High Chromosome Number in hematological cancer cell lines is a Negative Predictor of Response to the inhibition of Aurora B and C by GSK1070916

<p>Abstract</p> <p>Background</p> <p>Aurora kinases play critical roles in mitosis and are being evaluated as therapeutic targets in cancer. GSK1070916 is a potent, selective, ATP competitive inhibitor of Aurora kinase B and C. Translation of predictive biomarkers to the clinic can benefit patients by identifying the tumors that are more likely to respond to therapies, especially novel inhibitors such as GSK1070916.</p> <p>Methods</p> <p>59 Hematological cancer-derived cell lines were used as models for response where <it>in vitro </it>sensitivity to GSK1070916 was based on both time and degree of cell death. The response data was analyzed along with karyotype, transcriptomics and somatic mutation profiles to determine predictors of response.</p> <p>Results</p> <p>20 cell lines were sensitive and 39 were resistant to treatment with GSK1070916. High chromosome number was more prevalent in resistant cell lines (p-value = 0.0098, Fisher Exact Test). Greater resistance was also found in cell lines harboring polyploid subpopulations (p-value = 0.00014, Unpaired t-test). A review of NOTCH1 mutations in T-ALL cell lines showed an association between NOTCH1 mutation status and chromosome number (p-value = 0.0066, Fisher Exact Test).</p> <p>Conclusions</p> <p>High chromosome number associated with resistance to the inhibition of Aurora B and C suggests cells with a mechanism to bypass the high ploidy checkpoint are resistant to GSK1070916. High chromosome number, a hallmark trait of many late stage hematological malignancies, varies in prevalence among hematological malignancy subtypes. The high frequency and relative ease of measurement make high chromosome number a viable negative predictive marker for GSK1070916.</p

Rearrangement of 11q23 Chromosome Region in Acute Myeloid Leukemias in Children

Aim. To study characteristics of 11q23 involvement, age-specific differences in the incidence of these chromosomal markers in acute myeloid leukemias (AML) in children, and to determine their prognostic significance in patients treated according to the protocols applied in leading Russian pediatric hematological clinics. Methods. The chromosomal analysis of bone marrow and peripheral blood cells has been performed prior to initiation of treatment in 395 children with primary AML aged from 0 to 16 years. The patients were treated in pediatric hematological clinics of Moscow and Moscow Region and in Yekaterinburg District Children’s Hospital No. 1. Clinical outcomes of 300 followed-up pediatric patients treated with similar modern therapy protocols were analyzed to evaluate the prognostic impact of 11q23/MLL abnormalities. To determine the incidence of 11q23/MLL rearrangements in AML of different age groups, we examined not only children, but also adult patients (n = 212). Results. In AML, the frequency of changes in the 11q23 region exceeded 40 % in children aged from 0 to 2 years. The frequency decrease with age and in patients over 40 years it was only 2 %. Significant heterogeneity of changes in karyotypes with 11q23/MLL rearrangements was observed: both various translocations with different regions of other chromosomes, and 11q23 deletions were detected. In addition, a great variability of numerical and structural additional chromosomal abnormalities was observed. The 10-year relapse-free survival rates (30.4 ± 6.7 %) and overall survival rates (35.1 ± 7.0 %) in AML with changes in the 11q23 region (n = 61) were significantly lower than those in patients from the intermediate risk group (n = 103): 48.9 ± 5.8 % and 43.8 ± 7.5 %, respectively (p = 0.035). The data are close to those in the high-risk group (n = 44): 35.9 ± 8.1 % and 38.3 ± 7.6 %, respectively. The study failed to confirm the published data that t(9;11) is a more favorable prognostic factor, and that t(6;11) and t(10;11) are less favorable ones than all other 11q23 translocations. Our results did not confirm a negative prognostic effect of additional chromosome abnormalities associated with 11q23 rearrangements. Conclusion. Pediatric AML patients with 11q23 abnormalities should be included in a high-risk group if therapy is performed according protocols applied in leading hematological centers of Russia