Scientists Successfully Crack The "Genetic Code" of Rare Leukemia

In the field of medical research, leukemia remains a major threat to human health. Acute myeloid leukemia (AML), a member of the leukemia family, presents a heavy burden on countless patients and their families with its complex and diverse subtypes and aggressive disease progression. Among these, acute megakaryocytic leukemia (AMKL), due to its rarity and highly aggressive nature, remains a pressing challenge for the medical community.

Fortunately, a study published in the international journal Blood, titled "RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and Wnt pathway activation," by scientists from Yale University and other institutions, has shed light on the mysteries of AMKL and offered new hope for treatment.

Although AMKL accounts for a small proportion of childhood leukemia, the disease progresses rapidly and carries a dismal prognosis. Traditional treatments are often ineffective, with high relapse rates, prompting scientists to search for new therapeutic targets and strategies. In recent years, the rapid development of cutting-edge technologies such as gene editing and multi-omics analysis has enabled a deeper understanding of the pathogenesis of leukemia. The role of RNA modification, particularly N6-methyladenosine (m6A) modification and the Wnt signaling pathway in tumorigenesis and progression, has become a hot topic of research.

In this study, researchers focused on a key gene mutation in AMKL, resulting in the formation of the RBM15-MKL1 fusion protein. This mutation, which occurs primarily in children, leads to dysregulation of the m6A modification process. m6A, a chemical modification that adds a methyl group to RNA, acts like a "tag" to influence RNA stability, translation, and transport, thereby regulating gene expression. Using a multi-omics approach, the researchers revealed for the first time how the RBM15-MKL1 fusion protein retains the RNA binding and m6A modification functions of RBM15 while selectively regulating distinct messenger RNA targets, including Frizzled genes, which play key roles in the Wnt signaling pathway.

Figure 1. Targeting pathogenic RNA mechanisms in RBM15-MKL1 acute megakaryoblastic leukemia. (Mayday M Y, et al., 2025)

The Wnt signaling pathway plays a crucial role in cell proliferation, differentiation, and survival, and its aberrant activation is associated with the development of various cancers. Studies have shown that the RBM15-MKL1 fusion protein upregulates Frizzled gene expression through m6A modification. Inhibition of METTL3, a key enzyme involved in m6A modification, can downregulate the expression of these genes, thereby inhibiting the growth of AMKL cells. In experiments, researchers treated mouse AMKL cells with the METTL3 inhibitor STM3675. This not only induced apoptosis in vitro but also prolonged the survival of transplanted mice. This discovery not only reveals a key pathogenesis of AMKL but also provides a potential target for the development of new therapeutic strategies.

This study is remarkable for its innovative nature and interdisciplinary collaboration. By integrating the expertise of multiple laboratories, the researchers deeply dissected the interactions between the RBM15-MKL1 fusion protein and RNA, and how these interactions influence leukemia progression. This multi-omics approach enables scientists to understand the complexity of the disease at the molecular level and offers the potential for future precision medicine. In addition, the researchers found that other types of AMKL also have abnormal activation of the Wnt signaling pathway, suggesting that the Wnt signaling pathway may be a common pathogenesis of AMKL. This discovery provides a theoretical basis for the development of drugs targeting the Wnt signaling pathway, which is expected to bring new treatment hope to all AMKL patients.

Reference

Mayday M Y, et al. RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and WNT pathway activation. Blood, 2025.