CaMKK2 Identifies Biologically Aggressive Chronic Lymphocytic Leukemia and Regulates Leukemic Survival and Nurse-Like Cell Support

Background/ObjectivesIdentification of prognostic biomarkers that capture biologically aggressive disease remains a major need in chronic lymphocytic leukemia (CLL). Aberrant calcium signaling contributes to leukemic survival; however, the clinical relevance of Ca{superscript 2}/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a calcium-responsive kinase, has not been defined. This study evaluated CaMKK2 as a candidate prognostic biomarker and functional regulator in CLL. MethodsCaMKK2 expression was quantified in purified CD19 CLL cells from a clinically annotated cohort balanced by immunoglobulin heavy chain variable region (IGHV) mutation status. Associations with time-to-treatment and overall survival were analyzed. Functional relevance was assessed by pharmacologic inhibition of CaMKK2 in primary CLL cells using metabolic (MTS) and apoptosis (Annexin V/PI) assays. Correlations between CaMKK2 expression and inhibitor sensitivity were determined. The impact of CaMKK2 inhibition on nurse-like cell (NLC) differentiation and macrophage-mediated leukemic support was evaluated in ex vivo culture systems. ResultsElevated CaMKK2 expression was enriched in IGHV-unmutated CLL and associated with shorter time-to-treatment and inferior overall survival. CaMKK2 inhibition reduced primary CLL viability in a dose-dependent manner and induced apoptosis, with sensitivity correlating with CaMKK2 expression levels. Inhibition also attenuated CD163 macrophage polarization and impaired NLC-mediated support of leukemic cells. ConclusionsCaMKK2 expression identifies biologically aggressive CLL and functionally contributes to leukemic persistence. These findings position CaMKK2 as a prognostically relevant biomarker with therapeutic implications, supporting further evaluation of CaMKK2-targeted strategies in high-risk CLL. Sample SummaryChronic lymphocytic leukemia (CLL) shows marked variability in clinical outcome, highlighting the need for biomarkers that identify patients at higher risk of progression and guide therapeutic strategies. Calcium signaling supports leukemia cell survival, yet the clinical relevance of the calcium-responsive enzyme CaMKK2 has not been established. In this study, we demonstrate that elevated CaMKK2 expression in patient-derived leukemia cells is associated with more aggressive disease and earlier need for treatment. Laboratory experiments further show that inhibiting CaMKK2 reduces leukemia cell survival and disrupts supportive macrophage-like cells within the tumor microenvironment. These results position CaMKK2 as a candidate prognostic biomarker that reflects biologically high-risk disease and may inform therapeutic development. Future studies are warranted to determine whether CaMKK2-based risk stratification or targeted inhibition could improve management of patients with CLL.