Determining the contribution of NPM1 heterozygosity to NPM-ALK-induced lymphomagenesis

Heterozygous expression of Nucleophosmin (NPM1) predisposes to hematological malignancies in the mouse and cooperates with Myc in lymphomagenesis. NPM1 is therefore regarded as a haploinsufficient tumor suppressor. Heterozygous loss of NPM1 occurs as a result of the t(2;5) which generates the oncogenic fusion tyrosine kinase, NPM-Anaplastic Lymphoma Kinase (ALK), a molecule underlying the pathogenesis of Anaplastic Large Cell Lymphoma (ALCL). Given the aforementioned role of NPM1 as a tumor suppressor we hypothesized that NPM1 heterozygosity would cooperate with NPM-ALK in lymphomagenesis. In the event, we observed no difference in tumor latency, incidence or phenotype in NPM-ALK-transgenic mice heterozygous for NPM1 relative to transgenic mice expressing both NPM1 alleles. We propose that whilst the t(2;5) simultaneously reduces NPM1 allelic dosage and creates the NPM-ALK fusion protein, the two events do not cooperate in the pathogenesis of ALCL in our mouse model. These data indicate that a tumor-suppressive role for NPM1 may be dependant on cellular and/or genetic context. ALCL = Anaplastic Large Cell Lymphoma, ALK = Anaplastic Lymphoma Kinase, NPM1 = Nucleophosmin, MPD = myeloproliferative disorder, ML = myeloid leukemia