The BCL-2 family constitutes a crucial checkpoint in the cell death pathway. BID is a member of the """"""""BH3-only"""""""" subset of this family and requires its conserved BH3 domain for its pro-apoptotic function. BID plays an important role in the apoptotic pathway downstream of death receptors such as TNF RI and Fas (1-7). Cleavage by caspase 8 and myristoylation serves as an activating molecular switch which facilitates targeting of BID to mitochondria(8) where it activates multidomain proapoptotic members such as BAK or BAX, mediating the release of cytochrome c and activation of downstream effector caspases (9). Bid-deficient mice are viable and develop normally, however hepatocytes are resistant to anti-Fas-induced hepatocellular apoptosis(10). BID thus plays an important role in mediating a mitochondrial amplification loop downstream of death receptors in certain cell types such as hepatocytes. Yet many other cells, including activated lymphocytes, are killed by Fas in in vitro assays, directly activating downstream effector caspases for the promotion of apoptosis(11). However, as Bid-deficient mice age or are challenged by chronic viral infection, we've discovered that BID is also singularly required in vivo to maintain homeostasis in so-called Type I cells including B cells, T cells, and the myelomonocytic lineage(12). As Bid-deficient mice age, they display a myeloid hyperplasia and then progress to Chronic myelomonocytic leukemia at high incidence. The founding family member, BCL-2 was cloned at the t(14:18) chromosomal breakpoint, the molecular hallmark of follicular B cell lymphoma establishing a new class of oncogenes in which the aberration is in cell death rather than proliferation(13-15). Transgenic mice over expressing BCL-2 in myeloid cells develop a myeloproliferative disorder, and when crossed with mice harboring a mutation in the Fas receptor, progress to AML, implicating a synergistic role for the Fas pathway and Bcl-2 in tumor suppression of the myeloid lineage(16). The role of pro-apoptotic members in normal myeloid homeostasis has not been well characterized. We propose that BID is the critical proapoptotic intermediate that mediates death receptor signaling in the myeloid lineage and that its inactivations promotes myeloid leukemogenesis by prolonging the life of these vulnerable cells, allowing accumulation of additional mutations. This single """"""""BH3-only"""""""" protein therefore has potential to play a potent role in maintenance of normal myeloid homeostasis as well as tumor suppression. In this context, I propose the following specific aims: 1. Define the role of Bid in myeloid homeostasis. 2. Define the role of Bid in myeloid leukemogenesis. 3. Identify the secondary genetic changes that cooperate with loss of Bid in leukemogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA098394-03
Application #
7121955
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2004-09-30
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$130,329
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zinkel, S S; Yin, X M; Gross, A (2013) Rejuvenating Bi(d)ology. Oncogene 32:3213-3219
Biswas, S; Shi, Q; Wernick, A et al. (2013) The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice. Cell Death Differ 20:869-77
Liu, Y; Bertram, C C; Shi, Q et al. (2011) Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ 18:841-52
Zinkel, Sandra S; Hurov, Kristen E; Ong, Christy et al. (2005) A role for proapoptotic BID in the DNA-damage response. Cell 122:579-91