We read with great interest the paper by Yoshida et al. entitled “Marked upregulation of survivin and Aurora-B kinase are associated with disease progression in the myelodysplastic syndromes”.1
Aurora kinases are key players in ensuring accurate chromosome segregation during the cell cycle, maintaining genetic integrity in cell division.2 Over the last few years, much attention has been focused on the involvement of these proteins in the process of tumorigenesis. High Aurora-B and Aurora-A expression has been reported in various types of commonly occurring malignancy and, in some cases, correlated with aneuploidy and poor prognosis. Despite the many reports of high expression of Aurora-B and Aurora-A in solid tumors,3,4 information regarding expression in hematologic malignancies is still limited,5,6,7 especially in MDS.
Our study included 61 MDS patients, 31 male and 30 female (median age 66 years; range 15-91 years). According to WHO classification, there were 6 patients with refractory anemia (RA), 2 patients with refractory neutropenia (RN), 2 patients with isolated del(5q), 9 patients with ring sideroblasts (RARS), 28 patients with refractory cytopenia with multilineage dysplasia (RCMD), 3 patients with RA with excess of blasts 1 (RAEB-1), 5 patients with RA with excess of blasts 2 (RAEB-2), and 6 patients with therapy-related MDS. Four samples from healthy volunteers were used as controls. Among these patients, 85% were stratified as low risk and 15% as high risk according to IPSS.
Total RNA from MDS patients and donor bone marrow cells were isolated using Trizol reagent (Invitrogen, Carlsbad, CA, USA). To analyze aurora kinases genes, TaqMan Assays were used (Aurora-A: Hs00269212_m1 and Aurora-B: Hs00177782_m1; Applied Biosystems). β2-microglobulin (B2M: Hs99999907_m1) and Ubiquitin C (UBC: Hs00824723_m1) were chosen as endogeneous internal control for each sample. The comparative cycle threshold (Ct) method was used to determine the relative expression levels of Aurora-B and Aurora-A genes. Their expression was calculated as a relative quantification to the average value of B2M and UBC housekeeping genes. The Mann-Whitney and Kruskal-Wallis rank sum test was used for quantitative analysis comparing the expression level of aurora kinases in different groups.
Successful cytogenetic analyses (by G-banding) were available for 45 patients (74%). Of these, 27 (60%) were classified as having good IPSS cytogenetic risk, 10 (22.2%) as having intermediate risk, and 8 (17.8%) as poor risk. Among these 45 patients, at least one clonal alteration was observed in 25 cases (55.6%) (Table 1).
Although many studies have reported high expression of Aurora-B and Aurora-A in solid and hematologic cancers, in our study we did not find any association between clinical or laboratory features with prognostic impact (number of cytopenias, cytogenetic abnormalities, transfusion dependency, WHO classification and IPSS group) and the expression of both Aurora-B and Aurora-A kinases.
Recently, Lucena-Araujo et al.5 showed a significant association between high expression of Aurora-A and unfavorable cytogenetics in AML patients, but not with Aurora-B. Furthermore, Ye et al.6 analyzed 20 patients with MDS and did not detect any significant correlation of Aurora-A gene expression with bone marrow blast counts, viability of CD34 blast cells, cytogenetic abnormalities or IPSS score.
Our study included a good representative number of lower risk patients and this may have contributed to the absence of any statistical difference among groups (Table 2). However, no difference was found when only the lower risk groups (RA, RARS, RCMD) were compared, in contrast to that reported by Yoshida et al.1
One possible explanation for these different results could be related to the genetic variation between study populations. Some studies showed that the difference in the incidence of chromosomal abnormalities in MDS patients varies according to the group under study (low vs. high risk), with possible geographical and ethnic influences. 8 According to the Brazilian National MDS Register,9 Magalhaes observed significant differences between other American, European and Asian reports, and even between Brazilian geographical regions; indicating that racial miscegenation might play a role.
Despite the limited information regarding the expression of Aurora-B kinase in hematologic malignancies, our data suggest that Aurora-B expression may not have a prognostic significance in MDS patients, as shown in other tumors. This may reflect the heterogeneous presentation of MDS and the diversity of the mechanisms involved in its pathogenesis.
- Yoshida A, Zokumasu K, Wano Y, Yamauchi T, Imamura S, Takagi K. Marked upregulation of Survivin and Aurora-B kinase are associated with disease progression in the myelodysplastic syndromes. Haematologica. 2012. Google Scholar
- Katayama H, Brinkley WR, Sen S. The aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev. 2003; 22(4):451-64. PubMedhttps://doi.org/10.1023/A:1023789416385Google Scholar
- Lin ZZ, Jeng YM, Hu FC, Pan HW, Tsao HW, Lai PL. Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B overexpression in HCC. BMC Cancer. 2010; 10:461-75. PubMedhttps://doi.org/10.1186/1471-2407-10-461Google Scholar
- Lassman S, Danciu M, Muller M, Weis R, Makowiec F, Schulte-Monting J. Aurora A is differentially expressed and regulated in chromosomal and microsatellite instable sporadic colorectal cancers. Mod Pathol. 2009; 22:1385-97. PubMedhttps://doi.org/10.1038/modpathol.2009.111Google Scholar
- Lucena-Araujo AR, Oliveira FM, Leite-Cueva SD, Santos GA, Falcao RP, Rego EM. High expression of AURKA and AURKB is associated with unfavorable cytogenetic abnormalities and high white blood cell count in patients with acute myeloid leukemia. Leuk Res. 2011; 35(2):260-4. PubMedhttps://doi.org/10.1016/j.leukres.2010.07.034Google Scholar
- Ye D, Garcia-Manero G, Kantarjian HM, Xiao L, Vadhan-Raj S, Fernandez MlH. Analysis of Aurora kinase A expression in CD34+ blast cells isolated from patients with myelodysplastic syndromes and acute myeloid leukemia. J Hematop. 2009; 2(1):2-8. PubMedhttps://doi.org/10.1007/s12308-008-0019-3Google Scholar
- Huang XF, Luo SK, Xu J, Li J, Xu DR, Wang LH. Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia. Blood. 2008; 111(5):2854-65. PubMedhttps://doi.org/10.1182/blood-2007-07-099325Google Scholar
- Matsuda A, Germing U, Jinnai I, Misumi M, Kuendgen A, Knipp S. Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes. Blood. 2005; 106(8):2633-40. PubMedhttps://doi.org/10.1182/blood-2005-01-0040Google Scholar
- Magalhães SMM, Madeira TS, Bittencourt R. Epidemiological and clinicopathological data from the Brazilian registry of patients with myelodysplastic syndromes and comparative analysis between different geographic areas. Blood. 2010; 116Google Scholar