title: ETV6-RUNX1 promotes survival of early B lineage progenitor cells via a dysregulated erythropoietin receptor.
abstract: ETV6-RUNX1 gene fusion is usually an early, prenatal event in childhood acute lymphoblastic leukemia (ALL). Transformation results in the generation of a persistent (> 14 years) preleukemic clone, which postnatally converts to ALL after the acquisition of necessary secondary genetic alterations. Many cancer cells show some expression of the erythropoietin receptor (EPOR) gene, although the "functionality" of any EPOR complexes and their relevant signaling pathways in nonerythroid cells has not been validated. EPOR mRNA is selectively and ectopically expressed in ETV6-RUNX1(+) ALL, but the presence of a functional EPOR on the cell surface and its role in leukemogenesis driven by ETV6-RUNX1 remains to be identified. Here, we show that ETV6-RUNX1 directly binds the EPOR promoter and that expression of ETV6-RUNX1 alone in normal pre-B cells is sufficient to activate EPOR transcription. We further reveal that murine and human ETV6-RUNX1(+) cells expressing EPOR mRNA have EPO ligand binding activity that correlates with an increased cell survival through activation of the JAK2-STAT5 pathway and up-regulation of antiapoptotic BCL-XL. These data support the contention that ETV6-RUNX1 directly activates ectopic expression of a functional EPOR and provides cell survival signals that may contribute critically to persistence of covert premalignant clones in children.
authors: Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Sutton, UK.
authors: Veronica
authors: V
authors: Torrano
authors: Julia
authors: J
authors: Procter
authors: Penny
authors: P
authors: Cardus
authors: Mel
authors: M
authors: Greaves
authors: Anthony M
authors: AM
authors: Ford
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011230:Precancerous Conditions / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000502:physiology*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D017467:Receptors, Erythropoietin; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein