PKC isoforms in hematopoietic lineages and myeloid/lymphoid leukemias: mechanistic insights and therapeutic prospects.

Leukemia remains a major clinical challenge due to high rates of drug resistance and recurrence, necessitating the identification of novel therapeutic targets. Protein kinase C (PKC) family, a central signaling hub regulating cell proliferation, differentiation, and apoptosis, has been implicated in hematological malignancies for decades. However, the context-dependent and often contradictory functions of PKC isoforms across different hematopoietic lineages have hindered the development of effective targeted therapies. Here, we systematically review the roles of PKC isoforms in normal hematopoiesis and the pathogenesis of myeloid and lymphoid leukemias, adopting a dual lineage- and isoform-centric perspective to resolve the long-standing functional paradox of PKC signaling. We first delineate the lineage-specific regulatory functions of distinct PKC subfamilies in hematopoietic stem cell maintenance and lineage commitment. We then comprehensively analyze the dual oncogenic and tumor-suppressive roles of individual PKC isoforms in major leukemia subtypes, highlighting their critical involvement in drug resistance and leukemia stem cell survival. Finally, we evaluate current PKC-targeted therapeutic strategies and propose future directions for lineage-specific precision therapy. This review provides a unified framework for understanding PKC signaling in hematopoiesis and leukemia, offering novel insights into overcoming therapeutic resistance and improving patient outcomes.