Deciphering the untranslated message in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) patients currently present with an overall favorable prognosis achieved through intense chemotherapy regimens. Additional challenges that are still posed today concern those patients that present with therapy resistance or relapse. In this per-spective it will be crucial to further unravel the molecular basis of T-ALL biology and identify novel targets for development of innovative therapy protocols. Technological advances in the field have opened new possibilities to dissect the T-ALL transcriptome and recent findings un-derscore the importance of noncoding RNA molecules, such as miRNAs and lncRNAs, next to protein coding genes in various cancer entities and also T-ALL. In this thesis, my aim was to landscape the expression of these noncoding RNAs in T-ALL to complement the previously published protein coding gene expression profiles. In this way, nov-el oncogenic aspects in T-ALL could be unraveled, for example when an lncRNA or miRNA is de-tected in a known T-ALL oncogenic pathway or when it could point at complete novel oncogen-ic mechanisms

T-ALL and thymocytes : a message of noncoding RNAs

In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs. In this review, we give a detailed overview of the studies that describe the noncoding RNAome in T-ALL oncogenesis and normal T cell development

Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that can be classified into different molecular genetic subtypes according to their mRNA gene expression profile. In this study, we applied RNA sequencing to investigate the full spectrum of miRNA expression in primary T-ALL patient samples, T-ALL leukemia cell lines and healthy donor thymocytes. Notably, this analysis revealed that genetic subtypes of human T-ALL also display unique miRNA expression signatures, which are largely conserved in human T-ALL cell lines with corresponding genetic background. Furthermore, small RNA-sequencing also unraveled the variety of isoforms that are expressed for each miRNA in T-ALL and showed that a significant number of miRNAs are actually represented by an alternative isomiR. Finally, comparison of CD34(+) and CD4(+) CD8(+) healthy donor thymocytes and T-ALL miRNA profiles allowed identifying several novel miRNAs with putative oncogenic or tumor suppressor functions in T-ALL. Altogether, this study provides a comprehensive overview of miRNA expression in normal and malignant T-cells and sets the stage for functional evaluation of novel miRNAs in T-ALL disease biology

Long non-coding RNAs in leukemia : biology and clinical impact

Purpose of review: Over the last years, long non-coding RNAs (lncRNAs) have emerged as putative regulators of malignant hematopoietic development. Here, we review recent literature on the involvement of lncRNAs in leukemia, including their role in driving or sustaining disease and their potential impact on diagnosis, classification, and prognosis. Recent findings: Leukemogenesis is a complex process resulting from the accumulation of multiple genetic alterations. Over the last years, advances in high-throughput sequencing and transcriptome profiling have enabled the identification of lncRNAs involved in leukemia development. lncRNAs are able to distinguish different subtypes of human leukemia and several reports have identified specific patterns of lncRNA expression associated with clinical patient characteristics. Although functional studies on the actual role of these lncRNAs during transformation remain scarce, emerging evidence suggests that complex interactions between coding and non-coding transcript are truly involved in leukemia development. Summary: Introduction of lncRNAs as an additional layer of complexity in human leukemia might provide new molecular genetic insights in the biology of this disease and could create unique opportunities for the identification of novel drug targets and diagnostic or prognostic biomarkers