Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells

Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance, yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements, and are sufficient to fully reprogram differentiated GBM cells to ‘induced’ TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies novel therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies

Delineation of the cellular pathway and molecular mechanisms of Notch1-mediated early T lineage development

T lineage development takes place outside the bone marrow (BM) in a dedicated organ, the thymus. Containing no long-termed self-renewing progenitors, the thymus requires periodic importations of progenitors from the BM. Within the thymus, Notch1 ligands, Delta-like 4, induce Notch1 signaling in incoming progenitors and initiate T cell differentiation programming. This thesis work aims to further elucidate mechanisms downstream of Notch1 during early T lineage development. In the first chapter, I describe a small subset of myeloid progenitors that still retain T lymphoid developmental potential. Yet these progenitors are unlike to contribute to the thymopoiesis under normal physiological conditions, as they lack proper chemokine receptors for optimal thymic homing. In the second chapter, I demonstrate TCF1 is a Notch1 target gene and IL7Rα is a TCF1 target gene. IL7R signaling has been shown to provide the trophic signals during T lineage development. This, in addition to the fact that TCF1 regulates key T lineage genes, such as TCRα and CD3ϵ, suggests TCF1 may function as a critical mediator that couples the specification process in T lineage differentiation with the survival requirement. Lastly, Notch1 is previously shown to be able to dimerize. In the third chapter, I show that, while dispensable to impose the T cell fate on multipotent progenitors, Notch1 dimerization is required to differentiate DN3 thymocytes to the CD4 +CD8+ DP stage in part through activation of cMyc expression. Given that Notch1 regulates key target genes via dimerization and developmental stage-specific blocks ensue when dimerization is prevented, this finding is of potential clinical interest, as it may be possible to develop a new class of Notch inhibitors that selectively block Notch1 dimerization-dependent outcomes, such as leukemogenesis

Multimodal Therapy of an Intramedullary Cervical Primitive Neuroectodermal Tumor in an Adult

Primitive neuroectodermal tumors (PNETs) are malignant, poorly differentiated neoplasms derived from the neural crest.1 They include cerebellar medulloblastomas but can also arise in the cerebral cortex (supratentorial PNETs), pineal region (pineoblastomas), spinal cord, cauda equina, and peripheral nerves.2 Only a few cases of primary intraspinal PNETs have been reported in children3-14 and in adults.15-17 To our knowledge, there has only been one previously reported case of intramedullary PNET of the cervical spine in an adult.17 In this article, we present a rare adult patient with a primary intramedullary cervical PNET and describe his treatment regimen and outcome