Nucleophosmin-anaplastic lymphoma kinase fusion protein (NPM-ALK)

The **Nucleophosmin-anaplastic lymphoma kinase fusion protein (NPM-ALK)** is a chimeric oncogenic tyrosine kinase created by the t(2;5)(p23;q35) chromosomal translocation that fuses the N-terminal region of nucleophosmin (NPM1) to the C-terminal catalytic domain of anaplastic lymphoma kinase (ALK). NPM-ALK is constitutively active, drives ligand-independent kinase signaling, and promotes transformation, proliferation, and survival of lymphoid cells. It is the principal molecular driver of ALK-positive anaplastic large cell lymphoma (ALCL), where it deregulates multiple signaling pathways, including JAK/STAT, PI3K/AKT, and MEK/ERK, and is a validated therapeutic target for ALK kinase inhibitors[1][2][3][4]. Detection of the fusion protein, either by IHC or molecular methods, is diagnostic for ALK-positive ALCL. Targeted therapies include ALK inhibitors and Hsp90 inhibitors, though resistance can develop through kinase domain mutations or other mechanisms.

Other names

NPM/ALKNPM–ALKnucleophosmin–ALK fusion protein

Inhibition of ALK kinase activity (direct ATP-competitive inhibitors) Destabilization/degradation via Hsp90 inhibition[3] Blockade of downstream signaling (JAK/STAT3, PI3K/AKT, RAS/MAPK, MEK/ERK, mTOR, JNK/c-Jun)[2]