This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beaupre, D. M. Articles by Kurzrock, R. Search for Related Content PubMed PubMed Citation Articles by Beaupre, D. M. Articles by Kurzrock, R.

Autocrine Interleukin-1ß Production in Leukemia

Evidence for the Involvement of Mutated RAS6¹

Departments of Bioimmunotherapy [D. M. B., M. T., Z. E., R. K.], Molecular Hematology [F. C. M.], Thoracic and Cardiovascular Surgery [R. J. C., J. A. R.], and Laboratory Medicine [M. A.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and The Hospital for Sick Children, Division of Hematology, M5G 1X8 Toronto, Canada [M. H. F.]

Interleukin (IL)-1ß is constitutively expressed in many leukemias and operates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic leukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-1ß and have mutations in the K-RAS and N-RAS genes, respectively. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1ß promoter elements [nuclear factor (NF)-IL6/CREB, NFB1, NFB, and NF-IL6], consistent with the activation of an upstream signaling pathway. To determine whether activated Ras was involved, two structurally distinct classes of farnesyltransferase (FTase) inhibitors (the monoterpenes and a peptidomimetic) and an adenoviral vector expressing antisense targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a concentration-dependent decrease in both NF-IL6/CREB binding to the IL-1ß promoter and IL-1ß protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21^Ras and IL-1ß protein levels. Growth suppression was observed after FTase inhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1ß to the cultures. Our observations suggest that mutated RAS genes may mediate autocrine IL-1ß production in some leukemias by stimulating signal transduction pathways that activate the IL-1ß promoter.

This article has been cited by other articles:

				N. Yanamandra, N. M. Colaco, N. A. Parquet, R. W. Buzzeo, D. Boulware, G. Wright, L. E. Perez, W. S. Dalton, and D. M. Beaupre Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia Clin. Cancer Res., January 15, 2006; 12(2): 591 - 599. [Abstract] [Full Text] [PDF]

				S. Muerkoster, A. Arlt, B. Sipos, M. Witt, M. Grossmann, G. Kloppel, H. Kalthoff, U. R. Folsch, and H. Schafer Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit {beta}TRCP1 Relates to Constitutive Nuclear Factor-{kappa}B Activation and Chemoresistance in Pancreatic Carcinoma Cells Cancer Res., February 15, 2005; 65(4): 1316 - 1324. [Abstract] [Full Text] [PDF]

				H.-J. Na, S.-J. Lee, Y.-C. Kang, Y.-L. Cho, W.-D. Nam, P. K. M. Kim, K.-S. Ha, H.-T. Chung, H. Lee, Y.-G. Kwon, et al. Inhibition of Farnesyltransferase Prevents Collagen-Induced Arthritis by Down-Regulation of Inflammatory Gene Expression through Suppression of p21ras-Dependent NF-{kappa}B Activation J. Immunol., July 15, 2004; 173(2): 1276 - 1283. [Abstract] [Full Text] [PDF]

				R. Kurzrock, H. M. Kantarjian, J. E. Cortes, N. Singhania, D. A. Thomas, E. F. Wilson, J. J. Wright, E. J. Freireich, M. Talpaz, and S. M. Sebti Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting Blood, December 15, 2003; 102(13): 4527 - 4534. [Abstract] [Full Text] [PDF]

				H. Y. Li, F. R. Appelbaum, C. L. Willman, R. A. Zager, and D. E. Banker Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses Blood, May 1, 2003; 101(9): 3628 - 3634. [Abstract] [Full Text] [PDF]

				Y. Saijo, M. Tanaka, M. Miki, K. Usui, T. Suzuki, M. Maemondo, X. Hong, R. Tazawa, T. Kikuchi, K. Matsushima, et al. Proinflammatory Cytokine IL-1{beta} Promotes Tumor Growth of Lewis Lung Carcinoma by Induction of Angiogenic Factors: In Vivo Analysis of Tumor-Stromal Interaction J. Immunol., July 1, 2002; 169(1): 469 - 475. [Abstract] [Full Text] [PDF]

				A. Arlt, J. Vorndamm, S. Muerkoster, H. Yu, W. E. Schmidt, U. R. Folsch, and H. Schafer Autocrine Production of Interleukin 1{beta} Confers Constitutive Nuclear Factor {kappa}B Activity and Chemoresistance in Pancreatic Carcinoma Cell Lines Cancer Res., February 1, 2002; 62(3): 910 - 916. [Abstract] [Full Text] [PDF]