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

Abstract

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 alpha (PML/RARalpha), we used a well-established PML-RARalpha (PRalpha) mouse model. Pim2 coexpression in PRalpha-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRalpha cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRalpha alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRalpha cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRalpha. 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-RARalpha), cooperates with PRalpha to induce APL-like disease.

Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression

“…Regardless, the approach described here may allow us to rapidly identify progression mutations that are relevant for human AML and provides an important proof of concept that this mouse model of AML is functionally related to its human counterpart. Mutations in several known oncogenes, including K-RAS and FLT3 (and dysregulated expression of BCL2), have been previously shown to cooperate with PML-RARA in this mouse APL model (29)(30)(31)(32)(33); importantly, these mutations occur in many AML subtypes, not just APL. The mutations that spontaneously arise in this mouse model of human APL can now be identified by whole genome sequencing using next-generation platforms; this provides a physiologic system for the detection of leukemia progression mutations that are also relevant for human AML pathogenesis.…”

Genome-wide analysis of histone H3 acetylation patterns in AML identifies PRDX2 as an epigenetically silenced tumor suppressor gene

“…PRDX2 cDNA was shuttled into the PMY retroviral destination vector. 20 Myc cloned into murine stem cell virus (MSCV) retroviral vector was a kind gift from Dr M. H. Tomasson (Washington University School of Medicine, St Louis, MO). 21 To generate MSCV constructs that express both human PRDX2 cDNA and c-Myc, PRDX2 with internal ribosome entry site (IRES) was amplified from PRDX2-PMY vector with the use of primers flanked on both ends with BglII sites.…”

“…Retroviruses that used PMY, PMY-PRDX2, MSCV-EGFP, MSCV-c-Myc-EGFP, or MSCV-PRDX2-c-Myc-EGFP plasmids were prepared as described previously. 20 Primary BM cell isolation, retroviral transduction, and BM transplantation BMT was performed as described. 20 A total of 1 ϫ 10 5 EGFP ϩ cells along with 1 ϫ 10 5 wild-type BM cells were injected intravenously into lethally irradiated (8 Gy) syngeneic mice.…”

“…20 Primary BM cell isolation, retroviral transduction, and BM transplantation BMT was performed as described. 20 A total of 1 ϫ 10 5 EGFP ϩ cells along with 1 ϫ 10 5 wild-type BM cells were injected intravenously into lethally irradiated (8 Gy) syngeneic mice. 20 Mice were followed to determine the incidence of leukemia development.…”

“…20 A total of 1 ϫ 10 5 EGFP ϩ cells along with 1 ϫ 10 5 wild-type BM cells were injected intravenously into lethally irradiated (8 Gy) syngeneic mice. 20 Mice were followed to determine the incidence of leukemia development. 20 …”