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

被引：165

作者：

Mueller, BU ^{[1
]}

Pabst, T

Fos, J

Petkovic, V

Fey, MF

Asou, N

Buergi, U

Tenen, DG

机构：

[1] Univ Hosp Bern, Dept Internal Med, CH-3010 Bern, Switzerland

[2] Univ Hosp Bern, Dept Clin Res, CH-3010 Bern, Switzerland

[3] Univ Hosp Bern, Inst Med Oncol, CH-3010 Bern, Switzerland

[4] Kumamoto Univ Hosp, Kumamoto, Japan

[5] Harvard Univ, Sch Med, Harvard Inst Med, Boston, MA 02115 USA

来源：

BLOOD | 2006年 / 107卷 / 08期

关键词：

D O I：

10.1182/blood-2005-07-3068

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-incluced 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-incluced 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).

引用

页码：3330 / 3338

页数：9

共 33 条

[1] Neutrophils deficient in PU.1 do not terminally differentiate or become functionally competent [J].

Anderson, KL ;

Smith, KA ;

Pio, F ;

Torbett, BE ;

Maki, RA .

BLOOD, 1998, 92 (05) :1576-1585

[2] Visualizing PU.1 activity during hematopoiesis [J].

Back, J ;

Allman, D ;

Chan, S ;

Kastner, P .

EXPERIMENTAL HEMATOLOGY, 2005, 33 (04) :395-402

[3] Octamer binding factors and their coactivator can activate the murine PU.1 (spi-1) promoter [J].

Chen, HM ;

Zhang, P ;

Radomska, HS ;

Hetherington, CJ ;

Zhang, DE ;

Tenen, DG .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (26) :15743-15752

[4] NEUTROPHILS AND MONOCYTES EXPRESS HIGH-LEVELS OF PU.1 (SPI-1) BUT NOT SPI-B [J].

CHEN, HM ;

ZHANG, P ;

VOSO, MT ;

HOHAUS, S ;

GONZALEZ, DA ;

GLASS, CK ;

ZHANG, DE ;

TENEN, DG .

BLOOD, 1995, 85 (10) :2918-2928

[5]

CHEN HM, 1995, ONCOGENE, V11, P1549

[6] PU. 1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain [J].

Cook, WD ;

McCaw, BJ ;

Herring, C ;

John, DL ;

Foote, SJ ;

Nutt, SL ;

Adams, JM .

BLOOD, 2004, 104 (12) :3437-3444

[7] Retrovirus-delivered siRNA [J].

Devroe E. ;

Silver P.A. .

BMC Biotechnology, 2 (1)

[8] C/EBPβ:: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells [J].

Duprez, E ;

Wagner, K ;

Koch, H ;

Tenen, DG .

EMBO JOURNAL, 2003, 22 (21) :5806-5816

[9] Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia [J].

Grignani, F ;

De Matteis, S ;

Nervi, C ;

Tomassoni, L ;

Gelmetti, V ;

Cioce, M ;

Fanelli, M ;

Ruthardt, M ;

Ferrara, FF ;

Zamir, I ;

Seiser, C ;

Grignani, F ;

Lazar, MA ;

Minucci, S ;

Pelicci, PG .

NATURE, 1998, 391 (6669) :815-818

[10] THE ACUTE PROMYELOCYTIC LEUKEMIA-SPECIFIC PML-RAR-ALPHA FUSION PROTEIN INHIBITS DIFFERENTIATION AND PROMOTES SURVIVAL OF MYELOID PRECURSOR CELLS [J].

GRIGNANI, F ;

FERRUCCI, PF ;

TESTA, U ;

TALAMO, G ;

FAGIOLI, M ;

ALCALAY, M ;

MENCARELLI, A ;

GRIGNANI, F ;

PESCHLE, C ;

NICOLETTI, I ;

PELICCI, PG .

CELL, 1993, 74 (03) :423-431

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