4.7 Article

Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes

期刊

BLOOD
卷 138, 期 24, 页码 2526-2538

出版社

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021011711

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资金

  1. National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases [R56 AI114593-01A1, R01 AI130152-01A1]
  2. NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant [R01 AR046000]
  3. Leukemia and Lymphoma Society Scholar Award [1349-18]
  4. Siteman Investment Program Research Development Award
  5. Hu and Zeng Predoctoral Scholarship
  6. NIH, NIAMS [P30 AR073752]
  7. NIH, National Cancer Institute Cancer Center Support Grant [P30CA91842]
  8. Institute of Clinical and Translational Sciences/Clinical and Translational Science Award from the National Center for Research Resources [UL1TR000448]
  9. NIH
  10. NIH Roadmap for Medical Research

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The study reveals the essential role of c-MYC in B cell proliferation and its involvement in tumor suppression through TFAP4, providing protection against the transformation of developing B cells.
The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in >10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYChigh B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC-driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.

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