ABSTRACT Flt3-internal tandem duplications (Flt3-ITD) is a prevalent mutation in acute myeloid leukemia (AML). We recently reported arsenic trioxide (ATO) and Flt3 inhibition synergize to induce apoptosis in Flt3-ITD cells. However, the signaling effect of ATO in these cells has not been elucidated. Here, we demonstrate that the treatment of ATO potently induces the activation of extracellular regulated kinase (ERK)- mitogen activated protein kinase (MAPK), and modestly activates p38-MAPK in BaF3-Flt3-ITD cells, among other major (PI3-kinase-Akt, c-jun N-terminal kinase [JNK]) signaling pathways examined. In contrast, in BaF3-Flt3-wild type (WT) cells, slight activation of p38, but none for others, was observed. As MAPK kinase (MEK), as well as p38 inhibition is reported to enhance ATO-induced apoptosis in AML and various hematological malignancies, our results suggest that Flt3 mutation status is important for the effect of these combinations.
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nullS. Suzuki, H. Inaba, T. Satoh, T. Okazaki and S. Takahashi, "Activation of ERK and P38 by the Addition of Arsenic Trioxide in Flt3-ITD Cells," Open Journal of Blood Diseases, Vol. 1 No. 2, 2011, pp. 9-11. doi: 10.4236/ojbd.2011.12003.
 S. Takahashi, “Downstream Molecular Pathways of Flt3 in the Pathogenesis of Acute Myeloid Leukemia: Biology and Therapeutic Implications,” Journal of Hematology & Oncology, Vol. 4, No. 13, 2011, pp. 1-10.
S. Takahashi, “Current Findings for Recurring Mutations in Acute Myeloid Leukemia,” Journal of Hematology & Oncology, Vol. 4, No. 36, 2011, pp. 1-11.
M. B. Miranda, T. F. McGuire and D. E. Johnson, “Importance of MEK-1/-2 Signaling in Monocytic and Granulocytic Differentiation of Myeloid Cell Lines,” Leukemia, Vol. 16, No. 4, 2002, pp. 683-692.
M. Milella, S. M. Kornblau, Z. Estrov, et al., “Therapeutic Targeting of the MEK/MAPK Signal Transduction Module in Acute Myeloid Leukemia,” Journal of Clinical Investigation, Vol. 108, No. 6, 2001, pp. 851-859.
S. Takahashi, “Combination Therapy with Arsenic Trioxide for Hematological Malignancies,” Anti-Cancer Agents in Medicinal Chemistry, Vol. 10, No. 6, 2010, pp. 504-510.
P. Lunghi, A. Tabilio, F. Lo-Coco, P. G. Pelicci and A. Bonati, “Arsenic Trioxide (ATO) and MEK1 Inhibition Synergize to Induce Apoptosis in Acute Promyelocytic Leukemia Cells,” Leukemia, Vol. 19, No. 2, 2005, pp. 234-244. doi:10.1038/sj.leu.2403585
P. Lunghi, A. Costanzo, L. Salvatore, et al., “MEK1 Inhibition Sensitizes Primary Acute Myelogenous Leukemia to Arsenic Trioxide-Induced Apoptosis,” Blood, Vol. 107, No. 11, 2006, pp. 4549-4553.
S. Takahashi, H. Harigae, H. Yokoyama, et al., “Synergistic Effect of Arsenic Trioxide and Flt3 Inhibition on Cells with Flt3 Internal Tandem Duplication,” International Journal of Hematology, Vol. 84, No. 3, 2006, pp. 256-261. doi:10.1532/IJH97.06076
S. Takahashi, H. Harigae, J. Kameoka, T. Sasaki and M. Kaku, “AML1B Transcriptional Repressor Function is Impaired by the Flt3 Internal Tandem Duplication,” British Journal of Haematology, Vol. 130, No. 3, 2005, pp. 428-436. doi:10.1186/1756-8722-4-13
S. Takahashi, H. Harigae, M. Kaku, T. Sasaki and J. D. Licht, “Flt3 Mutation Activates p21(WAF1/CIP1) Gene Expression through the Action of STAT5,” Biochemical and Biophysical Research Communications, Vol. 316, No. 1, 2004, pp. 85-92. doi:10.1186/1756-8722-4-36
M. Hirosawa, M. Nakahara, R. Otosaka, et al., “The p38 Pathway Inhibitor SB202190 Activates MEK/MAPK to Stimulate the Growth of Leukemia Cells,” Leukemia Research, Vol. 33, No. 5, 2009, pp. 693-699.
J. Wen, H. Y. Cheng, Y. Feng, et al., “P38 MAPK Inhibition Enhancing ATO-Induced Cytotoxicity Against Multiple Myeloma Cells,” British Journal of Haematology, Vol. 140, No. 2, 2008, pp. 169-180.
A. Verma, M. Mohindru, D. K. Deb, et al., “Activation of Rac1 and the p38 Mitogen-Activated Protein Kinase Pathway in Response to Arsenic Trioxide,” Journal of Biological Chemistry, Vol. 277, No. 47, 2002, pp. 44988- 44995. doi:10.1074/jbc.M207176200
P. Lunghi, N. Giuliani, L. Mazzera, et al., “Targeting MEK/MAPK Signal Transduction Module Potentiates ATO-Induced Apoptosis in Multiple Myeloma Cells through Multiple Signaling Pathways,” Blood, Vol. 112, No. 6, 2008, pp. 2450-2462.
D. Douer and M. S. Tallman, “Arsenic Trioxide: New Clinical Experience with an Old Medication in Hematologic Malignancies,” Journal of Clinical Oncology, Vol. 23, No. 10, 2005, pp. 2396-2410.
M. Cavigelli, W. W. Li, A. Lin, et al., “The Tumor Promoter Arsenite Stimulates AP-1 Activity by Inhibiting a JNK Phosphatase,” The European Molecular Biology Or- ganization Journal, Vol. 15, No. 22, 1996, pp. 6269- 6279.
S. Ludwig, A. Hoffmeyer, M. Goebeler, et al., “The Stress Inducer Arsenite Activates Mitogen-Activated Pro- tein Kinases Extracellular Signal-Regulated Kinases 1 and 2 via a MAPK Kinase 6/p38-Dependent Pathway,” Journal of Biological Chemistry, Vol. 273, No. 4, 1998, pp. 1917-1922. doi:10.1074/jbc.273.4.1917
C. Huang, W. Y. Ma, J. Li, A. Goranson and Z. Dong, “Requirement of Erk, but Not JNK, for Arsenite-Induced Cell Transformation,” Journal of Biological Chemistry, Vol. 274, No. 21, 1999, pp. 14595-14601.
P. Baines, J. Fisher, L. Truran, et al., “The MEK Inhibitor, PD98059, Reduces Survival but Does Not Block Acute Myeloid Leukemia Blast Maturation in vitro,” European Journal of Haematology, Vol. 64, No. 4, 2000, pp. 211- 218. doi:10.1034/j.1600-0609.2000.90139.x
P. Lunghi, A. Tabilio, P. P. Dall'Aglio, et al., “Downmodulation of ERK Activity Inhibits the Proliferation and Induces the Apoptosis of Primary Acute Myelogenous Leukemia Blasts,” Leukemia, Vol. 17, No. 9, 2003, pp. 1783-1793. doi:10.1038/sj.leu.2403032
M. A. Morgan, O. Dolp and C. W. Reuter, “Cell-Cycle- Dependent Activation of Mitogen-Activated Protein Kinase (MEK-1/2) in Myeloid Leukemia Cell Lines and Induction of Growth Inhibition and Apoptosis by Inhibitors of RAS Signaling,” Blood, Vol. 97, No. 6, 2001, pp. 1823-1834. doi:10.1182/blood.V97.6.1823
S. Takahashi, “Inhibition of the MEK/MAPK Signal Transduction Pathway Strongly Impairs the Growth of Flt3-ITD Cells,” American Journal of Hematology, Vol. 81, No. 2, 2006, pp. 154-155. doi:10.1002/ajh.20520