|
|
Blood, 15 February 2005, Vol. 105, No. 4, pp. 1759-1767.
Prepublished online as a Blood First Edition Paper on October 21, 2004; DOI 10.1182/blood-2004-05-2006.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival
Kyu-Tae Kim,
Kristin Baird,
Joon-Young Ahn,
Paul Meltzer,
Michael Lilly,
Mark Levis, and
Donald Small
From the Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; the Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; and the Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA.
Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukemogenesis, and their presence is associated with poor prognosis in acute myeloid leukemia (AML). To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild-type FLT3 expression. Microarrays were used with RNA harvested before and after inhibition of FLT3 signaling. Pim-1 was found to be one of the most significantly down-regulated genes upon FLT3 inhibition. Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. Quantitative polymerase chain reaction (QPCR) confirmed the microarray results and demonstrated approximately 10-fold decreases in Pim-1 expression in response to FLT3 inhibition. Pim-1 protein also decreased rapidly in parallel with decreasing autophosphorylation activity of FLT3. Enforced expression of either the 44-kDa or 33-kDa Pim-1 isotypes resulted in increased resistance to FLT3 inhibition-mediated cytotoxicity and apoptosis. In contrast, expression of a dominant-negative Pim-1 construct accelerated cytotoxicity in response to FLT3 inhibition and inhibited colony growth of FLT3/ITD-transformed BaF3 cells. These findings demonstrate that constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. This up-regulation contributes to the proliferative and antiapoptotic pathways induced by FLT3 signaling. (Blood. 2005;105: 1759-1767)
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. Morishita, R. Katayama, K. Sekimizu, T. Tsuruo, and N. Fujita
Pim Kinases Promote Cell Cycle Progression by Phosphorylating and Down-regulating p27Kip1 at the Transcriptional and Posttranscriptional Levels
Cancer Res.,
July 1, 2008;
68(13):
5076 - 5085.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bullinger, K. Dohner, R. Kranz, C. Stirner, S. Frohling, C. Scholl, Y. H. Kim, R. F. Schlenk, R. Tibshirani, H. Dohner, et al.
An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML
Blood,
May 1, 2008;
111(9):
4490 - 4495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Li, O. Piloto, H. B. Nguyen, K. Greenberg, K. Takamiya, F. Racke, D. Huso, and D. Small
Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model
Blood,
April 1, 2008;
111(7):
3849 - 3858.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Sallmyr, J. Fan, K. Datta, K.-T. Kim, D. Grosu, P. Shapiro, D. Small, and F. Rassool
Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML
Blood,
March 15, 2008;
111(6):
3173 - 3182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wang, J. Wang, B. W. Blaser, A.-M. Duchemin, D. F. Kusewitt, T. Liu, M. A. Caligiuri, and R. Briesewitz
Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia
Blood,
September 15, 2007;
110(6):
2075 - 2083.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Allantaz, D. Chaussabel, D. Stichweh, L. Bennett, W. Allman, A. Mejias, M. Ardura, W. Chung, C. Wise, K. Palucka, et al.
Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade
J. Exp. Med.,
September 3, 2007;
204(9):
2131 - 2144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Pogacic, A. N. Bullock, O. Fedorov, P. Filippakopoulos, C. Gasser, A. Biondi, S. Meyer-Monard, S. Knapp, and J. Schwaller
Structural Analysis Identifies Imidazo[1,2-b]Pyridazines as PIM Kinase Inhibitors with In vitro Antileukemic Activity
Cancer Res.,
July 15, 2007;
67(14):
6916 - 6924.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-L. Hu, E. Passegue, S. Fong, C. Largman, and H. J. Lawrence
Evidence that the Pim1 kinase gene is a direct target of HOXA9
Blood,
June 1, 2007;
109(11):
4732 - 4738.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Testa and R. Riccioni
Deregulation of apoptosis in acute myeloid leukemia
Haematologica,
January 1, 2007;
92(1):
81 - 94.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Y. Chung, G. Morrone, J. J. Schuringa, M. Plasilova, J.-H. Shieh, Y. Zhang, P. Zhou, and M. A.S. Moore
Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation
Cancer Res.,
December 15, 2006;
66(24):
11781 - 11791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Heiss, K. Masson, C. Sundberg, M. Pedersen, J. Sun, S. Bengtsson, and L. Ronnstrand
Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2
Blood,
September 1, 2006;
108(5):
1542 - 1550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Rocnik, R. Okabe, J.-C. Yu, B. H. Lee, N. Giese, D. P. Schenkein, and D. G. Gilliland
Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD
Blood,
August 15, 2006;
108(4):
1339 - 1345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. W. Parcells, A. K. Ikeda, T. Simms-Waldrip, T. B. Moore, and K. M. Sakamoto
FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia
Stem Cells,
May 1, 2006;
24(5):
1174 - 1184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Zeng, I. J. Samudio, W. Zhang, Z. Estrov, H. Pelicano, D. Harris, O. Frolova, N. Hail Jr., W. Chen, S. M. Kornblau, et al.
Simultaneous Inhibition of PDK1/AKT and Fms-Like Tyrosine Kinase 3 Signaling by a Small-Molecule KP372-1 Induces Mitochondrial Dysfunction and Apoptosis in Acute Myelogenous Leukemia.
Cancer Res.,
April 1, 2006;
66(7):
3737 - 3746.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Adam, V. Pogacic, M. Bendit, R. Chappuis, M. C. Nawijn, J. Duyster, C. J. Fox, C. B. Thompson, J. Cools, and J. Schwaller
Targeting PIM Kinases Impairs Survival of Hematopoietic Cells Transformed by Kinase Inhibitor-Sensitive and Kinase Inhibitor-Resistant Forms of Fms-Like Tyrosine Kinase 3 and BCR/ABL.
Cancer Res.,
April 1, 2006;
66(7):
3828 - 3835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Luo, Q. Li, J. O'Neal, F. Kreisel, M. M. Le Beau, and M. H. Tomasson
c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations
Blood,
October 1, 2005;
106(7):
2452 - 2461.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
