Reprogramming leukemia cells to terminal differentiation and growth arrest by RNA interference of PU.1.
Malignant transformation often leads to both loss of normal proliferation control and inhibition of cell differentiation. Some tumor cells can be stimulated to reenter their differentiation program and to undergo terminal growth arrest. The in vitro differentiation of mouse erythroleukemia (MEL) cells is an important example of tumor cell reprogramming. MEL cells are malignant erythroblasts that are blocked from differentiating into mature RBC due to dysregulated expression of the transcription factor PU.1, which binds to and represses GATA-1, the major transcriptional regulator of erythropoiesis. We used RNA interference to ask whether inhibiting PU.1 synthesis was sufficient to cause MEL cells to lose their malignant properties. We report here that transfection of MEL cells with a PU.1-specific short interfering RNA oligonucleotide causes the cells to resume erythroid differentiation, accumulate hemoglobin, and undergo terminal growth arrest. RNA interference directed at specific, aberrantly expressed transcription factors may hold promise for the development of potent antitumor therapies in other hematologic malignancies.
Papetti
Michael
M
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Skoultchi
Arthur I
AI
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006454:Hemoglobins / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D006454:Hemoglobins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1