Essential thrombocytosis (ET) is a chronic myeloproliferative disorder with an unregulated surplus of platelets. Complications of ET include stroke, heart attack, and formation of blood clots. Althoug Show more
Essential thrombocytosis (ET) is a chronic myeloproliferative disorder with an unregulated surplus of platelets. Complications of ET include stroke, heart attack, and formation of blood clots. Although platelet-enhancing mutations have been identified in ET cohorts, genetic networks causally implicated in thrombotic risk remain unestablished. In this study, we aim to identify novel ET-related miRNA-mRNA regulatory networks through comparisons of transcriptomes between healthy controls and ET patients. Four network discovery algorithms have been employed, including (a) Pearson correlation network, (b) sparse supervised canonical correlation analysis (sSCCA), (c) sparse partial correlation network analysis (SPACE), and, (d) (sparse) Bayesian network analysis-all through a combined data-driven and knowledge-based analysis. The result predicts a close relationship between an 8-miRNA set (miR-9, miR-490-5p, miR-490-3p, miR-182, miR-34a, miR-196b, miR-34b*, miR-181a-2*) and a 9-mRNA set (CAV2, LAPTM4B, TIMP1, PKIG, WASF1, MMP1, ERVH-4, NME4, HSD17B12). The majority of the identified variables have been linked to hematologic functions by a number of studies. Furthermore, it is observed that the selected mRNAs are highly relevant to ET disease, and provide an initial framework for dissecting both platelet-enhancing and functional consequences of dysregulated platelet production. Show less
Human blood platelets have important, regulatory functions in diverse hemostatic and pathological disorders, including vascular remodeling, inflammation, and wound repair. Microarray analysis was used Show more
Human blood platelets have important, regulatory functions in diverse hemostatic and pathological disorders, including vascular remodeling, inflammation, and wound repair. Microarray analysis was used to study the molecular basis of essential thrombocythemia, a myeloproliferative disorder with quantitative and qualitative platelet defects associated with cardiovascular and thrombohemorrhagic symptoms, not infrequently neurological. A platelet-expressed gene (HSD17B3) encoding type 3 17beta-hydroxysteroid dehydrogenase (previously characterized as a testis-specific enzyme catalyzing the final step in gonadal synthesis of testosterone) was selectively down-regulated in ET platelets, with reciprocal induction of the type 12 enzyme (HSD17B12). Functional 17beta-HSD3 activity corresponding to approximately 10% of that found in murine testis was demonstrated in normal platelets. The induction of HSD17B12 in ET platelets was unassociated with a concomitant increase in androgen biosynthesis, suggesting distinct functions and/or substrate specificities of the types 3 and 12 enzymes. Application of a molecular assay distinguished ET from normal platelets in 20 consecutive patients (p < 0.0001). These data provide the first evidence that distinct subtypes of steroidogenic 17beta-HSDs are functionally present in human blood platelets, and that the expression patterns of HSD17B3 and HSD17B12 are associated with an uncommon platelet disorder manifest by quantitative and qualitative platelet defects. Show less