Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation.
Overexpression of the transcription factor Spi-1/PU.1 in mice leads to acute erythroleukemia characterized by a differentiation block at the proerythroblastic stage. In this study, we made use of a new cellular system allowing us to reach graded expression of Spi-1 in preleukemic cells to dissect mechanisms of Spi-1/ PU-1 in erythroleukemogenesis. This system is based on conditional production of 1 or 2 spi-1-interfering RNAs stably inserted into spi-1 transgenic proerythroblasts. We show that Spi-1 knock-down was sufficient to reinstate the erythroid differentiation program. This differentiation process was associated with an exit from the cell cycle. Evidence is provided that in the presence of erythropoietin (Epo), Spi-1 displays an antiapoptotic role that is independent of its function in blocking erythroid differentiation. Apoptosis inhibited by Spi-1 did not involve activation of the Fas/FasL signaling pathway nor a failure to activate Epo receptor (EpoR). Furthermore, we found that reducing the Spi-1 level yields to ERK dephosphorylation and increased phosphorylation of AKT and STAT5, suggesting that Spi-1 may affect major signaling pathways downstream of the EpoR in erythroid cells. These findings reveal 2 distinct roles for Spi-1 during erythroleukemogenesis: Spi-1 blocks the erythroid differentiation program and acts to impair apoptotic death in cooperation with an Epo signaling.
Rimmelé
Pauline
P
Institut Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite 528, Paris, France.
Kosmider
Olivier
O
Mayeux
Patrick
P
Moreau-Gachelin
Françoise
F
Guillouf
Christel
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation; D004900:Erythroblasts / Q000473:pathology / Q000502:physiology; D004920:Erythropoiesis / Q000502:physiology; D004921:Erythropoietin / Q000502:physiology*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
D004921:Erythropoietin; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017467:Receptors, Erythropoietin; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1