Abstract
BackgroundThe clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely recognized for dividing patients into groups that are related to their prognoses. However, the regulatory programs associated with the IGVH statuses are poorly understood, and markers that can precisely predict survival outcomes have yet to be identified.MethodsIn this study, (i) we reconstructed gene regulatory networks in CLL by applying an information-theoretic approach to the expression profiles of 5 cohorts. (ii) We applied master regulator analysis (MRA) to these networks to identify transcription factors (TFs) that regulate an IGVH mutational status signature. The IGVH mutational status signature was developed by searching for differentially expressed genes between the IGVH mutational statuses in numerous CLL cohorts. (iii) To evaluate the biological implication of the inferred regulators, prognostic values were determined using time to treatment (TTT) and overall survival (OS) in two different cohorts.ResultsA robust IGVH expression signature was obtained, and various TFs emerged as regulators of the signature in most of the reconstructed networks. The TF targets expression profiles exhibited significant differences with respect to survival, which allowed the definition of a reduced profile with a high value for OS. TCF7 and its targets stood out for their roles in progression.ConclusionTFs and their targets, which were obtained merely from inferred regulatory associations, have prognostic implications and reflect a regulatory context for prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2189-6) contains supplementary material, which is available to authorized users.
Highlights
The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage
The immunoglobulin heavy chain variable (IGVH) mutational status expression profile Using a combination of CLL expression profiles, we used a microarray meta-analysis approach to obtain an IGVH mutational status signature
GSE26525 and GSE36907 were determined to be of lower quality after six quantitative quality control (QC) measures were taken into consideration; they were removed from the meta-analysis
Summary
The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. Two major molecular subtypes are recognized, which are characterized by a high or low number of somatic hypermutations in the variable region of the immunoglobulin genes This feature is known as the immunoglobulin heavy chain variable (IGVH) gene mutational status and is related to prognostic evolution, in which patients with an unmutated IGVH status have a less favorable prognosis than patients with a mutated. Due to the importance of the IGVH status in disease course determination, several expression studies have focused on comparisons of the mutated IGVH vs unmutated IGVH CLL forms [7,8,9] These studies have identified genes that are not functionally related and cannot elucidate biological mechanisms to distinguish between risk classes. Searching for the relevant prognostic biomarker surrogates for IGVH mutational status remains a necessity
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