The fundamental role of the homing process in CLL progression prompted us to analyze the impact of NEDD9, a crucial regulator of lymphocyte migration, in CLL pathogenesis. Adhesion molecules such as VLA-4 or CD44 mediate homing, adhesion, and retention of CLL cells in lymphoid organs, contributing to disease progression and therapy resistance. Chemotaxis via chemokine receptors including CXCR4 or CXCR5 regulates CLL cell trafficking via tissue gradients of the their ligands CXCL12 and CXCL13. Massive tissue infiltration of CLL cells leads to splenomegaly and lymphadenopathy and may be responsible for residual disease after therapy. Homing into the secondary lymphoid organs and the bone marrow is essential for CLL cells to settle into tumor protective niches and receive pro-survival signals. ĬLL cells are highly dependent on the tumor microenvironment. Despite the undeniable improvement in CLL treatment, resistance to these compounds still pose a challenge in aggressive cases. Recently, monoclonal antibodies, B-cell receptor (BCR) inhibitors and BCL-2 inhibitors have demonstrated highly promising therapeutic efficacy, and impressive results were achieved with their combinations. Collectively, our study provides evidence for a functional role of NEDD9 in CLL pathogenesis that involves intrinsic defects in adhesion, migration and homing.Ĭhronic lymphocytic leukemia (CLL) is characterized by clonal proliferation of mature CD5-positive B-cells that accumulate in the blood and lymphoid organs. Blocking activity of prominent NEDD9 effectors, including AURKA and HDAC6, effectively reduced CLL cell migration and chemotaxis. Additionally, CLL lymph nodes frequently expressed high NEDD9 levels, with a subset of patients showing NEDD9 expression enriched in the CLL proliferation centers. In CLL patients, peripheral NEDD9 expression was associated with adhesion and migration signatures as well as leukocyte count. NEDD9 was required for efficient CLL cell homing, chemotaxis, migration and adhesion. We show that global or B-cell-specific deletion of Nedd9 in chronic lymphocytic leukemia (CLL) mouse models delayed CLL development, markedly reduced disease burden and resulted in significant survival benefit. NEDD9 promotes B-cell adhesion, migration and chemotaxis, pivotal processes for malignant development. The scaffold protein NEDD9 is frequently upregulated and hyperphosphorylated in cancers, and is associated with poor clinical outcome.
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