ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression

Mueller, Beatrice U; Pabst, Thomas; Fos, José; Petkovic, Vibor; Fey, Martin F; Asou, Norio; Buergi, Ulrich; Tenen, Daniel G (2006). ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood, 107(8), pp. 3330-8. Washington, D.C.: American Society of Hematology 10.1182/blood-2005-07-3068

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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 alpha (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).

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology > Centre of Competence for Psychosomatic Medicine
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Müller, Beatrice Ursula; Pabst, Thomas; Fos Trigas, José; Pegiazoglou, Ioannis; Fey, Martin and Bürgi, Ulrich

ISSN:

0006-4971

ISBN:

16352814

Publisher:

American Society of Hematology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:46

Last Modified:

17 Mar 2015 21:45

Publisher DOI:

10.1182/blood-2005-07-3068

PubMed ID:

16352814

Web of Science ID:

000236833500053

URI:

https://boris.unibe.ch/id/eprint/18995 (FactScience: 1356)

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