title: Gatekeeper function of the RUNX1 transcription factor in acute leukemia.
abstract: The RUNX1 gene encodes the alpha subunit of the core binding factor (CBF) and is a common target of genetic mutations in acute leukemia. We propose that RUNX1 is a gatekeeper gene, the disruption of which leads to the exodus of a subset of hematopoietic progenitors with increased self-renewal potential from the normal environmental controls of homeostasis. This pool of "escaped" cells is the target of secondary mutations, accumulating over time to induce the aggressive manifestation of acute leukemia. Evidence from patient and animal studies supports the concept that RUNX1 mutations are the initiating event in different leukemia subtypes, but also suggests that diverse mechanisms are used to subvert RUNX1 function. One common result is the inhibition of differentiation-but its effect impinges on different lineages and stages of differentiation, depending on the mutation or fusion partner. A number of different approaches have led to the identification of secondary events that lead to the overt acute phase; however, the majority is unknown. Finally, the concept of the "leukemia stem cell" and its therapeutic importance is discussed in light of the RUNX1 gatekeeper function.
authors.affiliation: Heinrich-Pette-Institut, Martinistr. 52, D-20251 Hamburg, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Niebuhr
authors.forename: Meike
authors.initials: M
authors.lastname: Fischer
authors.forename: Maike
authors.initials: M
authors.lastname: Täger
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D014157:Transcription Factors