP ) gene at 9q34 as an MLL fusion partner in a patient with de novo acute myeloid leukemia

Identification of a novel RAS GTPase‐activating protein ( RASGAP ) gene at 9q34 as an MLL fusion... The t(9;11) has been described in patients with acute myeloid leukemia (AML), and two genes (AF9 (at 9p21) and FBP17 (at 9q34)) have been cloned as fusion partners of the MLL gene. From an AML‐M5 with a t(9;11)(q34;q23), we identified a novel MLL fusion partner, AF9Q34. The AF9Q34 protein shows high homology with nGAP, a RAS GTPase‐activating protein (RASGAP), and contains the highly conserved GRD and FLR motifs characteristic of RASGAPs. Recently, the rat homologue (DAB2IP) also was identified and reported to act as a RASGAP both in vivo and in vitro. RASGAPs negatively regulate the activity of RAS proteins that modulate diverse cellular processes by cycling between an inactive GDP‐bound and an active GTP‐bound state. In addition, the NH2 terminus harbors an amino acid stretch with homology to the pleckstrin homology (PH) domain implicated in regulating the interaction between RAS and the catalytic domain of RASGAP. As a result of the breakpoint in the AF9Q34–MLL fusion protein, this PH domain is disrupted. This suggests that because of the translocation, the normal function of the AF9Q34 gene is aborted. Thus, AF9Q34 encodes a novel RASGAP gene that appears to be deregulated as a result of the translocation. The identification of this RASGAP protein in a novel MLL fusion implies that an indirect RAS‐deregulating mechanism could be involved in leukemic transformation. © 2004 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Genes, Chromosomes and Cancer Wiley

Identification of a novel RAS GTPase‐activating protein ( RASGAP ) gene at 9q34 as an MLL fusion partner in a patient with de novo acute myeloid leukemia

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References (41)

Publisher
Wiley
Copyright
Copyright © 2004 Wiley‐Liss, Inc., A Wiley Company
ISSN
1045-2257
eISSN
1098-2264
DOI
10.1002/gcc.20004
pmid
14978793
Publisher site
See Article on Publisher Site

Abstract

The t(9;11) has been described in patients with acute myeloid leukemia (AML), and two genes (AF9 (at 9p21) and FBP17 (at 9q34)) have been cloned as fusion partners of the MLL gene. From an AML‐M5 with a t(9;11)(q34;q23), we identified a novel MLL fusion partner, AF9Q34. The AF9Q34 protein shows high homology with nGAP, a RAS GTPase‐activating protein (RASGAP), and contains the highly conserved GRD and FLR motifs characteristic of RASGAPs. Recently, the rat homologue (DAB2IP) also was identified and reported to act as a RASGAP both in vivo and in vitro. RASGAPs negatively regulate the activity of RAS proteins that modulate diverse cellular processes by cycling between an inactive GDP‐bound and an active GTP‐bound state. In addition, the NH2 terminus harbors an amino acid stretch with homology to the pleckstrin homology (PH) domain implicated in regulating the interaction between RAS and the catalytic domain of RASGAP. As a result of the breakpoint in the AF9Q34–MLL fusion protein, this PH domain is disrupted. This suggests that because of the translocation, the normal function of the AF9Q34 gene is aborted. Thus, AF9Q34 encodes a novel RASGAP gene that appears to be deregulated as a result of the translocation. The identification of this RASGAP protein in a novel MLL fusion implies that an indirect RAS‐deregulating mechanism could be involved in leukemic transformation. © 2004 Wiley‐Liss, Inc.

Journal

Genes, Chromosomes and Cancer – Wiley

Published: Apr 1, 2004

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