Disease relevance of RARS

• Moreover, we have previously reported that G-CSF inhibits Fas-induced caspase activation in sideroblastic anemia (RARS) [1].
• MDS patients examined were put into two groups; refractory anemia (RA) or RA with ringed sideroblasts (RA/RARS) and RA with excess of blasts (RAEB) or RAEB in transformation (RAEB/RAEB-t) [2].
• Patients with RARS and thrombocytosis who normalized their platelet counts showed a concomitant reduction in S-TPO [3].
• Myelodysplastic syndrome (RARS) with +i(12p) abnormality in a patient 10 months after diagnosis and successful treatment of a mediastinal germ cell tumor (MGCT) [4].
• In myelodysplasia, c-mpl expression was elevated in 44% of chronic myelomonocytic leukemia (CMML), 42% of refractory anemia with excess myeloblasts (RAEB), and RAEB in transformation to acute leukemia (RAEBt), but not in refractory anemia (RA) and RA with ringed sideroblasts (RARS) [5].

High impact information on RARS

• The arginyl-tRNA synthetase of the bruchid beetle larvae discriminates between L-arginine and L-canavanine, and canavanyl proteins are not synthesized [6].
• Evidence for this hypothesis is based on data suggesting that enzymes for biosynthesis of arginine and tryptophan, and for arginine tRNA ligase, have shorter divergence times than the underlying lineages [7].
• Patients with RA and RARS with a higher percentage of Bmi-1+ cells showed disease progression to RAEB [8].
• Higher positivity rate of Bmi-1 was preferentially seen in refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and MDS-AML compared with refractory anemia (RA) and RA with ringed sideroblasts (RARS) [8].
• The proportion of RARS erythroblasts that were MtF+ increased further upon in vitro maturation [9].

Chemical compound and disease context of RARS

• In the present study, we analyzed the expression of platelet glycoprotein (GP) Ia/IIa, IIb/IIIa, Ib/IX, and IV in 21 MDS patients (12 RA, 2 RARS, 4 RAEB, 1 RAEB-T, 2 CMML) and healthy controls by flowcytometric analysis and quantitation of platelet GP RNA using fluorescence-based PCR [10].
• We report on a 21-year-old man with a mediastinal germ cell tumor (MGCT) who developed a myelodysplastic syndrome (MDS) (refractory anemia with ringed sideroblasts, RARS) 10 months after the start of successful treatment with cisplatin, etoposide, ifosfamide, and paclitaxel [4].
• We examined the efficacy of thalidomide in 34 patients with myelodysplastic syndromes (MDS): five RAEB-T, four RAEB, three CMML, six RARS, and 16 RA [11].
• ATG, cyclosporine, and methylprednisone induced complete (N=4) or partial (N=1) remission in five patients (16% of total; RA, two patients; RARS, two patients; and RAEB, one patient) [12].
• DESIGN AND METHODS: In a pilot phase II study we treated 26 patients with low risk MDS (13 RA, 2 RARS, 2 CMML, 9 RAEB with blasts < 10%) with amifostine (200 mg/m(2 )x 3/week for 4 weeks) [13].

Biological context of RARS

• Caspase inhibition reduced apoptosis, increased proliferation and enhanced erythroid colony growth from CD34+ cells in RARS, but showed no effect on normal cells [14].
• This may suggest that the increased platelet counts observed in RARS may be caused by increased S-TPO levels [3].
• In vitro erythropoiesis was decreased in most of the patients, with significantly lower number of BFU-E in "advanced" MDS than in RA/RARS patients [15].
• RESULTS: In untreated RARS, the proportion of hypochromic erythrocytes (Hypo-e, median 6.2%, range 1.1-8%) and hypochromic reticulocytes (Hypo-r, median 45%, range 22-48%), as well as mean corpuscular volume (MCV, median 101 fL) were significantly elevated compared to corresponding values in controls [16].
• DNA sequence analysis identified an open reading frame of 1983 nucleotides with 87% homology to other mammalian ArgRS genes [17].

Anatomical context of RARS

• Burst-forming units erythroid (BFU-E, 75 +/- 88/10(4) CD34+ cells, X +/- s.d.) and colony-forming units E (CFU-E) were observed in eight of the 13 cases (62%) with refractory anemia with or without ring sideroblasts (RA and RARS) and one of the five cases with RA with excess of blasts or in transformation (RAEB and RAEB-T) [18].
• FACS and morphology analysis after 7 days of suspension culture demonstrated partial differentiation along the erythroid lineage in cases with RA/RARS (75%) and RAEB/RAEB-T (66%) reflected by the presence of erythroblasts and normoblasts with variable expression of CD34, CD36 and Glycophorin A [18].
• We studied bone marrow from 10 RARS patients, two of whom were also investigated after successful treatment [14].
• Treatment with granulocyte colony-stimulating factor plus erythropoietin may improve haemoglobin levels in patients with ringsideroblastic anaemia (RARS) and reduce bone marrow apoptosis [14].
• Patients with a low risk of developing acute leukaemia were included, i.e. refractory anaemia (RA), RA with ringed sideroblasts (RARS) and RA with excess blasts (RAEB), providing the percentage of myeloblasts in the bone marrow did not exceed 10% [19].

Associations of RARS with chemical compounds

• Like arginyl-tRNA synthetases from other organisms, human placental arginyl-tRNA synthetase catalyzes the arginine-dependent ATP-PPi exchange reaction only in the presence of tRNA [20].
• Thus, serum tryptase concentrations were higher in RA (16.6 +/- 14.3 ng/ml), RARS (12.9 +/- 8.2), and CMML (16.5 +/- 7.6) compared to RAEB/-t (8.7 +/- 3.8) [21].
• Crucial role of the high-loop lysine for the catalytic activity of arginyl-tRNA synthetase [22].
• A single nucleotide change, resulting in a Cys to Tyr substitution at position 599 of arginyl-tRNA synthetase, is responsible for the defective phenotype of the thermosensitive and arginine hyper-auxotroph Arg-1 cell line [23].
• The three regions that are crucial for activation of ArgRS are the terminal adenosine, the D-loop, and the anticodon stem-loop of tRNA [24].

Physical interactions of RARS

• Herein, we have demonstrated that the N-terminal domain of pro-EMAPII interacts with the N-terminal extension of human cytoplasmic arginyl-tRNA synthetase (RRS) using genetic and immunoprecipitation analyses [25].
• The EPRS repeats also showed the binding activity to the N-terminal motif of arginyl-tRNA synthetase as well as to various nucleic acids, including tRNA [26].

Other interactions of RARS

• The C-terminal appended domain of human cytosolic leucyl-tRNA synthetase is indispensable in its interaction with arginyl-tRNA synthetase in the multi-tRNA synthetase complex [27].
• PGP positivity was rare in 'low risk' MDS (RA and RARS: 2/12 cases) as opposed to 'high risk' MDS (RAEB, RAEB-T, CMML: 25/60 cases) and MDS-AML (7/10 cases) (p = 0.04) [28].
• Moreover, their expression inversely correlates with tumor diameter and with RARS expression (P < 0.05), but directly correlates with p43 secretion (P < 0.02) [29].
• Increased levels of platelet GPIb and GPIIb RNA were significantly more prominent among patients with RAEB(-T)/CMML (p<0. 05) in comparison to patients with RA/RARS [10].
• The above data suggest that the combination of rhEpo and GM-CSF should be recommended in all cases with RARS [30].

Analytical, diagnostic and therapeutic context of RARS

• Fas ligation increased apoptosis and decreased colony growth equally in RARS and controls, but caused significantly more caspase activation in RARS (P < 0.01) [14].
• Using ELISA technology we measured endogenous serum levels in 93 patients with MDS: 29 RA, 1 RARS, 31 RAEB, 23 RAEBt, 9 CMML [31].
• Refractory cytopenia with multilineage dysplasia and RAEB II seemed to have different prognoses from RA or RARS and RAEB I, respectively [32].
• TUNEL labeling of bone marrow from 24 patients with MDS revealed significant positivity in 10 of 11 patients with refractory anemia (RA), five of seven with RA and excess of blasts (RAEB), all three patients with RAEB in transformation (RAEB-t), and all three patients with RA with ring sideroblasts (RARS) [33].
• The Chronic Leukemia Working Party of the EBMT has collected data on 118 patients of median age 24 years (range 0.3 to 53 years) who underwent an allogeneic bone marrow transplantation from unrelated donors for treatment of MDS or secondary AML (RA/RARS, n = 24; RAEB, n = 26; RAEB-t, n = 34; CMML, n = 12; sAML, n = 22) between 1986 and 1996 [34].

References