TY - JOUR
T1 - Pim2 cooperates with PML-RARalpha to induce acute myeloid leukemia in a bone marrow transplantation model
AU - Agrawal-Singh, Shuchi
AU - Koschmieder, Steffen
AU - Gelsing, Sandra
AU - Stocking, Carol
AU - Stehling, Martin
AU - Thiede, Christian
AU - Thoennissen, Nils H
AU - Köhler, Gabriele
AU - Valk, Peter J M
AU - Delwel, Ruud
AU - Mills, Ken
AU - Bäumer, Nicole
AU - Tickenbrock, Lara
AU - Hansen, Klaus
AU - Berdel, Wolfgang E
AU - Müller-Tidow, Carsten
AU - Serve, Hubert
N1 - Keywords: Animals; Base Sequence; Bone Marrow Transplantation; DNA Primers; Female; Gene Expression; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Transplantation; Oncogene Proteins, Fusion; Oncogenes; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Tretinoin; fms-Like Tyrosine Kinase 3
PY - 2010/6/3
Y1 - 2010/6/3
N2 - 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 α (PML/RARα), we used a well-established PML-RARα (PRα) mouse model. Pim2 coexpression in PRα-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRα cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRα alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRα cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRα. 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-RARα), cooperates with PRα to induce APL-like disease.
AB - 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 α (PML/RARα), we used a well-established PML-RARα (PRα) mouse model. Pim2 coexpression in PRα-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRα cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRα alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRα cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRα. 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-RARα), cooperates with PRα to induce APL-like disease.
U2 - 10.1182/blood-2009-03-210070
DO - 10.1182/blood-2009-03-210070
M3 - Journal article
C2 - 20215640
SN - 0006-4971
VL - 115
SP - 4507
EP - 4516
JO - Blood
JF - Blood
IS - 22
ER -