Acute myeloid leukemia, subtype M2b (AML-M2b), was first identified in 1959 by Professor Chongli Yang at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences (CAMS), based on clinical features, bone marrow morphology, and cytology. He termed it “subacute granulocytic leukemia.” In 1973, Rowley and colleagues abroad reported the same leukemia subtype through cytogenetic methods. By the late 1990s, the team led by Professor Jianxiang Wang demonstrated that the chromosomal translocation t(8;21) leads to rearrangement of the AML1 and ETO genes, producing the AML1-ETO (RUNX1::RUNX1T1) fusion gene—the molecular hallmark of AML-M2b. This marker has since been widely applied in differential diagnosis and minimal residual disease (MRD) monitoring.Although patients with t(8;21) AML generally have a favorable prognosis, 30%–40% still relapse, and post-relapse outcomes are typically poor, with limited therapeutic options and short survival. Over the past decade, Professors Wang and Qiu’s team has published a series of important studies in Cancer Research, Blood Cancer Journal, and Experimental Hematology & Oncology (EHO) in 2024, describing transcriptional heterogeneity for early risk stratification, identifying abnormal fatty acid metabolism in leukemogenesis, and highlighting the immune microenvironment as a potential monitoring target.
Most recently, their group has achieved further breakthroughs at both the transcriptomic and genomic levels, identifying novel pathogenic drivers and therapeutic targets.
Discovery 1: Single-Cell Analysis Reveals Leukemia Stem Cell Heterogeneity and Identifies IKZF2 as a Novel Target
Earlier work from the Wang/Qiu team showed that patients with t(8;21) AML exhibit marked heterogeneity in gene expression and co-mutation patterns, influencing prognosis [¹]. Advances in single-cell technologies now allow deeper resolution of this heterogeneity.
In their latest study, the researchers performed single-cell transcriptomic sequencing of leukemic cells from five t(8;21) AML patients, mapping cellular diversity. They identified a critical hematopoietic stem cell–like (HSC-like) subpopulation characterized by pronounced differentiation arrest, a quiescent state, and enhanced stemness. Importantly, the proportion of this HSC-like subpopulation correlated strongly with adverse clinical outcomes. Its gene expression profile also corresponded closely with previously reported transcriptional subtypes.
Through predictive modeling and experimental validation, IKZF2 was identified as the key regulator of this HSC-like population. IKZF2 was significantly enriched in more stem-like and quiescent cell subsets, with expression levels markedly higher in t(8;21) AML compared with other AML subtypes. Mechanistically, AML1-ETO fusion protein and associated epigenetic remodeling uniquely regulate IKZF2 expression, reflecting the distinct biology of t(8;21) AML.
Functional experiments confirmed that IKZF2 is essential for AML1-ETO–driven accumulation of abnormal hematopoietic stem cells and differentiation blockade. These findings position IKZF2 as a promising therapeutic target for eradicating leukemia stem cells in t(8;21) AML.
This study was published in August 2025 in the British Journal of Haematology under the title: “Single-cell transcriptome profiling reveals blast cell heterogeneity and identifies novel therapeutic target IKZF2 in t(8;21) acute myeloid leukemia.” Professors Jianxiang Wang and Shaowei Qiu served as co-corresponding authors. Dr. Yu Liu (now a resident physician at CAMS), Dr. Wenbing Liu (postdoctoral fellow), and Dr. Yihan Mei (now a resident physician at Sichuan Academy of Medical Sciences · Sichuan Provincial People’s Hospital) were co–first authors.
Discovery 2: CCND2 Mutation as a Critical “Second Hit” and mTOR Pathway as a Therapeutic Vulnerability
In earlier work, the group established a conditional, inducible AML1-ETO mouse model, which demonstrated abnormal accumulation of hematopoietic stem cells and differentiation arrest upon AML1-ETO induction [²]. However, AML1-ETO alone proved insufficient to drive full leukemic transformation, necessitating additional “second-hit” mutations.
While co-mutations in KIT, NRAS, and FLT3-ITD are well characterized, other potential cooperating mutations remain less understood. The team turned their attention to CCND2, a key cell cycle regulator. Mutations—especially near the conserved Thr280 residue [³]—stabilize CCND2 by preventing proteasomal degradation, leading to abnormal accumulation.
Though sporadic reports had described CCND2 mutations in t(8;21) AML, their functional role as bona fide second hits had not been proven. To address this, the researchers generated mice co-expressing AML1-ETO and mutant CCND2, which successfully developed leukemia. This confirmed CCND2 mutation as a functional driver of leukemogenesis in the t(8;21) setting.
Transcriptomic profiling revealed that mTOR signaling was significantly enriched in AML1-ETO + CCND2 mice compared with AML1-ETO alone. Strikingly, treatment with the mTOR inhibitor everolimus prolonged survival in these leukemic mice, providing a preclinical rationale for therapeutic targeting.
This study, published in June 2025 in the Journal of Leukocyte Biology, was titled: “AML1-ETO and CCND2 overexpression cooperate to drive acute myeloid leukemia initiation and progression.” Professors Jianxiang Wang, Shaowei Qiu, and Min Wang served as co-corresponding authors. Dr. Junli Mou (now a resident physician at the First Affiliated Hospital of Chongqing Medical University) and doctoral candidate Qianqian Huang were co–first authors.
Funding Support
These studies were supported by the National Key R&D Program of China, National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Tianjin Natural Science Foundation, and the Clinical Research Fund of the National Clinical Research Center for Hematologic Diseases.
About the Lead Investigators
- Professor Jianxiang Wang
- Chief Clinical Expert, Institute of Hematology & Blood Diseases Hospital, CAMS
- Director, National Clinical Research Center for Hematologic Diseases
- Professor, Chief Physician, Doctoral Supervisor
- Tenured Professor, Peking Union Medical College
- National “Hundred-Thousand-Ten Thousand Talents Project” awardee
- Former Chairman, 10th Hematology Branch of the Chinese Medical Association
- Vice President, Internal Medicine Branch and Hematology Branch of the Chinese Medical Doctor Association
- Recipient of multiple national and municipal honors, including Tianjin’s “Top Ten Physicians” and “China Good Doctor.” Professor Wang has long been engaged in both clinical practice and basic research in hematology, with particular expertise in leukemia and hematologic malignancies.
Professor Shaowei Qiu
- Director, Leukemia Diagnosis and Treatment Center, CAMS
- MD, Peking Union Medical College; Visiting Scholar, University of Alabama at Birmingham
- Master’s Supervisor, Peking Union Medical College
- Recognized as an Outstanding Young Talent in Tianjin Science & Technology
- Published in leading journals including Blood (2023), Leukemia (2022, 2024), Cancer Research (2024), Journal of Clinical Investigation (2019), Cancer Communications (2023), and Blood Cancer Journal (2024)
- Research focus: mechanisms of leukemogenesis, therapy resistance, and immunotherapy in acute leukemia
- Committee member of several national and municipal hematology and oncology associations
- PI of multiple national and regional research grants
