Pim2 cooperates with PML-RARalpha 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 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.
Agrawal-Singh
Shuchi
S
Department of Medicine, Hematology and Oncology, University of Muenster, Muenster, Germany.
Koschmieder
Steffen
S
Gelsing
Sandra
S
Stocking
Carol
C
Stehling
Martin
M
Thiede
Christian
C
Thoennissen
Nils H
NH
Köhler
Gabriele
G
Valk
Peter J M
PJ
Delwel
Ruud
R
Mills
Ken
K
Bäumer
Nicole
N
Tickenbrock
Lara
L
Hansen
Klaus
K
Berdel
Wolfgang E
WE
Müller-Tidow
Carsten
C
Serve
Hubert
H
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
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