2. Academic Validation
  3. Mutant NPM1-regulated estrogen signaling promotes leukemia cell survival by upregulating HGF and represents a therapeutic vulnerability

Mutant NPM1-regulated estrogen signaling promotes leukemia cell survival by upregulating HGF and represents a therapeutic vulnerability

  • Biochem Pharmacol. 2026 May:247:117796. doi: 10.1016/j.bcp.2026.117796.
Jing Yang 1,  Jun Ren 1,  Tinglu Tao 2,  Meixi Peng 3,  Wen Zhao 1,  Qiaoling Xiao 1,  Nan Wu 1,  Xinyi Chen 1,  Zihao Yuan 1,  Yi Zu 1,  Wei Cheng 4,  Ling Zhang 5
Affiliations

Affiliations

  • 1 Department of Oncology, The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 2 Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing 400037, China.
  • 3 Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
  • 4 Department of Oncology, The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
  • 5 Department of Oncology, The Beibei Affiliated Hospital of Chongqing Medical University, The Ninth People's Hospital of Chongqing, Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
PMID: 41679667 DOI: 10.1016/j.bcp.2026.117796
Abstract

Acute myeloid leukemia (AML) with mutated nucleophosmin 1 (NPM1) presents therapeutic challenge and exhibits a striking female predominance in clinical. However, the contribution of gender-specific factors, such as sex Hormones to the pathogenesis and therapeutic implications in NPM1-mutated AML remains elusive. In the present study, we found that NPM1-mutated AML showed female bias, particularly among the young, pre-menopausal age (20-49 years) group, and that female exhibited inferior overall survival compared to males. Subsequently, 17β-estradiol (E2), the primary circulating estrogen in pre-menopausal females, was shown to facilitate the proliferation of NPM1-mutated leukemia cells. Importantly, ovariectomy (OVX) alleviated the leukemia burden, while reintroduction of exogenous E2 accelerated disease progression in leukemia mouse models. Mechanistically, leukemia cells exhibited an Estrogen receptor α (ERα)-dominant/ERβ-low expression signature, which was maintained through NPM1 mutant-induced ubiquitination-dependent degradation of ERβ. The diminished ERβ level allowed ERα to act as the primary responder of E2, evidenced by the nuclear translocation of ERα following E2 treatment. Transcriptomic analysis identified hepatocyte growth factor (HGF) as the potential target of E2 signaling, and E2-mediated ERα activation transcriptionally upregulated HGF, thus promoting leukemia cell proliferation. Therapeutically, blockade of the E2/ER pathway using selective ER degrader fulvestrant inhibited the growth of NPM1-mutated AML cells, and its combination with chemotherapy drug cytarabine induced synergistic anti-leukemia effects in vitro and in vivo. Collectively, these data demonstrated the oncogenic role of E2/ERα signaling in NPM1-mutated leukemia and suggested that targeting E2/ERα signaling combined with standard chemotherapy may represent a promising regimen for female patients.

Keywords

17β-estradiol; Acute myeloid leukemia; Estrogen receptor; HGF; Nucleophosmin1.

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