Disease relevance of ABL2

• STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity [1].
• The human ABL2 (or ARG) gene codes for a nonreceptor tyrosine kinase is involved in translocation with the ETV6 gene in human leukemia and has an altered expression in several human carcinomas [2].
• The TEL/ARG oncogene associated with acute myeloid leukemia is formed by the t(1;12)(q25;p13) reciprocal translocation, which fuses part of the TEL gene to the tyrosine kinase, c-ARG [3].
• Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM [4].
• Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs) [5].

Psychiatry related information on ABL2

• ARG demonstrated a wide range of values (3-69 mm Hg), reflective of the severity of the erectile dysfunction on each patient [6].

High impact information on ABL2

• Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors alpha and beta, and potentially other tyrosine kinases [7].
• The SH2 domain of the ARG protein tyrosine kinase, which shares high amino acid-sequence homology with the SH2 domain of ABL, was less effective in activating the oncogenic potential of c-ABL [8].
• Apart from inhibition of the Abl protein tyrosine kinases, it also shows activity against platelet-derived growth factor receptor (PDGF-R), c-Kit, Abl-related gene (ARG), and their fusion proteins while sparing other kinases [9].
• The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts [10].
• Binding of tyrosine-phosphorylated c-ABL 1b by the relatively high-affinity ABL and ARG SH2 domains was quantitatively analyzed, and equilibrium dissociation constants for both interactions were estimated to be in the range of 5 x 10(-7) M [11].

Chemical compound and disease context of ABL2

• The aim of this randomised controlled trial was to investigate the efficacy of a mixture of beta-hydroxy-beta-methylbutyrate, glutamine and arginine (HMB/GLN/ARG) as nutritional treatment for rheumatoid cachexia [12].
• METHODS: Validation studies included normal volunteers administered with escalating doses of argatroban (ARG 102 Study), patients undergoing coronary interventional procedures (ARG 310), and patients receiving argatroban in conjuction with streptokinase for acute myocardial infarction (ARG 230) [13].

Biological context of ABL2

• Identification of an ETV6-ABL2 fusion transcript in combination with an ETV6 point mutation in a T-cell acute lymphoblastic leukaemia cell line [14].
• The anti-apoptotic factors such as Akt-1 were up-regulated, whereas the promotive genes of apoptosis such as ABL2 were down-regulated [15].
• STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC(50) of 200 nM [1].
• In this study, we investigated the growth-inhibitory effect of STI571 (signal transduction inhibitor number 571) on ETV6/ARG-expressing cells and its molecular mechanisms using HT93A, a cell line derived from a patient with AML-M3 carrying t(1;12) [1].
• Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c [1].

Anatomical context of ABL2

• Both cell lines ABL1 and ABL2 were CD3+, TCR alpha beta +, and CD4+ [16].
• Two T cell lines (ABL1 and ABL2) isolated from an LDA, demonstrated this form of specificity, mediating destruction specifically against the allogeneic acute lymphoblastic leukemic cells [16].
• Identical ETV6-ABL2 fusion transcripts have been reported in an acute myeloid leukaemia (AML) M3 cell line, carrying both a t(15;17)(q22;q21) and a t(1;12)(q25;p13) with unusual inducible differentiation to eosinophils, and in a patient with AML-M4eo [14].
• Here we address this question by analysing the oncogenic activity of ETV6/ARG in hematopoietic and fibroblast cells [17].
• When expressed in CHO cells, wild-type TEL/ARG induced the formation of fillopodia, in a fashion dependent on the C-terminal portion and intact kinase activity [18].

Associations of ABL2 with chemical compounds

• Activated RAS participates in a stable RAS-RIN1-ABL2 complex and stimulates the tyrosine kinase-activation function of RIN1 [19].
• Treatment of these cells with doxycycline, a tetracycline analogue, rapidly induced expression of the TEL/ARG protein [3].
• The Deltaarg knockouts expressed no ARG activity, lacked an intracellular ornithine pool, and were auxotrophic for ornithine or polyamines [20].
• Furthermore, the culturing of activated keratinocytes in the presence of an ARG inhibitor results in a twofold increase in nitrite accumulation providing evidence for an L-arginine substrate competition in human keratinocytes [21].
• ARG increased (P < 0.05) both insulin and glucose levels [22].

Regulatory relationships of ABL2

• TEL/ ARG cells also displayed an enhanced proliferative response to IL-3 and to insulin-like growth factor 1 [3].
• The TEL/ARG leukemia oncogene promotes viability and hyperresponsiveness to hematopoietic growth factors [3].

Other interactions of ABL2

• RIN1 binds to the ABL SH3 and SH2 domains, and these interactions stimulate ABL2 catalytic activity [19].
• Deletion of the RAS binding domain (RBD) strongly stimulated the ABL2 activation function of RIN1, suggesting that RAS activation results from the relief of RIN1 autoinhibition [19].
• A number of genes were down-regulated, which included LAR, ABL2, SKY, TDGF1 etc [23].
• One patient had a durable clinical response, and the follow-up biopsy showed negative expression for four of the PTKs, namely c-abl, ARG, PDGFR-alpha, and beta [24].
• The Ba/F3-tet-TEL/ARG cells remained interleukin (IL)-3 dependent without doxycycline but with doxycycline displayed a marked reduction in cell death in the absence of IL-3 [3].

Analytical, diagnostic and therapeutic context of ABL2

• Arterial samples for blood-gas analysis with a Radiometer ABL2 system were taken during periods in which plasma-pH was stable [25].
• 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 [10].
• METHODS: Tissue microarray blocks of 89 melanocytic lesions were evaluated by immunohistochemistry for the expression of selected PTKs: c-kit, c-abl, abl-related gene (ARG), platelet-derived growth factor receptors alpha (PDGFR-alpha) and beta (PDGFR-beta) [26].
• On the other hand, ghrelin raises basal glucose levels and enhances the hyperglycemic effect of ARG but not that of OGTT [22].
• These results demonstrate that targeting both bcr3/abl2 and VEGF can result in an additive tumor-suppressive action and may represent an excellent strategy to augment the efficacy of chemotherapy in CML [27].

References