title: Pim2 cooperates with PML-RARalpha 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.
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Muenster, Muenster, Germany.
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Sandra
authors.initials: S
authors.lastname: Gelsing
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
authors.forename: Martin
authors.initials: M
authors.lastname: Stehling
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Nils H
authors.initials: NH
authors.lastname: Thoennissen
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Ken
authors.initials: K
authors.lastname: Mills
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.forename: Lara
authors.initials: L
authors.lastname: Tickenbrock
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
mesh_terms: D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009857:Oncogenes; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D017931:DNA Primers; D015514:Oncogene Proteins, Fusion; C490587:PIM2 protein, human; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D017346:Protein Serine-Threonine Kinases