AP2M1 Amplification Orchestrates Notch‐Mediated Chemoresistance in Hematopoietic Stem Cells of Acute Myeloid Leukemia Patients
Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by chemotherapy resistance, leading to poor patient outcomes. This study investigates the role of adaptor protein complex 2 subunit mu 1 (AP2M1) in hematopoiesis and drug response. Utilizing multimodal analyses on bone marrow samples from AML patients and healthy controls, zebrafish models, and human AML cell lines, it is identified that dysregulation of AP2M1 impairs hematopoietic stem and progenitor cell (HSPC) development, underscoring its critical role in hematopoiesis. AP2M1 expression distinctly differentiates normal from malignant cells, surpassing well-recognized cancer stem cell markers, ATP-binding cassette transporters, known for drug efflux and chemoresistance. Elevated AP2M1 levels in AML HSPCs correlate with poor clinical outcomes, as its overexpression reduces apoptosis, enhances stemness, and increases drug resistance. In vivo experiments reveal that AP2M1 directly modulates Notch1 expression, amplifying pro-tumorigenic effects through the Notch1 signaling pathway. These findings highlight the pivotal role of AP2M1 in AML pathogenesis, primarily through its regulation of NOTCH1 expression and signaling cascades. These findings unravel AP2M1 as a previously unrecognized factor in AML pathogenesis and suggest a treatment strategy for AML, focusing on the AP2M1-NOTCH1 axis.
Authors
- Sang Hoon Ahn (ORCID: https://orcid.org/0000-0002-3629-4624)
- Dong Min Lim (ORCID: https://orcid.org/0000-0003-0697-0211)
- Hee Young Ju (ORCID: https://orcid.org/0000-0001-6744-0412)
- Chang‐Kyu Oh (ORCID: https://orcid.org/0000-0003-2327-0006)
- Hansong Lee
- Ninib Baryawno (ORCID: https://orcid.org/0000-0001-6054-4163)
- Hye Jin Heo (ORCID: https://orcid.org/0000-0002-4929-798X)
- Kyungjae Myung
- Yun Hak Kim (ORCID: https://orcid.org/0000-0002-9796-8266)
- Hyunsoo Cho (ORCID: https://orcid.org/0000-0003-2651-6403)
- Tae Sik Goh (ORCID: https://orcid.org/0000-0003-1861-5647)
- Chae Rin Lee
- Keon Hee Yoo (ORCID: https://orcid.org/0000-0002-5980-7912)
- H. Kim
- Seong K. Mun (ORCID: https://orcid.org/0000-0001-9661-7918)
- Yeuni Yu (ORCID: https://orcid.org/0000-0002-7544-1711)
- Dokyoung Kim (ORCID: https://orcid.org/0000-0002-7756-3560)
- Eun Jung Kwon (ORCID: https://orcid.org/0000-0001-9290-5218)
- Ki Sun Jung
- Sun Young Lee (ORCID: https://orcid.org/0000-0001-8637-1248)
- Dongjun Lee (ORCID: https://orcid.org/0000-0001-6828-401X)
- Kihun Kim (ORCID: https://orcid.org/0000-0001-6445-6881)
- Eun Young Choi (ORCID: https://orcid.org/0000-0002-2441-3374)
- Eun Sun Kim (ORCID: https://orcid.org/0000-0003-1820-459X)
- Yujin Kwon (ORCID: https://orcid.org/0000-0002-7106-973X)
- Seung Eun Baek (ORCID: https://orcid.org/0009-0004-4649-1084)
- Su‐Yeon Cho (ORCID: https://orcid.org/0009-0004-9160-0227)
- Won Kyu Kim (ORCID: https://orcid.org/0000-0001-5531-9500)
- Eun Kyoung Kim
Institutions
- Yonsei University (KR)
- Samsung Medical Center (KR)
- Seoul National University Hospital (KR)
- Karolinska Institutet (SE)
- Kyung Hee University (KR)
- Institute for Basic Science (KR)
- Kyung Hee University Medical Center (KR)
- Pusan National University Hospital (KR)
- Pusan National University Yangsan Hospital (KR)
- Pusan National University (KR)
- Korea Institute of Science and Technology (KR)
- Korea University of Science and Technology (KR)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-10-13
- DOI
- https://doi.org/10.1002/advs.202514566
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00