title: Cell of origin in radiation-induced premalignant thymocytes with differentiation capability in mice conditionally losing one Bcl11b allele.
abstract: Bcl11b is a haploinsufficient tumor suppressor, mutations or deletion of which has been found in 10-16% of T-cell acute lymphoblastic leukemias. Bcl11b(KO) (/+) heterozygous mice are susceptible to thymic lymphomas, a model of T-cell acute lymphoblastic leukemia, when γ-irradiated, and irradiated Bcl11b(KO) (/+) mice generate clonally expanding or premalignant thymocytes before thymic lymphoma development. Cells with radiation-induced DNA damages are assumed to be the cells of origin in tumors; however, which thymocyte is the tumor cell origin remains obscure. In this study we generated Bcl11b(flox/+) ;Lck-Cre and Bcl11b(flox/+) ;CD4-Cre mice; in the former, loss of one Bcl11b allele occurs in thymocytes at the immature CD4(-) CD8(-) stage, whereas in the latter the loss occurs in the more differentiated CD4(+) CD8(+) double-positive stage. We examined clonal expansion and differentiation of thymocytes in mice 60 days after 3 Gy γ-irradiation. Half (9/18) of the thymuses in the Bcl11b(flox/+) ;Lck-Cre group showed limited rearrangement sites at the T-cell receptor-β (TCRβ) locus, indicating clonal cell expansion, but none in the Bcl11b(flox/+) ;CD4-Cre group did. This indicates that the origin of the premalignant thymocytes is not in double-positive cells but immature thymocytes. Interestingly, those premalignant thymocytes underwent rearrangement at various different sites of the TCRα locus and the majority showed a higher expression of TCRβ and CD8, and more differentiated phenotypes. This suggests the existence of a subpopulation of immature cells within the premalignant cells that is capable of proliferating and continuously producing differentiated thymocytes.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Rieka
authors.initials: R
authors.lastname: Go
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirose
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsuragi
authors.forename: Miki
authors.initials: M
authors.lastname: Obata
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mishima
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.forename: Ryo
authors.initials: R
authors.lastname: Kominami
mesh_terms: D000483:Alleles; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D002454:Cell Differentiation / Q000235:genetics / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D060168:Thymocytes / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects*; D013953:Thymus Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C511143:Bcl11b protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins