Leukemia initiated by PMLRAR alpha: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable

The most common chromosomal translocation in acute promyelocytic leukemia ( APL), t15;17(q22;q21), creates PMLRAR alpha and RAR alpha PML fusion genes. We previously developed a mouse model of APL by expressing PMLRAR alpha in murine myeloid cells, In order to examine the mechanisms by which PMLRAR a lpha can initiate leukemia, we have now generated transgenic mice expressin g PMLRAR alpha m4 and RAR alpha m4, proteins that are unable to activate tr anscription in response to retinoic acid. PMLRAR alpha m4 transgenic mice d eveloped myeloid leukemia, demonstrating that transcriptional activation by PMLRAR alpha is not required for leukemic transformation. The characterist ics of the leukemias arising in the PMLRAR alpha m4 transgenic mice varied from those previously observed in our PMLRAR alpha transgenic mice, indicat ing that ligand responsiveness may influence the phenotype of the leukemic cells, The leukemias that arose in PMLRAR alpha m4 transgenic mice did not differentiate in response to retinoic acid therapy. This result supports th e hypothesis that a major therapeutic effect of retinoic acid is mediated d irectly through the PMLRAR alpha protein, However, a variable effect on sur vival suggested that this agent may be of some benefit in APL even when leu kemic cells are resistant to its differentiative effects. Transgenic mice e xpressing high levels of RAR alpha m4 have not developed leukemia, providin g evidence that the PML domain of PMLRAR alpha: plays a specific and critic al role in the pathogenesis of APL, (C) 2000 by The American Society of Hem atology.