The Co-receptor Neuropilin-1 Enhances Proliferation in Inv(16) Acute Myeloid Leukemia Via VEGF Signaling.

Details

• Alternative Title:
  Leukemia, 2025, v. 39, no. 2: The Co-receptor Neuropilin-1 Enhances Proliferation in Inv(16) Acute Myeloid Leukemia Via VEGF Signaling.
• Journal Article:
  Leukemia
• Personal Author:
  Hegde, Mahesh ; Ahmad, Mohd H. ; Lazaro, Roger Mulet ; Sugita, Mayumi ; Li, Rui ; Hu, Kai ; Gebhard, Claudia ; Guzman, Monica L. ; Bushweller, John H. ; Zhu, Lihua J. ; Brehm, Michael ; Wolfe, Scot A. ; Delwel, Ruud ; Castilla, Lucio H.
• Description:
  Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion oncoprotein CBFβ::MYH11 regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBFβ::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBFβ::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.
• Content Notes:
  Author manuscript
• Subjects:
  • Neuropilin-1
  • Leukemia, Myeloid, Acute
  • Humans
  • Cell Proliferation
  • Animals
  • Mice
  • Signal Transduction
  • Vascular Endothelial Growth Factor A
  • Chromosome Inversion
  • Oncogene Proteins, Fusion
  More +
• Source:
  Leukemia, 2025, v. 39, no. 2
• DOI:
  https://doi.org/10.1038/s41375-024-02471-9
• ISSN:
  0887-6924 ; 1476-5551
• Pubmed ID:
  39572712
• Pubmed Central ID:
  PMC12133020
• Document Type:
  Text
• Funding:
  R01CA204979/U.S. Department of Health & Human Services ; National Institutes of Health (NIH)/ ; S10 OD028576/CD/ODCDC CDC HHSUnited States/ ; R01CA234478/U.S. Department of Health & Human Services ; National Institutes of Health (NIH)/ ; R01 CA234478/CA/NCI NIH HHSUnited States/ ; R24 OD036199/OD/NIH HHSUnited States/ ; S10 OD028576/OD/NIH HHSUnited States/ ; R01 CA204979/CA/NCI NIH HHSUnited States/
• Genre:
  Journal Article
• Pages in Document:
  360-370 (25 pdf pages)
• Volume:
  39
• Issue:
  2
• Download URL:
  https://stacks.cdc.gov/view/cdc/261911/cdc_261911_DS1.pdf
• File Type:
  [PDF - 2.58 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:ad93e38deefdef61281fcda037709f6e573cc80952deb4535a9613589f520cf913ef336ff67c3fc73d8480cb28c9d72dffb23af761a76e72b1a5abe2bad536b1