Histone deacetylase (HDAC)-dependent transcriptional repression of the retinoic acid (RA)-signaling pathway underlies the differentiation block of acute promyelocytic leukemia. RA treatment relieves transcriptional repression and triggers differentiation of acute promyelocytic leukemia blasts, leading to disease remission. We report that transcriptional repression of RA signaling is a common mechanism in acute myeloid leukemias (AMLs). HDAC inhibitors restored RA-dependent transcriptional activation and triggered terminal differentiation of primary blasts from 23 AML patients. Accordingly, we show that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling. These findings relate alteration of the RA pathway to myeloid leukemogenesis and underscore the potential of transcriptional/differentiation therapy in AML.

Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia / F. F. Ferrara, F. Fazi, A. Bianchini, F. Padula, V. Gelmetti, S. Minucci, M. Mancini, P. G. Pelicci, F. Lo Coco, C. Nervi. - In: CANCER RESEARCH. - ISSN 0008-5472. - 61:1(2001 Jan 01), pp. 2-7-7.

Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia

S. Minucci;P. G. Pelicci;
2001

Abstract

Histone deacetylase (HDAC)-dependent transcriptional repression of the retinoic acid (RA)-signaling pathway underlies the differentiation block of acute promyelocytic leukemia. RA treatment relieves transcriptional repression and triggers differentiation of acute promyelocytic leukemia blasts, leading to disease remission. We report that transcriptional repression of RA signaling is a common mechanism in acute myeloid leukemias (AMLs). HDAC inhibitors restored RA-dependent transcriptional activation and triggered terminal differentiation of primary blasts from 23 AML patients. Accordingly, we show that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling. These findings relate alteration of the RA pathway to myeloid leukemogenesis and underscore the potential of transcriptional/differentiation therapy in AML.
Histones; Antineoplastic Agents; Histone Deacetylases; Humans; Hydroxamic Acids; Cell Differentiation; Enzyme Inhibitors; Leukemia, Myeloid, Acute; Gene Expression Regulation, Leukemic; Transcriptional Activation; Leukemia, Myelomonocytic, Acute; Acetylation; Tumor Cells, Cultured; Transcription Factors; Tretinoin; Core Binding Factor Alpha 2 Subunit; Histone Deacetylase Inhibitors; Signal Transduction; Oncogene Proteins, Fusion
Settore MED/04 - Patologia Generale
1-gen-2001
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/195085
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