Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms

Vibe Skov, Thomas Stauffer Larsen, Mads Thomassen, Caroline Hasselbalch Riley, Morten Jensen, Ole Weis Bjerrum, Torben A Kruse, Hans Carl Hasselbalch

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Abstract Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Histone deacetylases (HDACs) have a critical role in modulating gene expression and, accordingly, in the control of cell pathobiology and cancer development. HDAC inhibition has been shown to inhibit tumor growth (impaired myeloproliferation), to modulate the balance between pro- and antiapoptotic proteins in favor of apoptosis (enhanced apoptosis) and also to inhibit angiogenesis. Recently, enhanced HDAC enzyme activity has been found in CD34+cells from patients with PMF, enzyme activity levels highly exceeding those recorded in other chronic myeloproliferative neoplasms (CMPNs). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. Accordingly, HDAC inhibition is an obvious novel therapeutic approach in these neoplasms. Using global gene expression profiling of whole blood from patients with CMPNs, we have found a pronounced deregulation of HDAC genes, involving significant up-regulation of the HDAC genes 9 and 11, with the highest expression levels being found in patients with ET (HDAC9 and 11), PMF (HDAC9) and CMPNs (both HDAC9 and HDAC11). Furthermore, we have identified that the HDAC6 gene is progressively expressed in patients with ET, PV and PMF, reflecting a steady accumulation of abnormally expressed HDAC6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC genes were recorded in ET, in PMF and in the entire CMPN group, their down-regulation by HDAC inhibitors might be associated with decreased disease activity, including reduction of splenomegaly.
OriginalsprogEngelsk
TidsskriftLeukemia and Lymphoma
Vol/bind53
Udgave nummer1
Sider (fra-til)123-9
Antal sider7
ISSN1042-8194
DOI
StatusUdgivet - 2012

Fingeraftryk

Histone Deacetylases
Neoplasms
Polycythemia Vera
Apoptosis
Gene Expression Profiling
Enzymes
Epigenomics
Up-Regulation
Down-Regulation

Citer dette

Skov, Vibe ; Larsen, Thomas Stauffer ; Thomassen, Mads ; Riley, Caroline Hasselbalch ; Jensen, Morten ; Bjerrum, Ole Weis ; Kruse, Torben A ; Hasselbalch, Hans Carl. / Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms. I: Leukemia and Lymphoma. 2012 ; Bind 53, Nr. 1. s. 123-9.
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title = "Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms",
abstract = "Abstract Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Histone deacetylases (HDACs) have a critical role in modulating gene expression and, accordingly, in the control of cell pathobiology and cancer development. HDAC inhibition has been shown to inhibit tumor growth (impaired myeloproliferation), to modulate the balance between pro- and antiapoptotic proteins in favor of apoptosis (enhanced apoptosis) and also to inhibit angiogenesis. Recently, enhanced HDAC enzyme activity has been found in CD34+cells from patients with PMF, enzyme activity levels highly exceeding those recorded in other chronic myeloproliferative neoplasms (CMPNs). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. Accordingly, HDAC inhibition is an obvious novel therapeutic approach in these neoplasms. Using global gene expression profiling of whole blood from patients with CMPNs, we have found a pronounced deregulation of HDAC genes, involving significant up-regulation of the HDAC genes 9 and 11, with the highest expression levels being found in patients with ET (HDAC9 and 11), PMF (HDAC9) and CMPNs (both HDAC9 and HDAC11). Furthermore, we have identified that the HDAC6 gene is progressively expressed in patients with ET, PV and PMF, reflecting a steady accumulation of abnormally expressed HDAC6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC genes were recorded in ET, in PMF and in the entire CMPN group, their down-regulation by HDAC inhibitors might be associated with decreased disease activity, including reduction of splenomegaly.",
author = "Vibe Skov and Larsen, {Thomas Stauffer} and Mads Thomassen and Riley, {Caroline Hasselbalch} and Morten Jensen and Bjerrum, {Ole Weis} and Kruse, {Torben A} and Hasselbalch, {Hans Carl}",
year = "2012",
doi = "10.3109/10428194.2011.597905",
language = "English",
volume = "53",
pages = "123--9",
journal = "Leukemia and Lymphoma",
issn = "1042-8194",
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Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms. / Skov, Vibe; Larsen, Thomas Stauffer; Thomassen, Mads; Riley, Caroline Hasselbalch; Jensen, Morten; Bjerrum, Ole Weis; Kruse, Torben A; Hasselbalch, Hans Carl.

I: Leukemia and Lymphoma, Bind 53, Nr. 1, 2012, s. 123-9.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms

AU - Skov, Vibe

AU - Larsen, Thomas Stauffer

AU - Thomassen, Mads

AU - Riley, Caroline Hasselbalch

AU - Jensen, Morten

AU - Bjerrum, Ole Weis

AU - Kruse, Torben A

AU - Hasselbalch, Hans Carl

PY - 2012

Y1 - 2012

N2 - Abstract Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Histone deacetylases (HDACs) have a critical role in modulating gene expression and, accordingly, in the control of cell pathobiology and cancer development. HDAC inhibition has been shown to inhibit tumor growth (impaired myeloproliferation), to modulate the balance between pro- and antiapoptotic proteins in favor of apoptosis (enhanced apoptosis) and also to inhibit angiogenesis. Recently, enhanced HDAC enzyme activity has been found in CD34+cells from patients with PMF, enzyme activity levels highly exceeding those recorded in other chronic myeloproliferative neoplasms (CMPNs). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. Accordingly, HDAC inhibition is an obvious novel therapeutic approach in these neoplasms. Using global gene expression profiling of whole blood from patients with CMPNs, we have found a pronounced deregulation of HDAC genes, involving significant up-regulation of the HDAC genes 9 and 11, with the highest expression levels being found in patients with ET (HDAC9 and 11), PMF (HDAC9) and CMPNs (both HDAC9 and HDAC11). Furthermore, we have identified that the HDAC6 gene is progressively expressed in patients with ET, PV and PMF, reflecting a steady accumulation of abnormally expressed HDAC6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC genes were recorded in ET, in PMF and in the entire CMPN group, their down-regulation by HDAC inhibitors might be associated with decreased disease activity, including reduction of splenomegaly.

AB - Abstract Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Histone deacetylases (HDACs) have a critical role in modulating gene expression and, accordingly, in the control of cell pathobiology and cancer development. HDAC inhibition has been shown to inhibit tumor growth (impaired myeloproliferation), to modulate the balance between pro- and antiapoptotic proteins in favor of apoptosis (enhanced apoptosis) and also to inhibit angiogenesis. Recently, enhanced HDAC enzyme activity has been found in CD34+cells from patients with PMF, enzyme activity levels highly exceeding those recorded in other chronic myeloproliferative neoplasms (CMPNs). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. Accordingly, HDAC inhibition is an obvious novel therapeutic approach in these neoplasms. Using global gene expression profiling of whole blood from patients with CMPNs, we have found a pronounced deregulation of HDAC genes, involving significant up-regulation of the HDAC genes 9 and 11, with the highest expression levels being found in patients with ET (HDAC9 and 11), PMF (HDAC9) and CMPNs (both HDAC9 and HDAC11). Furthermore, we have identified that the HDAC6 gene is progressively expressed in patients with ET, PV and PMF, reflecting a steady accumulation of abnormally expressed HDAC6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC genes were recorded in ET, in PMF and in the entire CMPN group, their down-regulation by HDAC inhibitors might be associated with decreased disease activity, including reduction of splenomegaly.

U2 - 10.3109/10428194.2011.597905

DO - 10.3109/10428194.2011.597905

M3 - Journal article

VL - 53

SP - 123

EP - 129

JO - Leukemia and Lymphoma

JF - Leukemia and Lymphoma

SN - 1042-8194

IS - 1

ER -