The scaffold protein NEDD9 is necessary for leukemia-cell migration and disease progression in a mouse model of chronic lymphocytic leukemia.

Abstract

The scaffold protein NEDD9 is frequently upregulated and hyperphosphorylated in cancers, and is associated with poor clinical outcome. NEDD9 promotes B-cell adhesion, migration and chemotaxis, pivotal processes for malignant development. 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 was required for efficient CLL cell homing, chemotaxis, migration and adhesion. In CLL patients, peripheral NEDD9 expression was associated with adhesion and migration signatures as well as leukocyte count. Additionally, CLL lymph nodes frequently expressed high NEDD9 levels, with a subset of patients showing NEDD9 expression enriched in the CLL proliferation centers. Blocking activity of prominent NEDD9 effectors, including AURKA and HDAC6, effectively reduced CLL cell migration and chemotaxis. Collectively, our study provides evidence for a functional role of NEDD9 in CLL pathogenesis that involves intrinsic defects in adhesion, migration and homing.

• Authors: Lisa Rusyn, Sebastian Reinartz, Anastasia Nikiforov, Nelly Mikhael, Alexander Vom Stein, Viktoria Kohlhas, Johannes Bloehdorn, Stephan Stilgenbauer, Philipp Lohneis, Reinhard Buettner, Sandra Robrecht, Kirsten Fischer, Christian Pallasch, Michael Hallek, Phuong-Hien Nguyen, Tamina Seeger-Nukpezah
• Journal: Leukemia (Leukemia) Vol. 36 Issue 7 Pg. 1794-1805 (07 2022) ISSN: 1476-5551 [Electronic] England
• PMID: 35523865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Adaptor Proteins, Signal Transducing
• NEDD9 protein, mouse
• Aurora Kinase A

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Aurora Kinase A
• Cell Movement
• Disease Models, Animal
• Disease Progression
• Leukemia, Lymphocytic, Chronic, B-Cell (pathology)
• Mice