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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3330-3338.
Prepublished online as a Blood First Edition Paper on December 13, 2005; DOI 10.1182/blood-2005-07-3068.
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NEOPLASIA
ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression
Beatrice U. Mueller,
Thomas Pabst,
José Fos,
Vibor Petkovic,
Martin F. Fey,
Norio Asou,
Ulrich Buergi, and
Daniel G. Tenen
From the Department of Internal Medicine and the Department of Clinical Research, University Hospital, Bern, Switzerland; the Institute of Medical Oncology, University Hospital, Bern, Switzerland; Kumamoto University Hospital, Kumamoto, Japan; and Harvard Institutes of Medicine, Harvard Medical School, Boston, MA.
Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor  (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).
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