The hematopoietic system is key for studying stem cell signaling. Disruptions in Wnt, Notch, and TGF-β pathways can cause HSCs to transform into leukemic cells. This review aims to explore the patterns of genetic and epigenetic gene inactivation across leukemia subtypes to understand their roles in disease pathogenesis and therapy. These insights have spurred the creation of innovative targeted therapies. For instance, inhibitors of the JAK-STAT pathway have demonstrated encouraging results in clinical studies, particularly in enhancing hematologic responses and delaying disease progression in certain types of leukemia. The combination of targeted therapies that focus on signaling pathways with traditional chemotherapy has notably enhanced patient responses. Furthermore, recent research has underscored the significance of epigenetic modifications in regulating these signaling pathways. These reversible epigenetic modifications can be therapeutically targeted using agents such as DNA methyltransferase inhibitors or histone deacetylase inhibitors, restoring normal gene function. For example, aberrant DNA methylation and histone modifications can silence key regulators of signaling cascades or activate oncogenic pathways, thereby contributing to leukemic transformation. Next-generation sequencing (NGS) has enabled identification of specific leukemia subtypes, such as RUNX1-mutated AML or BCR-ABL1-positive ALL, allowing tailored therapeutic approaches. The identification of specific epigenetic alterations associated with signaling disruptions has facilitated the formulation of personalized treatment strategies. These advancements have not only enabled the molecular classification of leukemias but have also laid the foundation for truly personalized treatment approaches. By leveraging techniques such as next-generation sequencing (NGS) to identify patient-specific signaling abnormalities, clinicians can now implement targeted therapies with greater precision—ultimately improving response rates, minimizing resistance, and enhancing overall survival.
Askari et al. (Sun,) studied this question.