title: The clonal evolution of leukemic stem cells in T-cell acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Recent genome sequencing studies have identified a broad spectrum of gene mutations in T-cell acute lymphoblastic leukemia (T-ALL). The purpose of this review is to outline the latest advances in our understanding of how these mutations contribute to the formation of T-ALL.
  
  
  RESULTS
  Aberrant expression of transcription factors that control hematopoiesis can induce an aberrant stem cell-like program in T-cell progenitors, allowing the emergence of an ancestral or preleukemic stem cell (pre-LSC). In contrast, gain-of-function mutations of genes involved in signaling pathways regulating T-cell development, such as NOTCH1, interleukin-7, KIT and FLT3, are insufficient per se to initiate T-ALL but promote pre-LSC growth independent of the thymic niche. Loss-of-function mutations of epigenetic regulators, such as DNMT3A, have been identified in T-ALL, but their role in leukemogenesis remains to be defined.
  
  
  CONCLUSIONS
  Relapse is associated with clonal evolution from a population of pre-LSCs that acquire the whole set of malignant mutations leading to a full-blown T-ALL. Understanding the genetic events that underpin the pre-LSC will be crucial for reducing the risk of relapse.
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia.
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Tremblay
authors.forename: David J
authors.initials: DJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D060965:Clonal Evolution; D018450:Disease Progression; D044127:Epigenesis, Genetic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014157:Transcription Factors