Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation.

Abstract

Megakaryocyte morphogenesis employs a "hypertrophy-like" developmental program that is dependent on P-TEFb kinase activation and cytoskeletal remodeling. P-TEFb activation classically occurs by a feedback-regulated process of signal-induced, reversible release of active Cdk9-cyclin T modules from large, inactive 7SK small nuclear ribonucleoprotein particle (snRNP) complexes. Here, we have identified an alternative pathway of irreversible P-TEFb activation in megakaryopoiesis that is mediated by dissolution of the 7SK snRNP complex. In this pathway, calpain 2 cleavage of the core 7SK snRNP component MePCE promoted P-TEFb release and consequent upregulation of a cohort of cytoskeleton remodeling factors, including α-actinin-1. In a subset of human megakaryocytic leukemias, the transcription factor GATA1 undergoes truncating mutation (GATA1s). Here, we linked the GATA1s mutation to defects in megakaryocytic upregulation of calpain 2 and of P-TEFb-dependent cytoskeletal remodeling factors. Restoring calpain 2 expression in GATA1s mutant megakaryocytes rescued normal development, implicating this morphogenetic pathway as a target in human leukemogenesis.

• Authors: Kamaleldin E Elagib, Jeremy D Rubinstein, Lorrie L Delehanty, Valerie S Ngoh, Peter A Greer, Shuran Li, Jae K Lee, Zhe Li, Stuart H Orkin, Ivailo S Mihaylov, Adam N Goldfarb
• Journal: Developmental cell (Dev Cell) Vol. 27 Issue 6 Pg. 607-20 (Dec 23 2013) ISSN: 1878-1551 [Electronic] United States
• PMID: 24369834 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• GATA1 Transcription Factor
• RNA, Messenger
• Ribonucleoproteins, Small Nuclear
• Actinin
• Positive Transcriptional Elongation Factor B
• Calpain
• Capn1 protein, mouse

Topics

• Actinin (genetics, metabolism)
• Animals
• Blotting, Western
• Calpain (physiology)
• Cell Differentiation
• Cell Nucleus (genetics, metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism, pathology)
• Cells, Cultured
• Cytoskeleton (metabolism)
• Flow Cytometry
• GATA1 Transcription Factor (genetics, metabolism)
• Humans
• Immunoprecipitation
• Leukemia (metabolism, pathology)
• Megakaryocytes (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Morphogenesis
• Mutation (genetics)
• Positive Transcriptional Elongation Factor B (genetics, metabolism)
• Protein Binding
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Ribonucleoproteins, Small Nuclear (genetics, metabolism)
• Transcription, Genetic