AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model.
Activation-induced cytidine deaminase (AID) diversifies immunoglobulin through somatic hypermutation (SHM) and class-switch recombination (CSR). AID-transgenic mice develop T-lymphoma, indicating that constitutive expression of AID leads to tumorigenesis. Here, we transplanted mouse bone marrow cells transduced with AID. Twenty-four of the 32 recipient mice developed T-lymphoma 2-4 months after the transplantation. Surprisingly, unlike AID-transgenic mice, seven recipients developed B-leukemia/lymphoma with longer latencies. None of the mice suffered from myeloid leukemia. When we used nude mice as recipients, they developed only B-leukemia/lymphoma, presumably due to lack of thymus. Analysis of AID mutants suggested that an intact form with SHM activity is required for maximum ability of AID to induce lymphoma. Except for a K-ras active mutant in one case, specific mutations could not be identified in T-lymphoma; however, Notch1 was constitutively activated in most cases. Importantly, truncations of Ebf1 or Pax5 were observed in B-leukemia/lymphoma. In conclusion, this is the first report on the potential of AID overexpression to promote B-cell lymphomagenesis in a mouse model. Aberrant expression of AID in bone marrow cells induced leukemia/lymphoma in a cell-lineage-dependent manner, mainly through its function as a mutator.
Komeno
Y
Y
Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
Kitaura
J
J
Watanabe-Okochi
N
N
Kato
N
N
Oki
T
T
Nakahara
F
F
Harada
Y
Y
Harada
H
H
Shinkura
R
R
Nagaoka
H
H
Hayashi
Y
Y
Honjo
T
T
Kitamura
T
T
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D003564:Cytidine Deaminase / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016399:Lymphoma, T-Cell / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D012333:RNA, Messenger; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase