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.
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 NH(2) 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.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Anne R M
AR
von Bergh
Pauline M
PM
Wijers
Arjan J
AJ
Groot
Shama
S
van Zelderen-Bhola
J H Frederik
JH
Falkenburg
Philip M
PM
Kluin
Ed
E
Schuuring
D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D019457:Chromosome Breakage / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D050556:Fatty Acid-Binding Proteins; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018922:HL-60 Cells / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D019169:Jurkat Cells / Q000737:chemistry / Q000378:metabolism; D020014:K562 Cells / Q000737:chemistry / Q000378:metabolism; D007948:Leukemia, Monocytic, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D011519:Proto-Oncogenes; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics; D020298:U937 Cells / Q000737:chemistry / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
D002352:Carrier Proteins; C462952:DAB2IP protein, human; D004268:DNA-Binding Proteins; C433770:FNBP1 protein, human; D050556:Fatty Acid-Binding Proteins; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D020703:ras GTPase-Activating Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase