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

Shuchi Agrawal-Singh; Steffen Koschmieder; Sandra Gelsing; Carol Stocking; Martin Stehling; Christian Thiede; Nils H Thoennissen; Gabriele Köhler; Peter J M Valk; Ruud Delwel; Ken Mills; Nicole Bäumer; Lara Tickenbrock; Klaus Hansen; Wolfgang E Berdel; Carsten Müller-Tidow; Hubert Serve

doi:10.1182/blood-2009-03-210070

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

Shuchi Agrawal-Singh, Steffen Koschmieder, Sandra Gelsing, Carol Stocking, Martin Stehling, Christian Thiede, Nils H Thoennissen, Gabriele Köhler, Peter J M Valk, Ruud Delwel, Ken Mills, Nicole Bäumer, Lara Tickenbrock, Klaus Hansen, Wolfgang E Berdel, Carsten Müller-Tidow, Hubert Serve

10 Citations (Scopus)

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 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.

Original language	English
Journal	Blood
Volume	115
Issue number	22
Pages (from-to)	4507-16
Number of pages	9
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2009-03-210070
Publication status	Published - 3 Jun 2010

Access to Document

10.1182/blood-2009-03-210070

http://www.bloodjournal.org/content/bloodjournal/115/22/4507.full.pdf

Cite this

Agrawal-Singh, S., Koschmieder, S., Gelsing, S., Stocking, C., Stehling, M., Thiede, C., Thoennissen, N. H., Köhler, G., Valk, P. J. M., Delwel, R., Mills, K., Bäumer, N., Tickenbrock, L., Hansen, K., Berdel, W. E., Müller-Tidow, C., & Serve, H. (2010). Pim2 cooperates with PML-RARalpha to induce acute myeloid leukemia in a bone marrow transplantation model. Blood, 115(22), 4507-16. https://doi.org/10.1182/blood-2009-03-210070

Agrawal-Singh, S, Koschmieder, S, Gelsing, S, Stocking, C, Stehling, M, Thiede, C, Thoennissen, NH, Köhler, G, Valk, PJM, Delwel, R, Mills, K, Bäumer, N, Tickenbrock, L, Hansen, K, Berdel, WE, Müller-Tidow, C & Serve, H 2010, 'Pim2 cooperates with PML-RARalpha to induce acute myeloid leukemia in a bone marrow transplantation model', Blood, vol. 115, no. 22, pp. 4507-16. https://doi.org/10.1182/blood-2009-03-210070

@article{624b7fe0b03311df825b000ea68e967b,

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 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.",

author = "Shuchi Agrawal-Singh and Steffen Koschmieder and Sandra Gelsing and Carol Stocking and Martin Stehling and Christian Thiede and Thoennissen, {Nils H} and Gabriele K{\"o}hler and Valk, {Peter J M} and Ruud Delwel and Ken Mills and Nicole B{\"a}umer and Lara Tickenbrock and Klaus Hansen and Berdel, {Wolfgang E} and Carsten M{\"u}ller-Tidow and Hubert Serve",

note = "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",

year = "2010",

month = jun,

day = "3",

doi = "10.1182/blood-2009-03-210070",

language = "English",

volume = "115",

pages = "4507--16",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "22",

}

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 -

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

Abstract

Access to Document

Fingerprint

Cite this