title: Proteasome function is required for platelet production.
abstract: The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets. Consistent with decreased proplatelet formation, mice lacking PSMC1 in platelets (Psmc1(fl/fl) Pf4-Cre mice) exhibited severe thrombocytopenia and died shortly after birth. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA, rather than NF-κB, as has been previously suggested. Inhibition of RhoA or its downstream target, Rho-associated protein kinase (ROCK), restored megakaryocyte proplatelet formation in the setting of proteasome inhibition in vitro. Similarly, fasudil, a ROCK inhibitor used clinically to treat cerebral vasospasm, restored platelet counts in adult mice that were made thrombocytopenic by tamoxifen-induced suppression of proteasome activity in megakaryocytes and platelets (Psmc1(fl/fl) Pdgf-Cre-ER mice). These results indicate that proteasome function is critical for thrombopoiesis, and suggest inhibition of RhoA signaling as a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.
authors: Dallas S
authors: DS
authors: Shi
authors: Matthew C P
authors: MC
authors: Smith
authors: Robert A
authors: RA
authors: Campbell
authors: Patrick W
authors: PW
authors: Zimmerman
authors: Zechariah B
authors: ZB
authors: Franks
authors: Bjorn F
authors: BF
authors: Kraemer
authors: Kellie R
authors: KR
authors: Machlus
authors: Jing
authors: J
authors: Ling
authors: Patrick
authors: P
authors: Kamba
authors: Hansjörg
authors: H
authors: Schwertz
authors: Jesse W
authors: JW
authors: Rowley
authors: Rodney R
authors: RR
authors: Miles
authors: Zhi-Jian
authors: ZJ
authors: Liu
authors: Martha
authors: M
authors: Sola-Visner
authors: Joseph E
authors: JE
authors: Italiano
authors: Hilary
authors: H
authors: Christensen
authors: Walter H A
authors: WH
authors: Kahr
authors: Dean Y
authors: DY
authors: Li
authors: Andrew S
authors: AS
authors: Weyrich
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010978:Platelet Factor 4 / Q000502:physiology; D040201:Platelet Membrane Glycoprotein IIb / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D034061:Thrombopoiesis / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000502:physiology; D020742:rhoA GTP-Binding Protein
chemical_list: D016328:NF-kappa B; D040201:Platelet Membrane Glycoprotein IIb; D061988:Proteasome Inhibitors; D010978:Platelet Factor 4; D046988:Proteasome Endopeptidase Complex; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein