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Clin Cancer Res. 2015 May 15;21(10):2348-58. doi: 10.1158/1078-0432.CCR-14-1290. Epub 2015 Feb 16.

Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL.

Author information

1
Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. mstubbs@incyte.com.
2
Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Medical Oncology, Dana-Farber-Cancer Institute and Harvard Medical School, Boston, Massachusetts.
5
Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. Harvard Stem Cell Institute, Boston, Massachusetts.
7
Division of Hematology/Oncology, Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber-Cancer Institute, and Harvard Medical School, Boston, Massachusetts. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Harvard Stem Cell Institute, Boston, Massachusetts.

Abstract

PURPOSE:

Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms.

EXPERIMENTAL DESIGN:

A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform-specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B-cell malignancy-derived cell lines and a pediatric B-ALL were used to demonstrate pharmacologic efficacy.

RESULTS:

Nonselective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform-specific HDACi indicated that targeting HDAC1-3 with class I HDAC-specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA-mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo, whereas it was far less effective against other B-cell-derived malignancies.

CONCLUSIONS:

Here, we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.

PMID:
25688158
PMCID:
PMC4433811
DOI:
10.1158/1078-0432.CCR-14-1290
[Indexed for MEDLINE]
Free PMC Article

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