title: Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia.
abstract: In beta-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by beta-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle-promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X(L). The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.
authors.affiliation: Department of Pediatric Hematology-Oncology, Children's Cancer and Blood Foundation Laboratories, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Ilaria V
authors.initials: IV
authors.lastname: Libani
authors.forename: Ella C
authors.initials: EC
authors.lastname: Guy
authors.forename: Luca
authors.initials: L
authors.lastname: Melchiori
authors.forename: Raffaella
authors.initials: R
authors.lastname: Schiro
authors.forename: Pedro
authors.initials: P
authors.lastname: Ramos
authors.forename: Laura
authors.initials: L
authors.lastname: Breda
authors.forename: Thomas
authors.initials: T
authors.lastname: Scholzen
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: YiFang
authors.initials: Y
authors.lastname: Liu
authors.forename: Margrit
authors.initials: M
authors.lastname: Kernbach
authors.forename: Bettina
authors.initials: B
authors.lastname: Baron-Lühr
authors.forename: Matteo
authors.initials: M
authors.lastname: Porotto
authors.forename: Maria
authors.initials: M
authors.lastname: de Sousa
authors.forename: Eliezer A
authors.initials: EA
authors.lastname: Rachmilewitz
authors.forename: John D
authors.initials: JD
authors.lastname: Hood
authors.forename: M Domenica
authors.initials: MD
authors.lastname: Cappellini
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Giardina
authors.forename: Robert W
authors.initials: RW
authors.lastname: Grady
authors.forename: Johannes
authors.initials: J
authors.lastname: Gerdes
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D041905:Erythroid Cells / Q000473:pathology*; D004920:Erythropoiesis; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D013154:Spleen / Q000473:pathology; D017086:beta-Thalassemia / Q000097:blood*
chemical_list: C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D018844:Cyclin-Dependent Kinases