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Strong Correlation between the Expression Levels of HDAC4 and SIRT6 in Hematological Malignancies of the Adults

Abstract

Histone deacetylase enzymes, confirmed to have important role in the pathogenesis of leukemia, are promising targets of epigenetic treatment. However, in acute myeloid leukemia, our knowledge on their expression levels is limited, and controversial data have been published about their potential oncogenic or tumorsuppressor properties in solid tumors. In our study, the expression levels of HDAC4 and SIRT6 were evaluated via Western blot analysis in 45 bone marrow samples (2 uninfiltrated and 43 concerned by different kinds of hematological malignancies), including 32 specimens obtained from patients with newly diagnosed AML. Significantly higher HDAC4 level was detected in case of FLT3-ITD mutation compared to the group of patients without carrying this mutation (p < 0.05). Compared to the non-infiltrated samples, the expression level of HDAC4 in AML M5 patients has been proved to be significantly higher (p < 0.05). Decreasing expression levels of both HDAC4 and SIRT6 were observed during the induction treatment of FAB M5 type AML. Strong correlation has been proved between the expression levels of HDAC4 and SIRT6 (r = 0.722 in full cohort and r = 0.794 in AML), that confirms the recently suggested cooperation between NAD+-independent and NAD+-dependent HDAC enzymes in leukemia.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BCA:

Bicinchoninic acid assay

BSA:

Bovine serum albumin

CBP:

CREB-binding protein

CLL:

Chronic lymphocytic leukemia

FAB:

French-American-British Classification

FDA:

Food and Drug Administration

FLT3:

Fms-like tyrosine kinase 3

GCN5:

General control of amino acid synthesis 5

EDTA:

Ethylene-diamine-teraacetic acid

ETO:

Eight twenty one

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HCL:

Hairy cell leukemia

HL:

Hodgkin lymphoma

hMOF:

Human orthologue of the Drosophila melanogaster males absent on the first gene

HMT:

Histone methyltransferase

ITD:

Internal tandem duplication

JAK:

Janus kinase

MDS:

Myelodysplastic syndrome

MLL:

Mixed lineage leukemia

MPAL:

Mixed-phenotype acute leukemia

NCOR:

Nuclear receptor co-repressor

NPM1:

Nucleophosmin 1

NuRD:

Nucleosome remodeling deacetylase

PBX:

Pre-B-cell leukemia homeobox

PCBP2:

Poly(C)-binding protein 2

PRL3:

Phosphatase of regenerating liver cell 3

qPCR:

Quantitative polymerase chain reaction

RT:

Reverse transcription

SAHA:

Suberoylannilide hydroxamic acid

SDS:

Sodium dodecyl sulfate

SIRT:

Sirtuin

SMRT:

Silencing mediator of retinoid and thyroid hormone receptor

STAT:

Signal transducers and activators of transcription

TKD:

Tyrosine kinase domain

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Acknowledgments

The authors are grateful for Dóra Dedinszki, Zoltán Kónya (Department of Medical Chemistry, University of Debrecen) and Zsuzsanna Nagy (Department of Physiology, University of Debrecen) for the useful technical advices.

Our work was partially financed by Astellas Pharma Ltd.

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Correspondence to László Rejtő.

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The authors declare that they have no conflict of interest.

Author Contributions

Gaál Zs.: experimental procedures, design research, data analysis, writing the manuscript.

Oláh É.: design research, supervision of experimental procedures, correction of the manuscript.

Rejtő L.: collection of bone marrow specimens.

Erdődi F.: providing laboratory background (Department of Medical Chemistry), design research, supervision of experimental procedures, correction of the manuscript.

Csernoch L.: design research, supervision of experimental procedures, correction of the manuscript.

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Gaál, Z., Oláh, É., Rejtő, L. et al. Strong Correlation between the Expression Levels of HDAC4 and SIRT6 in Hematological Malignancies of the Adults. Pathol. Oncol. Res. 23, 493–504 (2017). https://doi.org/10.1007/s12253-016-0139-5

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  • DOI: https://doi.org/10.1007/s12253-016-0139-5

Keywords

  • Acute myeloid leukemia
  • Epigenetics
  • Histone deacetylation
  • HDAC4
  • SIRT6