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

Role of miRNAs in Cancer

MicroRNAs are the best representatives of the non-coding part of the genome and their functions are mostly linked to their target genes. During the process of carcinogenesis, both dysregulation of microRNAs and their target genes can explain the development of the disease. However, most of the target genes of microRNAs have not yet been elucidated. In this book, we add new information related to the functions of microRNAs in various tumors and their associated targetome

Functional dissection of transcriptional regulation during normal and malignant T-cell development : an integrative (epi)genomic approach

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive malignant disorder. While originally associated with poor prognosis, more recent intensified T-ALL therapy has led to remarkable improvements in survival of these patients. Unfortunately, these therapeutic schemes are associated with severe acute and long-term toxicities, thus demanding for further research in order to design more precision medicine oriented treatment. Importantly, for T-ALL patients with relapsed and refractory T-ALL, outcome remains extremely poor, thus urging further investigations to design therapies with further reduced relapse risk and/or novel treatment to cure relapsed cases. To shift towards this personalized medicine approach, a more profound understanding of the molecular basis of T-ALL progression is required. Several decades of genetic studies in T-ALL have uncovered a remarkable heterogeneous and complex landscape of combined oncogenic and loss-of-function mutations that contribute to malignant thymocyte transformation. One of the major challenges in T-ALL research is to unravel in detail how the diverse complement of oncogenes and tumor suppressors functionally contribute to T-ALL pathogenesis and response to therapy. To this end, I have studied the functional properties and cooperation of several key players that participate in normal and malignant T-cell development at the level of transcriptional regulatory networks. TLX1 is a major driver oncogene causing transformation of immature thymocytes towards T-ALL. Previous pioneering work partly uncovered its mode of action in relation to T-ALL formation, showing that ectopic overexpression of TLX1 in immature thymocytes causes repression of multiple T-ALL tumor suppressor genes. The study performed during this doctoral mandate, led to the observation of an unexpected antagonism between the TLX1 and NOTCH1 oncogenes, with activated TLX1 suppressing NOTCH1 and key NOTCH1 target genes. Based on this finding, we hypothesized that this unique interaction between both oncogenes could explain the presence of NOTCH1 mutations in most TLX1 driven T-ALL. Furthermore, the required cooperativity of NOTCH1 (pathway) activating mutations can also explain the very long latency of T-ALL development in a TLX1 driven leukemia mouse model (paper 1). In addition to NOTCH1 mutations, PHF6 loss-of-function mutations are also frequently observed, pointing at a further putative required cooperative genetic lesion for full-blown TLX1 driven T-ALL formation. Given the lack of insight into the normal cellular function of the epigenetic reader protein PHF6, I investigated its role during normal hematopoiesis and observed a profound effect of PHF6 loss on hematopoietic lineage development (paper 2). Moreover, in the context of TLX1 driven T-ALL formation, I identified the tyrosine kinase ‘interleukine-7 receptor’ (IL7R) as a robustly upregulated gene upon PHF6 knockdown. Given the role of IL7R signaling in survival of maturing thymocytes, this observation opens an exciting perspective that PHF6 loss is required as an essential cooperative event in TLX1 driven T-ALL pathogenesis by re-installment of TLX1 repressed IL7R expression. Importantly, in addition to paving the way for further animal modeling and mechanistic studies, this finding is also highly relevant in the context of design of novel therapies targeting IL7R downstream JAK-STAT signaling (paper 3). Until recently, transcriptional regulatory networks were mainly studied from a ‘gene-protein coding’ genomic viewpoint. Several studies have challenged this central dogma based on the proven role of non-coding RNAs in control of normal cellular behavior. Given this exciting new perspective on further expanding complexity of gene regulation during normal development and malignant transformation, I decided to study the role of such micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) in T-ALL perturbed transcriptional networks. More specifically, I studied the role of miRNAs under control of TAL1 (paper 4), unraveled the landscape of lncRNAs implicated in the NOTCH1 signaling pathway (paper 5) and performed the first landscaping of the TLX1 lncRNAome (paper 6). In conclusion, my work has contributed to novel insights into transcriptional networks in normal and malignant T-cell development, revealing several novel nodes for therapeutic intervention in the pursuit of personalized medicine development in the field of T-ALL research

Central Nervous System Tumors

Though the treatment of central nervous system (CNS) tumors has been challenging, new advances have helped us better understand the molecular and genetic makeup of many tumor types, and new chemotherapies and immunotherapies have extended survival in patients with aggressive primary CNS tumors. This book discusses pediatric and adult tumors of the CNS, the classification schemes used to categorize them, advances in surgical techniques, and several important genetic alterations found in these tumors. We hope this book contributes to the reader’s understanding of these tumors and provides the most up-to-date and cutting-edge discoveries in this exciting field