Clonally expanding thymocytes having lineage capability in gamma-ray-induced mouse atrophic thymus.
OBJECTIVE
To characterize, in the setting of gamma-ray-induced atrophic thymus, probable prelymphoma cells showing clonal growth and changes in signaling, including DNA damage checkpoint.


METHODS
A total of 111 and 45 mouse atrophic thymuses at 40 and 80 days, respectively, after gamma-irradiation were analyzed with polymerase chain reaction for D-J rearrangements at the TCRbeta locus, flow cytometry for cell cycle, and Western blotting for the activation of DNA damage checkpoints.


RESULTS
Limited D-J rearrangement patterns distinct from normal thymus were detected at high frequencies (43 of 111 for 40-day thymus and 21 of 45 for 80-day thymus). Those clonally expanded thymocytes mostly consisted of CD4(+)CD8(+) double-positive cells, indicating the retention of lineage capability. They exhibited pausing at a late G1 phase of cell cycle progression but did not show the activation of DNA damage checkpoints such as gammaH2AX, Chk1/2, or p53. Of interest is that 17 of the 52 thymuses showing normal D-J rearrangement patterns at 40 days after irradiation showed allelic loss at the Bcl11b tumor suppressor locus, also indicating clonal expansion.


CONCLUSIONS
The thymocytes of clonal growth detected resemble human chronic myeloid leukemia in possessing self-renewal and lineage capability, and therefore they can be a candidate of the lymphoma-initiating cells.
Yamamoto
Takashi
T
Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, Japan.
Morita
Shin-ichi
S
Go
Rieka
R
Obata
Miki
M
Katsuragi
Yoshinori
Y
Fujita
Yukari
Y
Maeda
Yoshitaka
Y
Yokoyama
Minesuke
M
Aoyagi
Yutaka
Y
Ichikawa
Hitoshi
H
Mishima
Yukio
Y
Kominami
Ryo
R
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001284:Atrophy / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000528:radiation effects; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000528:radiation effects; D004249:DNA Damage; D005720:Gamma Rays; D017353:Gene Deletion; D015329:Gene Rearrangement, T-Lymphocyte; D006657:Histones / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology*; D039942:Neuropilin-1 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013950:Thymus Gland / Q000473:pathology / Q000528:radiation effects*; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006657:Histones; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D039942:Neuropilin-1