Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (-308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (-174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/µL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)_IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.

SOX11 expression in chronic lymphocytic leukemia correlates with adverse prognostic markers.

The transcription factor SOX11 plays an important role in embryonic neurogenesis and tissue remodeling. Recent studies have shown aberrant expression of SOX11 in various types of aggressive B cell neoplasms. In this study, we have analyzed SOX11 transcription levels in 86 patients with diagnosis of chronic lymphocytic leukemia (CLL). Results were correlated with well-known prognostic factors such as immunoglobulin heavy chain variable (IGHV) gene mutational status, cytogenetics risk groups and clinicopathological characteristics of the disease. Overall, 35 % of cases showed SOX11 expression; meanwhile, the remaining 65 % lacked gene expression. The analysis taking into account the IGHV mutational status showed significant differences in SOX11 transcripts levels between mutated (0.004 ± 0.0001) and unmutated CLL patients (0.405 ± 0.011) (p < 0.0001), as well as a positive correlation between SOX11 mRNA expression and the percentage of IGHV homology (p = 0.0001). Furthermore, significantly lower SOX11 mRNA expression was detected in patients with deletion 13q14 as a single alteration (0.016 ± 0.008) than those observed in cases with deletions 11q/17p (0.35 ± 0.017) (p = 0.02). The correlation of gene expression with clinical evolution showed shorter treatment free survival (p = 0.043) and overall survival (p = 0.047) in SOX11 positive patients compared to SOX11 negative cases. Our findings show for the first time an association between SOX11 expression and some CLL poor prognostic factors. These results suggest SOX11 as a possible biomarker that adds new biological information that could contribute to a better understanding of this pathology.