Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia

Journal of Experimental Medicine

Volumn 207, Issue 4, 2010, Pages 731-750

  Callens, Celine ^a,b,d   Coulon, Séverine ^a,b   Naudin, Jerome ^a,b,c   Radford Weiss, Isabelle ^b,d   Boissel, Nicolas ^b,e   Raffoux, Emmanuel ^b,e   Wang, Pamella Huey Mei ^b,c   Agarwal, Saurabh ^b,c   Tamouza, Houda ^b,c   Paubelle, Etienne ^a,b   Asnafi, Vahid ^a,b,d   Ribeil, Jean Antoine ^a,b   Dessen, Philippe ^f   Canioni, Danielle ^b,d   Chandesris, Olivia ^b,d   Rubio, Marie Therese ^b,d   Beaumont, Carole ^b,g   Benhamou, Marc ^b,c   Dombret, Hervé ^b,e   Macintyre, Elizabeth ^a,b,d   Monteiro, Renato C ^b,c   Moura, Ivan Cruz ^b,c   Hermine, Olivier ^a,b,d   more..

^a CNRS   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c INSERM   (France)

^d HÔPITAL NECKER ENFANTS MALADES   (France)

^e SAINT LOUIS HOSPITAL   (France)

^f INSTITUT GUSTAVE ROUSSY   (France)

^g CENTRE DE RECHERCHE BIOMÉDICALE BICHAT BEAUJON CRB3   (France)

Author keywords

[No Author keywords available]

Indexed keywords

CALCIFEDIOL; COLECALCIFEROL RECEPTOR; DEFERASIROX; IRON CHELATING AGENT; MITOGEN ACTIVATED PROTEIN KINASE; REACTIVE OXYGEN METABOLITE; STRESS ACTIVATED PROTEIN KINASE;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; AGED; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BLAST CELL; BONE MARROW; CASE REPORT; CELL DIFFERENTIATION; CELL PROLIFERATION; CONTROLLED STUDY; FEMALE; HOMEOSTASIS; HUMAN; HUMAN CELL; IN VIVO STUDY; MALE; MONOCYTE; MOUSE; NONHUMAN; PANCYTOPENIA; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; STEM CELL;

AGED; ANIMALS; ANTIBODIES, MONOCLONAL; ANTIGENS, CD; ANTIGENS, CD11B; ANTIGENS, CD14; APOPTOSIS; BLOOD CELL COUNT; CELL DIFFERENTIATION; CELL LINE, TUMOR; CELL PROLIFERATION; CHOLECALCIFEROL; DRUG SYNERGISM; FEMALE; GENE EXPRESSION; GENE EXPRESSION PROFILING; GRANULOCYTES; HEMATOPOIETIC STEM CELLS; HOMEOSTASIS; HUMANS; HYDROXYCHOLECALCIFEROLS; IRON; IRON CHELATING AGENTS; JNK MITOGEN-ACTIVATED PROTEIN KINASES; KAPLAN-MEIERS ESTIMATE; LEUKEMIA, MYELOID, ACUTE; MALE; MICE; MICE, NUDE; MITOGEN-ACTIVATED PROTEIN KINASES; MONOCYTES; PHOSPHORYLATION; REACTIVE OXYGEN SPECIES; RECEPTORS, CALCITRIOL; RECEPTORS, TRANSFERRIN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 77951046942     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20091488     Document Type: Article

References (75)

1. Abe, E., C. Miyaura, H. Sakagami, M. Takeda, K. Konno, T. Yamazaki, S. Yoshiki, and T. Suda. 1981. Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. Proc. Natl. Acad. Sci. USA. 78:4990-4994. doi:10.1073/pnas.78.8.4990 (Pubitemid 12225607)
2. Adamson, J.W. 1994. The relationship of erythropoietin and iron metabolism to red blood cell production in humans. Semin. Oncol. 21:9-15.
3. Agramonte-Hevia, J., C. Hallal, C. Garay-Canales, C. Guerra-Araiza, I. Camacho-Arroyo, and E. Ortega Soto. 2003. 1alpha, 25-dihydroxyvitamin D3 alters Syk activation through FcgammaRII in monocytic THP-1 cells. J. Cell. Biochem. 89:1056-1076. doi:10.1002/jcb.10575
4. Amir-Moazami, O., C. Alexia, N. Charles, P. Launay, R.C. Monteiro, and M. Benhamou. 2008. Phospholipid scramblase 1 modulates a selected set of IgE receptor-mediated mast cell responses through LAT-dependent pathway. J. Biol. Chem. 283:25514-25523. doi:10.1074/jbc.M705320200
5. Bastie, J.N., N. Balitrand, F. Guidez, I. Guillemot, J. Larghero, C. Calabresse, C. Chomienne, and L. Delva. 2004. 1 alpha,25-dihydroxyvitamin D3 transrepresses retinoic acid transcriptional activity via vitamin D receptor in myeloid cells. Mol. Endocrinol. 18:2685-2699. doi:10.1210/me.2003-0412
6. Bennett, J.M., D. Catovsky, M.T. Daniel, G. Flandrin, D.A. Galton, H.R. Gralnick, and C. Sultan. 1976. Proposals for the classification of the acute leukaemias. French-American-British (FAB) cooperative group. Br. J. Haematol. 33:451-458. doi:10.1111/j.1365-2141.1976.tb03563.x
7. Boehrer, S., L. Adès, L. Galluzzi, N. Tajeddine, M. Tailler, C. Gardin, S. de Botton, P. Fenaux, and G. Kroemer. 2008. Erlotinib and gefitinib for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a preclinical comparison. Biochem. Pharmacol. 76:1417-1425. doi:10.1016/j.bcp. 2008.05.024
8. Callens, C., I.C. Moura, Y. Lepelletier, S. Coulon, A. Renand, M. Dussiot, D. Ghez, M. Benhamou, R.C. Monteiro, A. Bazarbachi, and O. Hermine. 2008. Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody. Leukemia. 22:42-48. doi:10.1038/sj.leu.2404958
9. Chaston, T.B., R.N. Watts, J. Yuan, and D.R. Richardson. 2004. Potent antitumor activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves fenton-derived free radical generation. Clin. Cancer Res. 10:7365-7374. doi:10.1158/1078-0432.CCR-04-0865
10. Chen, Z., S.J. Chen, and Z.Y. Wang. 1994. Retinoic acid and acute promyelocytic leukemia: a model of targetting treatment for human cancer. C. R. Acad. Sci. III. 317:1135-1141.
11. Chou, T.C., and P. Talalay. 1984. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22:27-55. doi:10.1016/0065-2571(84)90007-4
12. Daniels, T.R., T. Delgado, G. Helguera, and M.L. Penichet. 2006a. The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin. Immunol. 121:159-176. doi:10.1016/j.clim.2006.06.006
13. Daniels, T.R., T. Delgado, J.A. Rodriguez, G. Helguera, and M.L. Penichet. 2006b. The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin. Immunol. 121:144-158. doi:10.1016/j.clim.2006.06.010
14. Davies, M.J. 2005. The oxidative environment and protein damage. Biochim. Biophys. Acta. 1703:93-109.
15. Deeb, K.K., D.L. Trump, and C.S. Johnson. 2007. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer. 7:684-700. doi:10.1038/nrc2196
16. Espósito, B.P., S. Epsztejn, W. Breuer, and Z.I. Cabantchik. 2002. A review of fluorescence methods for assessing labile iron in cells and biological fluids. Anal. Biochem. 304:1-18. doi:10.1006/abio.2002.5611
17. Faulk, W.P., B.L. Hsi, and P.J. Stevens. 1980. Transferrin and transferrin receptors in carcinoma of the breast. Lancet. 2:390-392.
18. Fenton, R.H., F.B. Johnson, and L.E. Zimmerman. 1964. The combined use of microincineration and the Prussian blue reaction for a more sensitive histochemical demonstration of iron. J. Histochem. Cytochem. 12:153-155.
19. Ferrero, D., E. Campa, C. Dellacasa, S. Campana, C. Foli, and M. Boccadoro. 2004. Differentiating agents + low-dose chemotherapy in the management of old/poor prognosis patients with acute myeloid leukemia or myelodysplastic syndrome. Haematologica. 89:619-620.
20. Friedman, A.D. 2002. Transcriptional regulation of granulocyte and monocyte development. Oncogene. 21:3377-3390. doi:10.1038/sj.onc.1205324
21. Friedman, A.D. 2007. Transcriptional control of granulocyte and monocyte development. Oncogene. 26:6816-6828. doi:10.1038/sj.onc.1210764
22. Fröhling, S., C. Scholl, D.G. Gilliland, and R.L. Levine. 2005. Genetics of myeloid malignancies: pathogenetic and clinical implications. J. Clin. Oncol. 23:6285-6295. doi:10.1200/JCO.2005.05.010
23. Fu, D., and D.R. Richardson. 2007. Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclindependent kinase inhibitor p21CIP1/WAF1 by iron depletion. Blood. 110:752-761. doi:10.1182/blood-2007-03-076737 (Pubitemid 47105414)
24. Gatter, K.C., G. Brown, I.S. Trowbridge, R.E. Woolston, and D.Y. Mason. 1983. Transferrin receptors in human tissues: their distribution and possible clinical relevance. J. Clin. Pathol. 36:539-545. doi:10.1136/jcp.36.5.539
25. Gemelli, C., C. Orlandi, T. Zanocco Marani, A. Martello, T. Vignudelli, F. Ferrari, M. Montanari, S. Parenti, A. Testa, A. Grande, and S. Ferrari. 2008. The vitamin D3/HoxA10 pathway supports MafB function during the monocyte differentiation of human CD34+ hemopoietic progenitors. J. Immunol. 181:5660-5672.
26. Gilliland, D.G., C.T. Jordan, and C.A. Felix. 2004. The molecular basis of leukemia. Hematology (Am Soc Hematol Educ Program).80-97.
27. Hahn, C.K., J.E. Berchuck, K.N. Ross, R.M. Kakoza, K. Clauser, A.C. Schinzel, L. Ross, I. Galinsky, T.N. Davis, S.J. Silver, et al. 2009. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell. 16:281-294. doi:10.1016/j.ccr.2009.08.018
28. Himes, S.R., D.P. Sester, T. Ravasi, S.L. Cronau, T. Sasmono, and D.A. Hume. 2006. The JNK are important for development and survival of macrophages. J. Immunol. 176:2219-2228.
29. 3-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex. J. Exp. Med. 190:1583-1594. doi:10.1084/jem.190.11. 1583
30. Hughes, P.J., E. Marcinkowska, E. Gocek, G.P. Studzinski, and G. Brown. 2009. Vitamin D(3)-driven signals for myeloid cell differentiation-Implications for differentiation therapy. Leuk. Res. 10.1016/j.leukres.2009.09.010.
31. Ji, Y., and G.P. Studzinski. 2004. Retinoblastoma protein and CCAAT/enhancer-binding protein beta are required for 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. Cancer Res. 64: 370-377. doi:10.1158/00085472.CAN-03-3029 (Pubitemid 38114120)
32. Johnson, G.L., and R. Lapadat. 2002. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 298:1911-1912. doi:10.1126/science.1072682 (Pubitemid 35425238)
33. Jurutka, P.W., J.C. Hsieh, S. Nakajima, C.A. Haussler, G.K. Whitfield, and M.R. Haussler. 1996. Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation. Proc. Natl. Acad. Sci. USA. 93:3519-3524. doi:10.1073/pnas.93.8.3519
34. Kalyanaraman, B. 2007. Iron signaling and oxidant damage. Cardiovasc. Toxicol. 7:92-94. doi:10.1007/s1201200700251
35. Kansas, G.S., M.J. Muirhead, and M.O. Dailey. 1990. Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans. Blood. 76:2483-2492.
36. Kelly, L.M., and D.G. Gilliland. 2002. Genetics of myeloid leukemias. Annu. Rev. Genomics Hum. Genet. 3:179-198. doi:10.1146/annurev.genom.3.032802. 115046
37. Koeffler, H.P., T. Amatruda, N. Ikekawa, Y. Kobayashi, and H.F. DeLuca. 1984. Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25-dihydroxyvitamin D3 and its fluorinated analogues. Cancer Res. 44:5624-5628.
38. Koeffler, H.P., N. Aslanian, and J. O'Kelly. 2005. Vitamin D(2) analog (Paricalcitol; Zemplar) for treatment of myelodysplastic syndrome. Leuk. Res. 29:1259-1262. doi:10.1016/j.leukres.2005.04.003
39. Le, N.T., and D.R. Richardson. 2004. Iron chelators with high antiproliferative activity up- regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood. 104:2967-2975. doi:10.1182/blood-2004-05-1866
40. Lepelletier, Y., V. Camara-Clayette, H. Jin, A. Hermant, S. Coulon, M. Dussiot, M. Arcos-Fajardo, C. Baude, D. Canionni, R. Delarue, et al. 2007. Prevention of mantle lymphoma tumor establishment by routing transferrin receptor toward lysosomal compartments. Cancer Res. 67:1145-1154. doi:10.1158/000-85472.CAN-06-1962 (Pubitemid 46270772)
41. Lim, B.C., H.J. McArdle, and E.H. Morgan. 1987. Transferrinreceptor interaction and iron uptake by reticulocytes of vertebrate animals - a comparative study. J. Comp. Physiol. [B]. 157:363-371.
42. Livak, K.J., and T.D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402-408. doi:10.1006/meth.2001.1262 (Pubitemid 34164012)
43. Lopez-Bergami, P., C. Huang, J.S. Goydos, D. Yip, M. Bar-Eli, M. Herlyn, K.S. Smalley, A. Mahale, A. Eroshkin, S. Aaronson, and Z. Ronai. 2007. Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell. 11:447-460. doi:10.1016/j.ccr.2007.03.009 (Pubitemid 46670078)
44. Löwenberg, B., J.R. Downing, and A. Burnett. 1999. Acute myeloid leukemia. N. Engl. J. Med. 341:1051-1062. doi:10.1056/NEJM199909303411407
45. Löwenberg, B., G.J. Ossenkoppele, W. van Putten, H.C. Schouten, C. Graux, A. Ferrant, P. Sonneveld, J. Maertens, M. Jongen-Lavrencic, M. von Lilienfeld-Toal, et al; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. 2009. High-dose daunorubicin in older patients with acute myeloid leukemia. N. Engl. J. Med. 361:1235-1248. doi:10.1056/NEJMoa0901409
46. Martindale, J.L., and N.J. Holbrook. 2002. Cellular response to oxidative stress: signaling for suicide and survival. J. Cell. Physiol. 192:1-15. doi:10.1002/jcp.10119
47. Moura, I.C., M.N. Centelles, M. Arcos-Fajardo, D.M. Malheiros, J.F. Collawn, M.D. Cooper, and R.C. Monteiro. 2001. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J. Exp. Med. 194:417-425. doi:10.1084/jem.194.4.417
48. Moura, I.C., Y. Lepelletier, B. Arnulf, P. England, C. Baude, C. Beaumont, A. Bazarbachi, M. Benhamou, R.C. Monteiro, and O. Hermine. 2004. A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients. Blood. 103:1838-1845. doi:10.1182/blood2003072440
49. Mueller, B.U., T. Pabst, M. Osato, N. Asou, L.M. Johansen, M.D. Minden, G. Behre, W. Hiddemann, Y. Ito, and D.G. Tenen. 2002. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood. 100:998-1007. doi:10.1182/blood.V100.3.998 (Pubitemid 34832629)
50. Napier, I., P. Ponka, and D.R. Richardson. 2005. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 105:1867-1874. doi:10.1182/blood-2004-10-3856 (Pubitemid 40731766)
51. Nasr, R., M.C. Guillemin, O. Ferhi, H. Soilihi, L. Peres, C. Berthier, P. Rousselot, M. Robledo-Sarmiento, V. Lallemand-Breitenbach, B. Gourmel, et al. 2008. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat. Med. 14:1333-1342. doi:10.1038/nm.1891
52. Owusu-Ansah, E., and U. Banerjee. 2009. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 461:537-541. doi:10.1038/nature08313
53. Owusu-Ansah, E., A. Yavari, S. Mandal, and U. Banerjee. 2008. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat. Genet. 40:356-361. doi:10.1038/ng.2007.50 (Pubitemid 351311760)
54. Pullarkat, V. 2009. Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the eye? Blood. 114:5251-5255. doi:10.1182/blood2009-07-234062
55. Pullarkat, V., S. Blanchard, B. Tegtmeier, A. Dagis, K. Patane, J. Ito, and S.J. Forman. 2008. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 42:799-805. doi:10.1038/bmt.2008.262
56. Ravandi, F., A.K. Burnett, E.D. Agura, and H.M. Kantarjian. 2007. Progress in the treatment of acute myeloid leukemia. Cancer. 110:1900-1910. doi:10.1002/cncr.23000 (Pubitemid 350041630)
57. Renneville, A., C. Roumier, V. Biggio, O. Nibourel, N. Boissel, P. Fenaux, and C. Preudhomme. 2008. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 22:915-931. doi:10.1038/leu. 2008.19 (Pubitemid 351709343)
58. Ricciardi, M.R., T. McQueen, D. Chism, M. Milella, E. Estey, E. Kaldjian, J. Sebolt-Leopold, M. Konopleva, and M. Andreeff. 2005. Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia. Leukemia. 19:1543-1549. doi:10.1038/sj.leu.2403859
59. Richardson, D., P. Ponka, and E. Baker. 1994. The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell. Cancer Res. 54:685-689. (Pubitemid 24068323)
60. Richardson, D.R., D.S. Kalinowski, S. Lau, P.J. Jansson, and D.B. Lovejoy. 2009. Cancer cell iron metabolism and the development of potent iron chelators as antitumour agents. Biochim. Biophys. Acta. 1790:702-717.
61. Roumier, C., S. Lejeune-Dumoulin, A. Renneville, A.S. Goethgeluck, N. Philippe, P. Fenaux, and C. Preudhomme. 2006. Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients. Leukemia. 20:433-436. doi:10.1038/sj.leu.2404097 (Pubitemid 43291740)
62. Sattler, M., T. Winkler, S. Verma, C.H. Byrne, G. Shrikhande, R. Salgia, and J.D. Griffin. 1999. Hematopoietic growth factors signal through the formation of reactive oxygen species. Blood. 93:2928-2935. (Pubitemid 29200783)
63. Sieweke, M.H., and T. Graf. 1998. A transcription factor party during blood cell differentiation. Curr. Opin. Genet. Dev. 8:545-551. doi:10.1016/S0959-437X(98)800099 (Pubitemid 28477357)
64. Sieweke, M.H., H. Tekotte, J. Frampton, and T. Graf. 1996. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell. 85:49-60. doi:10.1016/S0092-8674(00)81081-8
65. Srivastava, M.D., and J.L. Ambrus. 2004. Effect of 1,25(OH)2 Vitamin D3 analogs on differentiation induction and cytokine modulation in blasts from acute myeloid leukemia patients. Leuk. Lymphoma. 45:2119-2126. doi:10.1080/1042819032000159924
66. Taghon, T., F. Stolz, M. De Smedt, M. Cnockaert, B. Verhasselt, J. Plum, and G. Leclercq. 2002. HOX-A10 regulates hematopoietic lineage commitment: evidence for a monocyte-specific transcription factor. Blood. 99:1197-1204. doi:10.1182/blood.V99.4.1197 (Pubitemid 34547071)
67. Tothova, Z., R. Kollipara, B.J. Huntly, B.H. Lee, D.H. Castrillon, D.E. Cullen, E.P. McDowell, S. Lazo-Kallanian, I.R. Williams, C. Sears, et al. 2007. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 128:325-339. doi:10.1016/j.cell.2007.01.003 (Pubitemid 46137992)
68. Trowbridge, I.S., and D.L. Domingo. 1981. Anti-transferrin receptor monoclonal antibody and toxin-antibody conjugates affect growth of human tumour cells. Nature. 294:171-173. doi:10.1038/294171a0
69. Trowbridge, I.S., and D.A. Shackelford. 1986. Structure and function of transferrin receptors and their relationship to cell growth. Biochem. Soc. Symp. 51:117-129.
70. Wang, Z.Y., and Z. Chen. 2008. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 111:2505-2515. doi:10.1182/blood2007-07-102798
71. Wang, X., and C.G. Proud. 2007. Methods for studying signal-dependent regulation of translation factor activity. Methods Enzymol. 431:113-142. doi:10.1016/S00766879(07)31007-0
72. Wang, Q., X. Wang, and G.P. Studzinski. 2003. Jun N-terminal kinase pathway enhances signaling of monocytic differentiation of human leukemia cells induced by 1,25-dihydroxyvitamin D3. J. Cell. Biochem. 89:1087-1101. doi:10.1002/jcb.10595 (Pubitemid 36959378)
73. Whitmarsh, A.J., and R.J. Davis. 1999. Signal transduction by MAP kinases: regulation by phosphorylation-dependent switches. Sci. STKE. 1999:PE1. doi:10.1126/stke.1999.1.pe1
74. Whitnall, M., J. Howard, P. Ponka, and D.R. Richardson. 2006. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc. Natl. Acad. Sci. USA. 103:14901-14906. doi:10.1073/pnas.0604979103 (Pubitemid 44527826)
75. Zhu, J., V. Lallemand-Breitenbach, and H. de Thé. 2001. Pathways of retinoic acidor arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission. Oncogene. 20:7257-7265. doi:10.1038/sj.onc.1204852 (Pubitemid 33107375)