An intrabody specific for the nucleophosmin carboxy-terminal mutant and fused to a nuclear localization sequence binds its antigen but fails to relocate it in the nucleus.

The cytoplasmic accumulation of NPM1 (NPMc+) is found in acute myeloid leukemia (AML) with NPM1 mutation. NPM1 must shuttle between nucleus and cytoplasm to assure physiological protein synthesis and, therefore, the elimination of NPMc+ is not a suitable therapeutic option. We isolated, characterized, and produced a functional scFv intrabody fused to nuclear localization signal(s) (NLS) that does not recognize NPM1 but binds to the mutant-specific C-terminal NES (nuclear export signal) of NPMc+, responsible for its cytoplasmic accumulation.

The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway.

Oncogene-induced senescence (OIS) is a barrier for tumor development. Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer. A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways.

EFA6A encodes two isoforms with distinct biological activities in neuronal cells.

The processes of neurite extension and remodeling require a close coordination between the cytoskeleton and the cell membranes. The small GTPase ARF6 (ADP-ribosylation factor 6) has a central role in regulating membrane traffic and actin dynamics, and its activity has been demonstrated to be involved in neurite elaboration. EFA6A has been shown to act as a guanine nucleotide exchange factor (GEF) for ARF6.

Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma.

Mutations leading to aberrant cytoplasmic localization of nucleophosmin (NPM) are the most frequent genetic alteration in acute myelogenous leukemia (AML). NPM binds the Arf tumor suppressor and protects it from degradation. The AML-associated NPM mutant (NPMmut) also binds p19Arf but is unable to protect it from degradation, which suggests that inactivation of p19Arf contributes to leukemogenesis in AMLs.