The Tyrosine Kinase Abl-Related Gene ARG Is Fused toETV6 in an AML-M4Eo Patient With a t(1;12)(q25;p13): Molecular Cloning of Both Reciprocal Transcripts

Abstract

The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients with 12p13 translocations fused to a number of different partners. We present here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at 12p13. By 3′rapid amplification of cDNA ends-polymerase chain reaction (3′RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARGinvolvement in a human malignancy.

Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array

“…ARG, a member of the abl family of tyrosine kinases, regulates cellular morphology and motility through interactions with the actin cytoskeleton 28,29 . ARG has been shown to be involved in the development of human leukemia (AML‐M3 and M4eo) 30,31 . In our study, all but one case of primary melanoma was positive for ARG and 8 (26%) of 31 metastatic melanomas were negative for ARG.…”

Cross-platform analysis of cancer microarray data improves gene expression based classification of phenotypes

“…Similarly, the intersection between the Bullinger and Valk data sets was not large ( Additional File 3 ). In contrast, the list obtained from the combined data set contained many genes well known to be involved in leukemia pathogenesis, like PBX3 [ 35 ], the retinoid receptor X [ 36 ], the ABL2 tyrosine kinase [ 37 ] or early growth response 2 [ 38 ]. In addition, many genes in the combined list are prominent oncogenes or tumour suppressors, like BCL2 [ 39 ] or ERBB3 [ 40 ].…”

Structure of the ABL2/ARG kinase in complex with dasatinib

“…ARG knockout mice exhibit defects in neuronal dendrite stability (Gourley et al, 2012;Moresco et al, 2005;Sfakianos et al, 2007), and ABL and ARG double-knockout mice are embryonically lethal, exhibiting defects in neural tube and heart development (Koleske et al, 1998). ABL and ARG activation is associated with cancers of organs such as breast and lung, and importantly is dysregulated in chronic myeloid leukemia (CML) and other leukemias (Ben-Neriah et al, 1986;Cazzaniga et al, 1999;Ganguly et al, 2012;Iijima et al, 2000;Mader et al, 2011;Rikova et al, 2007;Srinivasan & Plattner, 2006).…”