RSK signaling in myeloid malignancies: biology, disease dependency, and therapeutic targeting.

Acute myeloid leukemia (AML) and related myeloid malignancies remain clinically challenging despite recent advances in molecular profiling and targeted therapy. Although recurrent oncogenic drivers have improved disease classification and informed therapeutic development, durable disease control remains limited by signaling plasticity and therapeutic resistance of heterogeneous malignant stem and progenitor populations. These limitations drive continued interest in signaling dependencies that investigate oncogenic inputs across genetically diverse myeloid disease states. The p90 ribosomal S6 kinase (RSK) family has emerged as one such candidate. Positioned as a downstream convergence of MAPK/ERK and PI3K/PDK-1 signaling, RSK regulates proliferation, survival, translational control, inflammatory signaling, and cellular stress adaptation, all processes directly relevant to malignant progression. Growing evidence supports aberrant RSK activation in AML, functional dependency in FLT3-mutant AML and myeloproliferative neoplasms/myelofibrosis, and increasing translational interest in selective pharmacologic inhibition. Early preclinical studies demonstrate anti-leukemic activity through both genetic and pharmacologic targeting, while emerging clinical development of RSK inhibitors in solid tumors supports therapeutic feasibility. Here, we review the biologic role of RSK signaling in myeloid malignancies and discuss the therapeutic opportunities and challenges associated with targeting this signaling axis.