CaMKK2 Expression Correlates with High-Risk CLL Biology, and Pharmacologic Inhibition Is Associated with Reduced Leukemic Cell Survival and Nurse-like Cell Support In Vitro
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<jats:p>Background/Objectives: Chronic lymphocytic leukemia (CLL) is characterized by clinical and biological heterogeneity shaped by intrinsic signaling programs and microenvironmental interactions. Established biomarkers, including IGHV mutation status and TP53 alterations, provide important clinical and molecular information, but do not fully capture the diversity of pathways that sustain leukemic cell fitness. Aberrant calcium signaling contributes to leukemic survival; however, the clinical relevance of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a calcium-responsive kinase, has not been defined. This study evaluated CaMKK2 as a candidate marker associated with high-risk disease biology and a pathway of interest for further study. Methods: CaMKK2 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. Results: Elevated CaMKK2 expression was enriched in IGHV-unmutated CLL and associated with shorter time to treatment and inferior overall survival. Pharmacological inhibition of CaMKK2 was associated with reduced primary CLL viability in a dose-dependent manner and increased Annexin V/PI-defined total cell death with sensitivity correlating with CaMKK2 expression levels. Inhibition also attenuated CD163+ macrophage polarization and impaired NLC-mediated support of leukemic cells. Conclusions: CaMKK2 expression is associated with IGHV-unmutated, high-risk CLL biology. Pharmacologic inhibition of CaMKK2 was associated with reduced leukemic cell viability and altered macrophage phenotypes in ex vivo systems. These findings are exploratory, derived from a limited cohort, and support further investigation into the role of CaMKK2 in CLL biology, but do not establish independent prognostic value or direct on-target causality.</jats:p>
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Jauhari, Shekeab, Alicia D Cooper-Volkheimer, Vini Verma, Dilber Gökçe Kaplan, Fahmin Basher, J Brice Weinberg, Nelson J Chao, Luigi Racioppi, et al. (n.d.). CaMKK2 Expression Correlates with High-Risk CLL Biology, and Pharmacologic Inhibition Is Associated with Reduced Leukemic Cell Survival and Nurse-like Cell Support In Vitro. Cells, 15(14). pp. 1294–1294. 10.3390/cells15141294 Retrieved from https://hdl.handle.net/10161/35445.
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Scholars@Duke
Fahmin Basher
Fellowship: Duke University, Hematology & Medical Oncology (2021-2025)
Residency: University of Miami / Jackson Memorial Hospital (2018-2021)
Medical/Graduate: Medical University of South Carolina (2008-2018)
Doctor of Medicine, May 2018
Doctor of Philosophy in Microbiology & Immunology, May 2018
Undergraduate: University of South Carolina (2004-2008)
Bachelor of Science, Chemical Engineering
Bachelor of Science, Biological Sciences
Minor in Medical Humanities
Nelson Jen An Chao
My research interests are in two broad areas, clinical hematopoietic stem cell and cord blood transplantation and in the laboratory studies related to graft vs. host disease and immune reconstitution. On the clinical side we are currently conducting approximately 50 different clinical protocols ranging from preparatory regimens, supportive care studies and disease specific protocols. Most of these clinical studies are centered around studies of the sources of stem cells and the methods to improve the long term outcome. There are exploratory protocols for novel therapies such as dendritic cell therapy for several malignancies, antiangiogenesis therapy, graft engineering to prevent graft-versus-host disease and antigen specific T cells or non specific NK cells to prevent relapse. Moreover a strong focus of the program is to develop cord-blood transplantation for adult patients with hematologic malignancies. The laboratory studies center on understanding the immunological events that occur with graft-vs-host disease and methods to prevent this disease. The current efforts focus on understanding murine reconstitution following transplantation, use of a peptide polymer to block MHC class II recognition of minor histocompatibility antigens, use of T cell engineering to prevent graft-versus-host disease at the same time preserving a graft-versus-malignancy effect.
For more information see http://ed-media.mc.duke.edu/BMT.nsf
Luigi Racioppi
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.