Editor’s Note: The 30th Annual Congress of the European Hematology Association (EHA 2025) was held from June 12 to 15 in Milan, Italy, bringing together cutting-edge research and breakthroughs across the global hematology community. Among the highlights was an oral presentation (Abstract S170) by the team of Professor Xiaofan Zhu from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences. This study is the first to construct a single-cell atlas of pediatric NRAS-mutated myeloid malignancies, revealing mechanisms of lineage bias and identifying CDK6 as a potential therapeutic target—offering new hope for a mutation historically considered “undruggable.” Oncology Frontier – Hematology Frontier invited Prof. Zhu to discuss the key findings, translational prospects, and major developments in pediatric hematologic malignancies presented at EHA 2025.Oncology Frontier – Hematology Frontier: NRAS mutations are found across multiple myeloid malignancies but give rise to distinct disease phenotypes. Your study, using both patient-derived and mouse models, uncovers mechanisms of lineage bias. What key differences did you identify, particularly between JMML and MDS?
Prof. Xiaofan Zhu: NRAS mutations are indeed prevalent in various pediatric myeloid malignancies, including juvenile myelomonocytic leukemia (JMML) and myelodysplastic syndromes (MDS), but they display markedly different biological behavior and clinical manifestations. To explore how the same mutation can lead to distinct diseases, we conducted a systematic comparison using patient-derived single-cell omics data and functional mouse models.
We found that although both JMML and MDS harbor NRAS mutations, they arise from different progenitor cell subpopulations, leading to divergent differentiation trajectories. In JMML, mutated cells are broadly distributed across hematopoietic stem cells (HSCs) and multiple progenitors (GMPs, CLPs), displaying aggressive proliferative characteristics. In contrast, MDS-associated mutant cells are mainly concentrated at the lymphomyeloid progenitor (LMprog) stage, where we observed significant differentiation blockade and functional reprogramming.
Further integrative single-cell ATAC-seq and RNA-seq analysis revealed a dramatic increase in chromatin accessibility in LMprog cells in MDS. This coincided with the activation of key myeloid transcription factors such as RUNX1, CEBPA, and HIF1A, driving abnormal myeloid skewing and upregulation of proliferative regulators like CDK6. JMML, in contrast, lacked this level of epigenetic remodeling.
This is the first study to define, at single-cell resolution, the lineage-specific differentiation biases driven by NRAS mutations in distinct myeloid malignancies, providing valuable insight into the phenotypic diversity of NRAS-driven diseases.
Oncology Frontier – Hematology Frontier: Your team identified several potential targets, including FLT3 and CDK6. Which of these has the greatest translational promise? Have any moved into preclinical development or drug screening?
Prof. Xiaofan Zhu: After establishing the full single-cell landscape of NRAS-mutated pediatric myeloid malignancies, we identified several promising targets, with CDK6 standing out for its strong translational potential.
CDK6 is significantly upregulated in MDS patients and appears to be functionally essential for mutated cells. NRAS-driven MDS cells at the LMprog stage show a high dependency on CDK6 for maintaining their differentiation blockade and proliferative state. We validated this using the CDK6 inhibitor palbociclib in both in vitro and in vivo models. In patient-derived hematopoietic stem cells, NRAS-mutant mouse models, and MDS PDX models, we observed restored differentiation, increased apoptosis, and depletion of leukemia-initiating cells—strongly supporting CDK6 as a viable therapeutic target.
Comprehensive safety and efficacy assessments of palbociclib in mouse models have been completed, showing favorable results. The next phase will focus on screening combination strategies, including chemotherapy and immunotherapy, to identify synergistic treatment approaches.
Oncology Frontier – Hematology Frontier: NRAS has long been considered an “undruggable” target. Your study approaches it through lineage skewing and pathway dysregulation. How do you envision translating this research into precision therapy for high-risk pediatric myeloid malignancies?
Prof. Xiaofan Zhu: Indeed, the “undruggable” nature of NRAS has been a major obstacle. Our strategy was to circumvent the challenge of direct inhibition by targeting its downstream functional dependencies—particularly the role of CDK6 in enforcing myeloid skewing and differentiation arrest.
We plan to accelerate translation through three key pathways:
- Molecular subtyping based on single-cell profiling: This will support precise risk stratification and personalized treatment strategies for NRAS-mutant diseases.
- Development of CDK6-based combination therapies: We are currently conducting preclinical screening to evaluate synergy between CDK6 inhibitors and existing regimens, including low-dose chemotherapy, hypomethylating agents, and immunotherapies, with the goal of optimizing therapeutic efficacy.
- Initiation of early-phase clinical trials: We are actively preparing a clinical trial to evaluate the safety and preliminary efficacy of CDK6 inhibition in treatment-resistant pediatric MDS patients harboring NRAS mutations.
From “undruggable” to “precision-targetable,” we believe this functionally driven approach can open new avenues for treating high-risk NRAS-mutated pediatric myeloid malignancies.
Oncology Frontier – Hematology Frontier: Lastly, what are your impressions of attending EHA 2025 in person? Were there any other significant breakthroughs in pediatric hematologic malignancies that stood out to you?
Prof. Xiaofan Zhu: Attending EHA 2025 onsite was incredibly inspiring. The global academic community is clearly placing strong emphasis on pediatric hematology research. The conference atmosphere was vibrant, with extensive and meaningful academic exchange.
Several studies this year stood out as true breakthroughs:
- FLT3-ITD–mutant pediatric AML: A phase I/II trial of gilteritinib combined with chemotherapy showed promising activity and safety in relapsed/refractory cases, enabling some patients to proceed to hematopoietic stem cell transplantation—bringing new hope for this high-risk population.
- KMT2A-rearranged pediatric AML: Allogeneic HSCT combined with Menin inhibitors achieved over 80% 3-year overall survival, particularly when performed post-complete remission. This reinforces HSCT’s central role in KMT2A-r AML.
- CALGB 10403 in AYA ALL: The 10-year follow-up data of adolescents and young adults (AYA) treated with this protocol showed overall survival exceeding 50%. MRD-negative patients had particularly strong outcomes, with both DFS and OS above 80%. These findings highlight the importance of early MRD clearance and completing maintenance therapy.
Altogether, these studies not only provide new clinical evidence but also offer exciting directions for the future of pediatric hematologic oncology.
Acknowledgments Special thanks to Dr. Suyu Zong and the entire team at the Center for Pediatric Hematology and Oncology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, for their contributions to this study. We gratefully acknowledge the support of Prof. Yingchi Zhang, Prof. Xiaofan Zhu, and Prof. Wenyu Yang, as well as members of the Zhu/Zhang Laboratory: Tianyuan Hu, Xiaoli Chen, Peng Wu, Yunlong Chen, Yongjuan Duan, Jingliao Zhang, Jiarui Zheng, Linlin Jing, and Yuxin Huang.
Expert Profile
Chief Clinical Specialist, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
Chief Physician; Doctoral Advisor Recipient of State Council Special Allowance Recognized Expert of Outstanding Contribution, Tianjin Vice Chair, National Pediatric Leukemia Expert Committee, National Health Commission of China Chair-Elect, Pediatric Oncology Committee, Chinese Anti-Cancer Association Principal Investigator, CCCG-2025-ALL, Chinese Children’s Cancer Group Committee Member, Lymphoma Committee, Chinese Society of Clinical Oncology (CSCO) Editorial Board Member, Chinese Journal of Pediatrics, Chinese Journal of Hematology, and others Honors include: Second Prize, National Natural Science Award; Soong Ching-ling Pediatric Medicine Award; Women in Science Award; First Prize, Tianjin Natural Science Award
