The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2 V617F myeloproliferative neoplasm cells

Ariel Amaru Calzada, Katia Todoerti, Luca Donadoni, Anna Pellicioli, Giacomo Tuana, Raffaella Gatta, Antonino Neri, Guido Finazzi, Roberto Mantovani, Alessandro Rambaldi, Martino Introna, Luigia Lombardi, Josée Golay

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

We investigated the mechanism of action of the histone deacetylase inhibitor Givinostat (GVS) in Janus kinase 2 (JAK2) V617F myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses two- to threefold lower in a panel of JAK2 V617F MPN compared to JAK2 wild-type myeloid leukemia cell lines. By global gene expression analysis, we observed that at 6 hours, GVS modulated 293 common genes in the JAK2 V617F cell lines HEL and UKE1, of which 19 are implicated in cell cycle regulation and 33 in hematopoiesis. In particular, the hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2 V617F cells at both the RNA and protein level. GVS also inhibited JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 phosphorylation, but modulation of NFE2 and C-MYB was JAK2-independent, as shown using the JAK2 inhibitor TG101209. GVS had a direct effect on the NFE2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at lysine 9. Modulation by GVS of NFE2 was also observed in freshly isolated CD34 + cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation toward the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 inhibition and downmodulation of NFE2 and C-MYB transcription.

Original languageEnglish
JournalExperimental Hematology
Volume40
Issue number8
DOIs
Publication statusPublished - Aug 2012

Fingerprint

NF-E2 Transcription Factor
Janus Kinase 2
Histone Deacetylase Inhibitors
Neoplasms
STAT5 Transcription Factor
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
givinostat
Cell Line
Myeloid Leukemia
Hematopoiesis
Myeloid Cells
Histones
Lysine
Cell Cycle

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2 V617F myeloproliferative neoplasm cells. / Amaru Calzada, Ariel; Todoerti, Katia; Donadoni, Luca; Pellicioli, Anna; Tuana, Giacomo; Gatta, Raffaella; Neri, Antonino; Finazzi, Guido; Mantovani, Roberto; Rambaldi, Alessandro; Introna, Martino; Lombardi, Luigia; Golay, Josée.

In: Experimental Hematology, Vol. 40, No. 8, 08.2012.

Research output: Contribution to journalArticle

Amaru Calzada, A, Todoerti, K, Donadoni, L, Pellicioli, A, Tuana, G, Gatta, R, Neri, A, Finazzi, G, Mantovani, R, Rambaldi, A, Introna, M, Lombardi, L & Golay, J 2012, 'The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2 V617F myeloproliferative neoplasm cells', Experimental Hematology, vol. 40, no. 8. https://doi.org/10.1016/j.exphem.2012.04.007
Amaru Calzada, Ariel ; Todoerti, Katia ; Donadoni, Luca ; Pellicioli, Anna ; Tuana, Giacomo ; Gatta, Raffaella ; Neri, Antonino ; Finazzi, Guido ; Mantovani, Roberto ; Rambaldi, Alessandro ; Introna, Martino ; Lombardi, Luigia ; Golay, Josée. / The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2 V617F myeloproliferative neoplasm cells. In: Experimental Hematology. 2012 ; Vol. 40, No. 8.
@article{dcabbc382a784242abf6d0c2ac090b2e,
title = "The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2 V617F myeloproliferative neoplasm cells",
abstract = "We investigated the mechanism of action of the histone deacetylase inhibitor Givinostat (GVS) in Janus kinase 2 (JAK2) V617F myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses two- to threefold lower in a panel of JAK2 V617F MPN compared to JAK2 wild-type myeloid leukemia cell lines. By global gene expression analysis, we observed that at 6 hours, GVS modulated 293 common genes in the JAK2 V617F cell lines HEL and UKE1, of which 19 are implicated in cell cycle regulation and 33 in hematopoiesis. In particular, the hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2 V617F cells at both the RNA and protein level. GVS also inhibited JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 phosphorylation, but modulation of NFE2 and C-MYB was JAK2-independent, as shown using the JAK2 inhibitor TG101209. GVS had a direct effect on the NFE2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at lysine 9. Modulation by GVS of NFE2 was also observed in freshly isolated CD34 + cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation toward the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 inhibition and downmodulation of NFE2 and C-MYB transcription.",
author = "{Amaru Calzada}, Ariel and Katia Todoerti and Luca Donadoni and Anna Pellicioli and Giacomo Tuana and Raffaella Gatta and Antonino Neri and Guido Finazzi and Roberto Mantovani and Alessandro Rambaldi and Martino Introna and Luigia Lombardi and Jos{\'e}e Golay",
year = "2012",
month = "8",
doi = "10.1016/j.exphem.2012.04.007",
language = "English",
volume = "40",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2 V617F myeloproliferative neoplasm cells

AU - Amaru Calzada, Ariel

AU - Todoerti, Katia

AU - Donadoni, Luca

AU - Pellicioli, Anna

AU - Tuana, Giacomo

AU - Gatta, Raffaella

AU - Neri, Antonino

AU - Finazzi, Guido

AU - Mantovani, Roberto

AU - Rambaldi, Alessandro

AU - Introna, Martino

AU - Lombardi, Luigia

AU - Golay, Josée

PY - 2012/8

Y1 - 2012/8

N2 - We investigated the mechanism of action of the histone deacetylase inhibitor Givinostat (GVS) in Janus kinase 2 (JAK2) V617F myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses two- to threefold lower in a panel of JAK2 V617F MPN compared to JAK2 wild-type myeloid leukemia cell lines. By global gene expression analysis, we observed that at 6 hours, GVS modulated 293 common genes in the JAK2 V617F cell lines HEL and UKE1, of which 19 are implicated in cell cycle regulation and 33 in hematopoiesis. In particular, the hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2 V617F cells at both the RNA and protein level. GVS also inhibited JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 phosphorylation, but modulation of NFE2 and C-MYB was JAK2-independent, as shown using the JAK2 inhibitor TG101209. GVS had a direct effect on the NFE2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at lysine 9. Modulation by GVS of NFE2 was also observed in freshly isolated CD34 + cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation toward the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 inhibition and downmodulation of NFE2 and C-MYB transcription.

AB - We investigated the mechanism of action of the histone deacetylase inhibitor Givinostat (GVS) in Janus kinase 2 (JAK2) V617F myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses two- to threefold lower in a panel of JAK2 V617F MPN compared to JAK2 wild-type myeloid leukemia cell lines. By global gene expression analysis, we observed that at 6 hours, GVS modulated 293 common genes in the JAK2 V617F cell lines HEL and UKE1, of which 19 are implicated in cell cycle regulation and 33 in hematopoiesis. In particular, the hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2 V617F cells at both the RNA and protein level. GVS also inhibited JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 phosphorylation, but modulation of NFE2 and C-MYB was JAK2-independent, as shown using the JAK2 inhibitor TG101209. GVS had a direct effect on the NFE2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at lysine 9. Modulation by GVS of NFE2 was also observed in freshly isolated CD34 + cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation toward the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 inhibition and downmodulation of NFE2 and C-MYB transcription.

UR - http://www.scopus.com/inward/record.url?scp=84864018748&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864018748&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2012.04.007

DO - 10.1016/j.exphem.2012.04.007

M3 - Article

C2 - 22579713

AN - SCOPUS:84864018748

VL - 40

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 8

ER -