The role of apoptosis in megakaryocytes and platelets

Research output: Contribution to journalReview ArticleOtherpeer-review

58 Citations (Scopus)

Abstract

The role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT-263 (navitoclax, which targets BCL2, BCL-XL [BCL2L1] and BCL2L2) and ABT-199 (a BCL2-specific agent) are showing great promise in early stage clinical trials. However, the major dose-limiting toxicity of navitoclax has proven to be thrombocytopenia, an on-target effect of inhibiting BCL-XL. It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL-XL is the critical pro-survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte.

Original languageEnglish
Pages (from-to)217-226
Number of pages10
JournalBritish Journal of Haematology
Volume165
Issue number2
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Apoptosis
  • BH3 mimetic
  • Megakaryocytes
  • Platelets
  • Thrombopoiesis

Cite this

@article{95c425c340ce4ad1ba17ec5fb69f0362,
title = "The role of apoptosis in megakaryocytes and platelets",
abstract = "The role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT-263 (navitoclax, which targets BCL2, BCL-XL [BCL2L1] and BCL2L2) and ABT-199 (a BCL2-specific agent) are showing great promise in early stage clinical trials. However, the major dose-limiting toxicity of navitoclax has proven to be thrombocytopenia, an on-target effect of inhibiting BCL-XL. It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL-XL is the critical pro-survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte.",
keywords = "Apoptosis, BH3 mimetic, Megakaryocytes, Platelets, Thrombopoiesis",
author = "Kile, {Benjamin T.}",
year = "2014",
doi = "10.1111/bjh.12757",
language = "English",
volume = "165",
pages = "217--226",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "John Wiley & Sons",
number = "2",

}

The role of apoptosis in megakaryocytes and platelets. / Kile, Benjamin T.

In: British Journal of Haematology, Vol. 165, No. 2, 2014, p. 217-226.

Research output: Contribution to journalReview ArticleOtherpeer-review

TY - JOUR

T1 - The role of apoptosis in megakaryocytes and platelets

AU - Kile, Benjamin T.

PY - 2014

Y1 - 2014

N2 - The role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT-263 (navitoclax, which targets BCL2, BCL-XL [BCL2L1] and BCL2L2) and ABT-199 (a BCL2-specific agent) are showing great promise in early stage clinical trials. However, the major dose-limiting toxicity of navitoclax has proven to be thrombocytopenia, an on-target effect of inhibiting BCL-XL. It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL-XL is the critical pro-survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte.

AB - The role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT-263 (navitoclax, which targets BCL2, BCL-XL [BCL2L1] and BCL2L2) and ABT-199 (a BCL2-specific agent) are showing great promise in early stage clinical trials. However, the major dose-limiting toxicity of navitoclax has proven to be thrombocytopenia, an on-target effect of inhibiting BCL-XL. It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL-XL is the critical pro-survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte.

KW - Apoptosis

KW - BH3 mimetic

KW - Megakaryocytes

KW - Platelets

KW - Thrombopoiesis

UR - http://www.scopus.com/inward/record.url?scp=84898058584&partnerID=8YFLogxK

U2 - 10.1111/bjh.12757

DO - 10.1111/bjh.12757

M3 - Review Article

VL - 165

SP - 217

EP - 226

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 2

ER -