CD5+CD23+ leukemic cell populations in TCL1 transgenic mice show significantly increased proliferation and Akt phosphorylation.
B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia. Deregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. We recently reported that levels of TCL1 expression in B-CLL are regulated by miR-29 and miR-181 that target 3' UTR of TCL1. To determine whether treatment with microRNAs targeting TCL1 can inhibit B-CLL in mice, we generated TCL1 transgenic mice using a construct containing the 3' and 5' UTRs of TCL1 under B-cell-specific Emicro promoter (Emicro-TCL1FL). At the age of 16-20 months, these mice showed B-CLL-like disease. Immunophenotyping revealed accumulation of CD5+CD23+B220+ population in spleens and lymph nodes. Our results show that CD5+CD23+ B-cell populations from Emicro-TCL1FL mice actively proliferate and show significantly increased levels of phospho-Akt. Emicro-TCL1FL mice showed immunological abnormalities similar to human B-CLL, including hypoimmunoglobulinemia, abnormal levels of cytokines and impaired immune response. These findings revealed biochemical and immunological similarities between Tcl1-driven B-CLL in mice and human B-CLL.
Efanov
A
A
Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program and Comprehensive Cancer Center, OSU School of Medicine, Ohio State University, Columbus, OH 43210, USA.
Zanesi
N
N
Nazaryan
N
N
Santanam
U
U
Palamarchuk
A
A
Croce
C M
CM
Pekarsky
Y
Y
D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D018956:CD5 Antigens / Q000378:metabolism*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism / Q000473:pathology
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D016207:Cytokines; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017455:Receptors, IgE; C090851:TCL1A protein, human; D051057:Proto-Oncogene Proteins c-akt