Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia

Giuseppe Cimino, Francesco Lo-Coco, Susanna Fenu, Lorena Travaglini, Erica Finolezzi, Marco Mancini, Mauro Nanni, Angela Careddu, Francesco Fazi, Fabrizio Padula, Roberto Fiorini, Maria Antonietta Aloe Spiriti, Maria Concetta Petti, Adriano Venditti, Sergio Amadori, Franco Mandelli, Pier Giuseppe Pelicci, Clara Nervi

Research output: Contribution to journalArticle

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Abstract

Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (≥50 μg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients.

Original languageEnglish
Pages (from-to)8903-8911
Number of pages9
JournalCancer Research
Volume66
Issue number17
DOIs
Publication statusPublished - Sep 1 2006

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Valproic Acid
Tretinoin
Acute Myeloid Leukemia
Histones
Chromatin
Therapeutics
Clone Cells
Histone Deacetylase Inhibitors
Histone Deacetylases
Chromatin Assembly and Disassembly
Cytogenetic Analysis
Myelodysplastic Syndromes
Fluorescence In Situ Hybridization
Epigenomics
Disease Progression
Cell Differentiation
Blood Cells
Leukemia
Gene Expression
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia. / Cimino, Giuseppe; Lo-Coco, Francesco; Fenu, Susanna; Travaglini, Lorena; Finolezzi, Erica; Mancini, Marco; Nanni, Mauro; Careddu, Angela; Fazi, Francesco; Padula, Fabrizio; Fiorini, Roberto; Spiriti, Maria Antonietta Aloe; Petti, Maria Concetta; Venditti, Adriano; Amadori, Sergio; Mandelli, Franco; Pelicci, Pier Giuseppe; Nervi, Clara.

In: Cancer Research, Vol. 66, No. 17, 01.09.2006, p. 8903-8911.

Research output: Contribution to journalArticle

Cimino, G, Lo-Coco, F, Fenu, S, Travaglini, L, Finolezzi, E, Mancini, M, Nanni, M, Careddu, A, Fazi, F, Padula, F, Fiorini, R, Spiriti, MAA, Petti, MC, Venditti, A, Amadori, S, Mandelli, F, Pelicci, PG & Nervi, C 2006, 'Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia', Cancer Research, vol. 66, no. 17, pp. 8903-8911. https://doi.org/10.1158/0008-5472.CAN-05-2726
Cimino, Giuseppe ; Lo-Coco, Francesco ; Fenu, Susanna ; Travaglini, Lorena ; Finolezzi, Erica ; Mancini, Marco ; Nanni, Mauro ; Careddu, Angela ; Fazi, Francesco ; Padula, Fabrizio ; Fiorini, Roberto ; Spiriti, Maria Antonietta Aloe ; Petti, Maria Concetta ; Venditti, Adriano ; Amadori, Sergio ; Mandelli, Franco ; Pelicci, Pier Giuseppe ; Nervi, Clara. / Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia. In: Cancer Research. 2006 ; Vol. 66, No. 17. pp. 8903-8911.
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AU - Lo-Coco, Francesco

AU - Fenu, Susanna

AU - Travaglini, Lorena

AU - Finolezzi, Erica

AU - Mancini, Marco

AU - Nanni, Mauro

AU - Careddu, Angela

AU - Fazi, Francesco

AU - Padula, Fabrizio

AU - Fiorini, Roberto

AU - Spiriti, Maria Antonietta Aloe

AU - Petti, Maria Concetta

AU - Venditti, Adriano

AU - Amadori, Sergio

AU - Mandelli, Franco

AU - Pelicci, Pier Giuseppe

AU - Nervi, Clara

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N2 - Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (≥50 μg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients.

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