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Bad-deficient mice develop diffuse large B cell lymphoma
Ann M Ranger1, Jiping Zha, Hisashi Harada
1Howard Hughes Medical Institute and Department of Pathology, Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Abstract:
The proapoptotic activity of the "BH3-only" molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins proved viable, and most cell types appeared to develop normally. BAD did not exclusively account for cell death after withdrawal of survival factors, but it was an intermediate for epidermal growth factor- or insulin-like growth factor I-countered apoptosis, consistent with a "sensitizing" BH3-only molecule. Lymphocytes developed normally with no premalignant hyperplasia, but they displayed subtle abnormalities in proliferation and IgG production. Despite the minimal phenotype, Bad-deficient mice progressed, with aging, to diffuse large B cell lymphoma of germinal center origin. Exposure of Bad-null mice to sublethal gamma-irradiation resulted in an increased incidence of pre-T cell and pro-/pre-B cell lymphoblastic leukemia/lymphoma. Thus, proapoptotic BAD suppresses tumorigenesis in the lymphocyte lineage.
Insights
The proapoptotic molecule BAD (Bcl-2-associated death promoter) suppresses lymphoma development in mice. Loss of BAD leads to increased cancer incidence, particularly in lymphocytes, highlighting its tumor-suppressive role.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The BH3-only protein BAD (Bcl-2-associated death promoter) regulates apoptosis.
- Survival factor signaling differentially controls BAD's proapoptotic activity.
Purpose of the Study:
- To investigate the in vivo role of BAD in apoptosis and tumorigenesis.
- To determine if BAD is essential for apoptosis induced by survival factor withdrawal.
Main Methods:
- Generation and analysis of Bad-deficient mice (lacking BAD long and BAD short isoforms).
- Assessment of cell development, apoptosis, lymphocyte function, and tumor incidence in Bad-null mice.
- Evaluation of apoptosis in response to epidermal growth factor (EGF) or insulin-like growth factor I (IGF-I) withdrawal.
Main Results:
- Bad-deficient mice were viable with largely normal cell development.
- BAD acts as a sensitizing BH3-only molecule, mediating apoptosis after EGF/IGF-I withdrawal.
- Lymphocytes showed subtle defects in proliferation and IgG production but no premalignant hyperplasia.
- Aging Bad-null mice developed diffuse large B cell lymphoma.
- Gamma-irradiation increased lymphoblastic leukemia/lymphoma incidence in Bad-null mice.
Conclusions:
- Proapoptotic BAD functions as a tumor suppressor in the lymphocyte lineage.
- BAD is crucial for mediating apoptosis in response to specific survival factor withdrawal.
- Loss of BAD predisposes to lymphomagenesis, particularly under stress conditions like irradiation.
