Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect

Kahia Messaoudi; Ashfaq Ali; Rameez Ishaq; Alberta Palazzo; Dominika Sliwa; Olivier Bluteau; Sylvie Souquère; Delphine Muller; Khadija M. Diop; Philippe Rameau; Valérie Lapierre; Jean Pierre Marolleau; Patrick Matthias; Isabelle Godin; Gérard Pierron; Steven G. Thomas; Stephen P. Watson; Nathalie Droin; William Vainchenker; Isabelle Plo; Hana Raslova; Najet Debili

doi:10.1038/s41467-017-01690-2

Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect

Kahia Messaoudi, Ashfaq Ali, Rameez Ishaq, Alberta Palazzo, Dominika Sliwa, Olivier Bluteau, Sylvie Souquère, Delphine Muller, Khadija M. Diop, Philippe Rameau, Valérie Lapierre, Jean Pierre Marolleau, Patrick Matthias, Isabelle Godin, Gérard Pierron, Steven G. Thomas, Stephen P. Watson, Nathalie Droin, William Vainchenker, Isabelle PloHana Raslova, Najet Debili

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

34 Citations (Scopus)

Résumé

Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

langue originale	Anglais
Numéro d'article	1786
journal	Nature Communications
Volume	8
Numéro de publication	1
Les DOIs	https://doi.org/10.1038/s41467-017-01690-2
état	Publié - 1 déc. 2017

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10.1038/s41467-017-01690-2

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Messaoudi, K., Ali, A., Ishaq, R., Palazzo, A., Sliwa, D., Bluteau, O., Souquère, S., Muller, D., Diop, K. M., Rameau, P., Lapierre, V., Marolleau, J. P., Matthias, P., Godin, I., Pierron, G., Thomas, S. G., Watson, S. P., Droin, N., Vainchenker, W., ... Debili, N. (2017). Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect. Nature Communications, 8(1), Article 1786. https://doi.org/10.1038/s41467-017-01690-2

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title = "Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect",

abstract = "Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.",

author = "Kahia Messaoudi and Ashfaq Ali and Rameez Ishaq and Alberta Palazzo and Dominika Sliwa and Olivier Bluteau and Sylvie Souqu{\`e}re and Delphine Muller and Diop, {Khadija M.} and Philippe Rameau and Val{\'e}rie Lapierre and Marolleau, {Jean Pierre} and Patrick Matthias and Isabelle Godin and G{\'e}rard Pierron and Thomas, {Steven G.} and Watson, {Stephen P.} and Nathalie Droin and William Vainchenker and Isabelle Plo and Hana Raslova and Najet Debili",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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Messaoudi, K, Ali, A, Ishaq, R, Palazzo, A, Sliwa, D, Bluteau, O, Souquère, S, Muller, D, Diop, KM, Rameau, P, Lapierre, V, Marolleau, JP, Matthias, P, Godin, I, Pierron, G, Thomas, SG, Watson, SP, Droin, N, Vainchenker, W, Plo, I, Raslova, H & Debili, N 2017, 'Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect', Nature Communications, VOL. 8, Numéro 1, 1786. https://doi.org/10.1038/s41467-017-01690-2

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T1 - Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect

AU - Messaoudi, Kahia

AU - Ali, Ashfaq

AU - Ishaq, Rameez

AU - Palazzo, Alberta

AU - Sliwa, Dominika

AU - Bluteau, Olivier

AU - Souquère, Sylvie

AU - Muller, Delphine

AU - Diop, Khadija M.

AU - Rameau, Philippe

AU - Lapierre, Valérie

AU - Marolleau, Jean Pierre

AU - Matthias, Patrick

AU - Godin, Isabelle

AU - Pierron, Gérard

AU - Thomas, Steven G.

AU - Watson, Stephen P.

AU - Droin, Nathalie

AU - Vainchenker, William

AU - Plo, Isabelle

AU - Raslova, Hana

AU - Debili, Najet

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

AB - Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

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DO - 10.1038/s41467-017-01690-2

M3 - Article

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AN - SCOPUS:85035348485

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

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