PTP4A2 Promotes Leukemogenesis through Inhibiting the p53 Tumor Suppressor Signaling Pathway in Leukemia-initiating Cells
Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is sustained by leukemia-initiating cells (LICs). While PTP4A2 phosphatase, as known as PRL2, is highly expressed in AML, the mechanisms by which PTP4A2 promotes leukemogenesis are largely unexplored. In this study, we demonstrate that PTP4A2 promotes AML by inhibiting the p53 tumor suppressor pathway in LICs. Using KMT2A-MLLT3-driven AML as a model, we found that PTP4A2 deficiency activates p53 and induces LIC apoptosis and senescence, thereby extending the survival of recipient mice repopulated with Ptp4a2-/- LICs. Mechanistically, PTP4A2 directly interacts with p53 and dephosphorylates it at serine 392, decreasing p53 stability and activity to enhance LIC proliferation and survival. Collectively, our findings identify p53 as a potential PTP4A2 substrate in leukemia cells and uncover a novel mechanism by which PTP4A2 enhances LIC maintenance.
Authors
- James C. Mulloy (ORCID: https://orcid.org/0009-0006-6265-938X)
- Z Zhang (ORCID: https://orcid.org/0000-0001-5527-7910)
- Yasmin Abaza (ORCID: https://orcid.org/0000-0002-9156-7912)
- Jayme Ogino (ORCID: https://orcid.org/0000-0003-1180-1666)
- Jessica K. Altman (ORCID: https://orcid.org/0000-0003-1987-1896)
- Shiyu Xiao (ORCID: https://orcid.org/0000-0002-1175-6845)
- Hongxia Chen (ORCID: https://orcid.org/0000-0003-1415-0950)
- Harris Perlman (ORCID: https://orcid.org/0000-0003-4174-608X)
- Madina Jh. SUKHANOVA (ORCID: https://orcid.org/0000-0002-1843-7038)
- Moiez Ali (ORCID: https://orcid.org/0000-0003-4516-612X)
- Yuzhi Jia (ORCID: https://orcid.org/0000-0002-6534-0036)
- Yali Dou (ORCID: https://orcid.org/0000-0002-4040-1429)
- Sergio Barajas
- Y Liu
- Christopher Borchers (ORCID: https://orcid.org/0000-0002-2887-2017)
- Elizabeth A. Eklund (ORCID: https://orcid.org/0000-0002-8578-6027)
- Lindsey D. Mayo (ORCID: https://orcid.org/0000-0002-5997-5166)
- Sasidhar Vemula
- Mohammed Abdullahel Amin
- Sophia Veranga
- Magdalena Sotelo
- Yuxia Yang
- Christine R. Zhang
- Loretta Li
- Irum Khan
- Wenjie Cai
- Tiffany M Mays
- Leonidas C. Platanias
- Sydney G Eggleston
- Yunpeng Bai
- Michihiro Kopbayashi
- Sophie Kimiko Kuriyama Hu (ORCID: https://orcid.org/0000-0003-0207-3388)
- Chonghua Yao
Institutions
- Northwestern University (US)
- University of Southern California (US)
- Cincinnati Children's Hospital Medical Center (US)
- Lurie Children's Hospital (US)
- Children's Hospital of Los Angeles (US)
- Western Michigan University (US)
- Chongqing University (CN)
- Purdue University West Lafayette (US)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shuguang Hospital (CN)
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1182/bloodadvances.2025018908
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 0.00