Proapoptotic BID is required for myeloid homeostasis and tumor suppression.
The proper expansion and contraction of hematopoietic cells requires tight regulation of cell death. BID, a "BH3-only" molecule, amplifies death receptor signals connecting the extrinsic to intrinsic pathways by triggering the mitochondrial pathway of apoptosis. Bid-deficient mice, as they age, spontaneously develop a myeloproliferative disorder, which progresses from myeloid hyperplasia to a fatal, clonal malignancy closely resembling chronic myelomonocytic leukemia (CMML). Thus, an apoptotic defect can result in myeloid leukemogenesis. Premalignant Bid-/- myeloid precursor cells are resistant to death receptor-induced apoptosis. Furthermore, a competitive reconstitution assay demonstrates that Bid-deficient long-term repopulating cells give rise to expanded myelomonocytic cells in vivo. Surprisingly, a single BH3-only molecule operating in the extrinsic death receptor pathway proved essential in vivo for physiologic cell death required to maintain myeloid homeostasis. Moreover, progression to CMML indicates that an upstream BH3-only molecule, BID, is required to suppress tumorigenesis.
Zinkel
Sandra S
SS
Howard Hughes Medical Institute, Department of Pathology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Ong
Christy C
CC
Ferguson
David O
DO
Iwasaki
Hiromi
H
Akashi
Koichi
K
Bronson
Roderick T
RT
Kutok
Jeffery L
JL
Alt
Frederick W
FW
Korsmeyer
Stanley J
SJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002869:Chromosome Aberrations; D005260:Female; D006706:Homeostasis; D015477:Leukemia, Myelomonocytic, Chronic / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000502:physiology*; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins