Pim2 cooperates with PML-RARα to induce acute myeloid leukemia in a bone marrow transplantation model

Although the potential role of Pim2 as a cooperative oncogene has been well described in lymphoma, its role in leukemia has remained largely unexplored. Here we show that high expression of Pim2 is observed in patients with acute promyelocytic leukemia (APL). To further characterize the cooperative role of Pim2 with promyelocytic leukemia/retinoic acid receptor (PML/RAR), we used a well-established PML-RAR (PR) mouse model. Pim2 coexpression in PR-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PR cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PR alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PR cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PR. However, it also clearly resembled an APL-like phenotype and showed signs of differentiation upon all-trans retinoic acid (ATRA) treatment in vitro. These results support the hypothesis that Pim2, which is also a known target of Flt3-ITD (another gene that cooperates with PML-RAR), cooperates with PR to induce APL-like disease. (Blood. 2010;115(22):4507-4516)