Leukemia with distinct phenotypes in transgenic mice expressing PML/RARα, PLZF/RARα or NPM/RARα

Abstract

Recurrent chromosomal translocations involving the RARα locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RARα gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RARα moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RARα transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RARα and hCG-PLZF/RARα TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RARα leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RARα TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RARα TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RARα oncoprotein was found to localize in the nucleolus, unlike PML/RARα and PLZF/RARα, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RARα and PML/RARα, but not PLZF/RARα leukemia, was responsive to all-trans retinoic acid (ATRA) or As₂O₃ treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.