Editor's Note :From December 7 to 10, 2024, the 66th Annual Meeting of the American Society of Hematology (ASH) convened in San Diego, bringing together leading experts to discuss pivotal advances in hematology. Among the highlights was a groundbreaking study by Dr. Shanshan Pei and his team from The First Affiliated Hospital,Zhejiang University and Liangzhu Laboratory. This study (Abstract #38), selected for oral presentation, identified the rare fusion gene TFG-ROS1 as an oncogenic driver in human myeloid leukemia. Furthermore, the team demonstrated effective treatment strategies using ALK/ROS1 inhibitors, achieving remission in a patient with refractory leukemia after multiple treatment failures. This study exemplifies the “bench-to-bedside” paradigm in precision medicine, showcasing its transformative potential for cancer care. Below is an in-depth exploration of the study and exclusive insights from Professor Pei.

Abstract #38 | The TFG-ROS1 Fusion Is an Oncogenic Driver of Human Myeloid Leukemia

Hematology Frontier: How did your team discover the TFG-ROS1 fusion gene, and can you briefly explain its characteristics?

Dr. Shanshan Pei:Our research began with a challenging clinical case identified by Dr. Sun Jie from The First Affiliated Hospital,Zhejiang University. The patient had refractory myeloid leukemia resistant to multiple therapies, including venetoclax, chemotherapy, and hematopoietic stem cell transplantation (HSCT). Genetic sequencing revealed a novel fusion between the TFG gene on chromosome 3 and the ROS1 gene on chromosome 6. This represented a previously unreported fusion with oncogenic potential.

Hematology Frontier: Can you elaborate on the major findings of your study?

Dr. Shanshan Pei:Our study employed molecular techniques to clone the TFG-ROS1 fusion gene and investigate its oncogenic mechanisms. Using in vitro and in vivo models (mouse models and patient-derived samples), we identified that the fusion gene activates ROS1 kinase and subsequently the downstream MEK/ERK signaling pathway. This activation drives aggressive disease proliferation and resistance to traditional therapies like venetoclax, azacitidine, and chemotherapy.

Additionally, single-cell RNA sequencing (scRNA-seq) revealed that TFG-ROS1 is present across multiple cell lineages, suggesting that the fusion likely originates in stem or progenitor cells. This discovery explains its poor prognosis and underscores the importance of early detection.

Hematology Frontier: Your study evaluated ALK/ROS1 inhibitors in AML patients with this fusion. What were the outcomes?

Dr. Shanshan Pei:Through drug screening and preclinical studies using mouse and patient-derived xenograft (PDX) models, we found that ALK/ROS1 inhibitors such as ceritinib significantly reduced leukemia burden in the bone marrow, peripheral blood, and spleen. These inhibitors showed rapid therapeutic responses, improving symptoms dramatically.

In collaboration with Professor Wu Tong’s team at Beijing Gaobo Borun Hospital, we applied a combination therapy of ceritinib, crizotinib, and HSCT to the patient. Remarkably, the patient has maintained remission for 13 months, demonstrating the potential of targeted therapies for TFG-ROS1-positive AML.

Hematology Frontier: What role did collaboration play in this research?

Dr. Shanshan Pei:In today’s fast-paced scientific environment, interdisciplinary collaboration is critical for advancing precision medicine. Our discovery resulted from the joint efforts of teams at The First Affiliated Hospital,Zhejiang University, Liangzhu Laboratory, and Beijing Gaobo Borun Hospital. By integrating clinical insights with foundational research, we successfully developed a targeted treatment strategy that benefited the patient.

Expert Profile

• Researcher, The First Affiliated Hospital,Zhejiang University and Liangzhu Laboratory
• Zhejiang University Hundred Talents Program Scholar and Doctoral Advisor
• National and Zhejiang Provincial Young Talent Award Recipient
• Principal Investigator, National Natural Science Foundation of China Projects and Zhejiang Provincial R&D Projects

Professor Pei specializes in translational research on acute myeloid leukemia (AML) and leukemia stem cells (LSCs). Her groundbreaking studies have been published in top journals such as Cancer Discovery and Cell Stem Cell, with over 30 SCI-indexed papers and more than 5,200 citations.

Research Achievements:

• First author or corresponding author on landmark publications in Cancer Discovery (2020, 2023) and Cell Stem Cell (2018).
• Recipient of ASH Abstract Achievement and Travel Awards.
• Holder of a U.S. small-molecule drug patent, with another clinical diagnostic patent application pending.
• Frequently invited to deliver oral presentations at international conferences, including ASH.