Proapoptotic BID is required for myeloid homeostasis and tumor suppression

Sandra S. Zinkel, Christy C. Ong, David O. Ferguson, Hiromi Iwasaki, Koichi Akashi, Roderick T. Bronson, Jeffery L. Kutok, Frederick W. Alt, Stanley J. Korsmeyer

Research output: Contribution to journalArticlepeer-review

146 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)229-239
Number of pages11
JournalGenes and Development
Volume17
Issue number2
DOIs
Publication statusPublished - Jan 15 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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