Publikationsserver der Universitätsbibliothek Marburg
Titel:PLZF/RARalpha binding partners and their influence on the induction of acute promyelocytic leukaemia
Autor:Frech, Miriam
Weitere Beteiligte: Renkawitz-Pohl, Renate (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0075
URN: urn:nbn:de:hebis:04-z2014-00752
DOI: https://doi.org/10.17192/z2014.0075
DDC: Naturwissenschaften
Titel (trans.):Interaktionspartner von PLZF/RARalpha und ihr Einfluss auf die Entwicklung akuter Promyelozytenleukämie
Publikationsdatum:2014-02-19
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Translokation, differentiation block, Chromosomenaberration, Leukämie, acute promyelocytic leukaemia, high molecular weight complex, Akute myeloische Leukämie

Summary:
The acute promyelocytic leukaemia (APL) accounts for 10% of the adult AML patients. APL patients carry chromosomal translocations involving the rarα gene on chromosome 17. The most frequent translocations lead to the expression of the fusion proteins PML/RARα (98%; t(15;17)) and PLZF/RARα (1%; t(11;17)) (X-RARα). The APL is characterised by a differentiation block at the promyelocytic stage and leads to an increased amount of myeloid blasts in the bone marrow and in the peripheral blood. Both X-RARα fusion proteins build high molecular weight (HMW) complexes, which are essential to excert the leukaemic potential. The purpose of this work was to validate and analyse binding partners of the PLZF/RARα fusion protein for their leukaemic potential. IT-based pathway analyses of 20 putative PLZF/RARα binding partners revealed the central proteins actin, c-Fos and Erk1/2. VASP, TFII-I and PI4KIIα were selected for further studies, due to their direct influence on the proteins mentioned above. The interaction studies validated the binding of PLZF/RARα with all three proteins: VASP, TFII-I and PI4KIIα. The binding occurs in all cases mainly through the RARα portion. The PLZF/RARα expression causes the dephosphorylation of the actin-associated phosphoprotein VASP, which leads to its cellular delocalisation. The hypophosphorylation of VASP is probably connected with the proteasomal degradation of the kinases PKA and/or PKG. Treatment with the standard APL therapeutic all-trans retinoic acid (ATRA) reestablished VASP phosphorylation in PLZF/RARα -expressing cells. The leukaemic fusion protein co-localised with the transcription factor TFII-I in the nucleus. Furthermore, the expression of both X-RARα fusion proteins causes the deregulation of TFII-I target genes. TFII-I is at least sequestered by PML/RARα, since ATRA treatment reverts in nearly all cases the aberrant expression of the TFII-I target genes. Additionally, the important TFII-I target gene c-fos, which is an protooncogene and part of the AP-1 transcription factor family was overexpressed in the presence of the X-RARα proteins. Moreover, PLZF/RARα caused the translocation of the lipid kinase PI4KIIα to the nucleus, leading to their co-localisation. It was shown before that PI4KIIα overexpression leads to an increased synthesis of PI(4)P and the subsequent induction of Erk1/2, while the expression of PLZF/RARα inhibits PI4KIIα activity. Further analyses showed that the sequestration of the kinase resulted in the inactivation of Erk1/2. ATRA treatment induced Erk1/2 activation in control and PML/RARα -expressing cells, but not in the ATRA-resistent PLZF/RARα -expressing cells. Differentiation experiments in murine haematopoietic progenitor cells showed that PI4KIIα expression is essential for the myeloid differentiation. However, the overexpression of PI4KIIα in PLZF/RARα -expressing cells alone could not overcome the differentiation block. In summary, the PLZF/RARα fusion protein disturbs the normal activity and functionality of its interaction partners, which contributes to the development of APL. New APL marker proteins and pathways were identified and validated. These marker proteins represent putative therapeutic targets. Further examinations could lead to an improved treatment of patients with the PLZF/RARα-associated APL.

Bibliographie / References

  1. Weissman, I. L., Anderson, D. J. & Gage, F. (2001). Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdiffe- rentiations. Annu Rev Cell Dev Biol 17, 387-403.
  2. Cilloni, D. & Saglio, G. (2012). Molecular pathways: BCR-ABL. Clin Cancer Res 18, 930-7.
  3. G., Pelicci, P. G., Nervi, C. & Ruthardt, M. (2002). AML-associated translocation products block vitamin D 3 -induced differentiation by seques- tering the vitamin D 3 receptor. Cancer Res 62, 7050-8.
  4. Lanotte, M., Martin-Thouvenin, V., Najman, S., Balerini, P., Va- lensi, F. & Berger, R. (1991). NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood 77, 1080-6.
  5. Geest, C. R. & Coffer, P. J. (2009). MAPK signaling pathways in the regulation of hematopoiesis. J Leukoc Biol 86, 237-50.
  6. Szabo, E., Preis, L. H., Brown, P. H. & Birrer, M. J. (1991). The role of jun and fos gene family members in 12-O-tetradecanoylphorbol-13- acetate induced hemopoietic differentiation. Cell Growth Differ 2, 475-82.
  7. Eckert, R. E. & Jones, S. L. (2007). Regulation of VASP serine 157 phosphorylation in human neutrophils after stimulation by a chemoattrac- tant. J Leukoc Biol 82, 1311-21.
  8. Minogue, S., Anderson, J. S., Waugh, M. G., dos Santos, M., Corless, S., Cramer, R. & Hsuan, J. J. (2001). Cloning of a human type II phosphatidylinositol 4-kinase reveals a novel lipid kinase family. J Biol Chem 276, 16635-40.
  9. Ham, J., Babij, C., Whitfield, J., Pfarr, C. M., Lallemand, D., Yaniv, M. & Rubin, L. L. (1995). A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 14, 927-39.
  10. Yang, W.-C. & Shih, H.-M. (2012). The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability. On- cogene doi: 10.1038/onc.2012.537.
  11. Beez, S., Demmer, P. & Puccetti, E. (2012). Targeting the acute promyelocytic leukemia-associated fusion proteins PML/RARα and PLZF/RARα with interfering peptides. PLoS One e48636, doi: 10.1371/journal.pone.0048636.
  12. Bayarsaihan, D., Makeyev, A. V. & Enkhmandakh, B. (2012). Epi- genetic modulation by TFII-I during embryonic stem cell differentiation. J Cell Biochem 113, 3056-60.
  13. Ramazzotti, G., Faenza, I., Fiume, R., Matteucci, A., Piazzi, M., Follo, M. Y. & Cocco, L. (2010). The physiology and pathology of inositide signaling in the nucleus. J Cell Physiol 226, 14-20.
  14. Protein phosphorylation regulated by cyclic nucleotide-dependent protein kinases in cell extracts and in intact human lymphocytes. Cell Signal 4, 189-99.
  15. Martelli, A. M., Cataldi, A., Manzoli, L., Billi, A. M., Rubbini, S., Gilmour, R. S. & Cocco, L. (1995). Inositides in nuclei of Friend cells: changes of polyphosphoinositide and diacylglycerol levels accompany cell differentiation. Cell Signal 7, 53-6.
  16. Martelli, A. M., Evangelisti, C., Chiarini, F., Grimaldi, C., Cap- pellini, A., Ognibene, A. & McCubrey, J. A. (2010). The emerging role of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamy- cin signaling network in normal myelopoiesis and leukemogenesis. Biochim Biophys Acta 1803, 991-1002.
  17. Waugh, M. G. (2012). Phosphatidylinositol 4-kinases, phosphatidylinosi- tol 4-phosphate and cancer. Cancer Lett 325, 125-31.
  18. Akashi, K., Traver, D. & Zon, L. I. (2005). The complex cartography of stem cell commitment. Cell 121, 160-2.
  19. Hou, Y., Wong, E., Martin, J., Schoenlein, P. V., Dostmann, W. R. & Browning, D. D. (2006). A role for cyclic-GMP dependent protein kinase in anoikis. Cell Signal 18, 882-8.
  20. Benz, P. M., Feller, S. M., Sickmann, A., Walter, U. & Renné T. (2008). Prostaglandin-induced VASP phosphorylation controls αII-spectrin breakdown in apoptotic cells. Int Immunopharmacol 8, 319-24.
  21. Versatility and nuances of the architecture of haematopoiesis -Implications for the nature of leukaemia. Leuk Res 36, 14-22.
  22. Lou, Y., Qian, W., Meng, H., Mai, W., Tong, H., Tong, Y., Huang, J. & Jin, J. (2012). High efficacy of arsenic trioxide plus all-trans retinoic acid based induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia. Leuk Res http://dx.doi.org/10.1016/j.leukres.2012.09.004.
  23. Sessler, R. J. & Noy, N. (2005). A Ligand-Activated Nuclear Loca- lization Signal in Cellular Retinoic Acid Binding Protein-II. Mol Cell 18, 343-53.
  24. Kim, C. J., Shimakage, M., Kushima, R., Mukaisho, K., Shinka, T., Okada, Y. & Inoue, H. (2003). Down-regulation of drs mRNA in human prostate carcinomas. Hum Pathol 34, 654-7.
  25. Hüttelmaier, S., Mayboroda, O., Harbeck, B., Jarchau, T., Jo- ckusch, B. M. & Rüdiger, M. (1998). The interaction of the cell- contact proteins VASP and vinculin is regulated by phosphatidylinositol- 4,5-bisphosphate. Curr Biol 8, 479-88.
  26. Kwiatkowski, A. V., Gertler, F. B. & Loureiro, J. J. (2003). Function and regulation of Ena/VASP proteins. Trends Cell Biol 13, 386-92.
  27. Lin, R. J. & Evans, R. M. (2000). Acquisition of Oncogenic Potential by RAR Chimeras in Acute Promyelocytic Leukemia through Formation of Homodimers. Mol Cell 5, 821-30.
  28. Nemeth, M. J. & Bodine, D. M. (2007). Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways. Cell Res 17, 746-58.
  29. Seshire, A., Rößiger, T., Frech, M., Beez, S., Hagemeyer, H. & Puccetti, E. (2012). Direct interaction of PU.1 with oncogenic transcrip- tion factors reduces its serine phosphorylation and promoter binding. Leu- kemia 26, 1338-47.
  30. Ceredig, R., Rolink, A. G. & Brown, G. (2009). Models of haemato- poiesis: seeing the wood for the trees. Nat Rev Immunol 9, 293-300.
  31. Zhao, Q., Tao, J., Zhu, Q., Jia, P. M., Dou, A. X., Li, X., Cheng, F., Waxman, S., Chen, G. Q., Chen, S. J., Lanotte, M., Chen, Z. & Tong, J. H. (2004). Rapid induction of cAMP/PKA pathway du- ring retinoic acid-induced acute promyelocytic leukemia cell differentiation. Leukemia 18, 285-92.
  32. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leu- kemia 19, 1345-9.
  33. Slovak, M. L., Gundacker, H., Bloomfield, C. D., Dewald, G., Ap- pelbaum, F. R., Larson, R. A., Tallman, M. S., Bennett, J. M., Stirewalt, D. L., Meshinchi, S., Willman, C. L., Ravindranath, Y., Alonzo, T. A., Carroll, A. J., Raimondi, S. C. & Heerema, N. A. (2006). A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies. Leukemia 20, 1295-7.
  34. Tussié-Luna, M. I., Rozo, L. & Roy, A. L. (2006). Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia. Oncogene 25, 3375-86.
  35. Puccetti, E., Sennewald, B., Fosca-Ferrara, F., Boehrer, S., Bian- chini, A., Hoelzer, D., Ottmann, O. G., Nervi, C. & Ruthardt, M. (2001). Down-stream regions of the POZ-domain influence the interac- tion of the t(11;17)-associated PLZF/RARα fusion protein with the histone- deacetylase recruiting co-repressor complex. Hematol J 2, 385-92.
  36. Maruoka, M., Sato, M., Yuan, Y., Ichiba, M., Fujii, R., Ogawa, T., Ishida-Kitagawa, N., Takeya, T. & Watanabe, N. (2012). Abi- 1-bridged tyrosine phosphorylation of VASP by Abelson kinase impairs as- sociation of VASP to focal adhesions and regulates leukaemic cell adhesion. Biochem J 441, 889-99.
  37. Shimakage, M., Takami, K., Kodama, K., Mano, M., Yutsudo, M. & Inoue, H. (2002). Expression of drs mRNA in human lung adenocarci- nomas. Hum Pathol 33, 615-9.
  38. Kubiseski, T. J., Chook, Y. M., Parris, W. E., Rozakis-Adcock, M. & Pawson, T. (1997). High affinity binding of the pleckstrin homology domain of mSos1 to phosphatidylinositol (4,5)-bisphosphate. J Biol Chem 272, 1799-804.
  39. de Thé, H., Le Bras, M. & Lallemand-Breitenbach, V. (2012). The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol 198, 11-21.
  40. Rajagopalan, D. & Agarwal, P. (2005). Inferring pathways from gene lists using a literature-derived network of biological relationships. Bioinfor- matics 21, 788-93.
  41. Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs. Carcinogenesis 28, 777-84.
  42. Meindl, A., Carvalho, M. R., Herrmann, K., Lorenz, B., Achatz, H., Lorenz, B., Apfelstedt-Sylla, E., Wittwer, B., Ross, M. & Mei- tinger, T. (1995). A gene (SRPX) encoding a sushi-repeat-containing pro- tein is deleted in patients with X-linked retinitis pigmentosa. Hum Mol Genet 4, 2339-46.
  43. Pérez Jurado, L. A., Wang, Y. K., Peoples, R., Coloma, A., Cruces, J. & Francke, U. (1998). A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum Mol Genet 7, 325-34.
  44. Takaku, M., Ueno, H. & Kurumizaka, H. (2011). Biochemical analy- sis of the human ENA/VASP-family proteins, MENA, VASP and EVL, in homologous recombination. J Biochem 149, 721-9.
  45. Boureux, A., Vignal, E., Faure, S. & Fort, P. (2007). Evolution of the Rho Family of Ras-Like GTPases in Eukaryotes. Mol Biol Evol 24, 203-16.
  46. Doulatov, S., Notta, F., Rice, K. L., Howell, L., Zelent, A., Licht, J. D. & Dick, J. E. (2009). PLZF is a regulator of homeostatic and cytokine-induced myeloid development. Genes Dev 23, 2076-87.
  47. Crusselle-Davis, V. J., Zhou, Z., Anantharaman, A., Moghimi, B., Dodev, T., Huang, S. & Bungert, J. (2007). Recruitment of coregulator complexes to the β-globin gene locus by TFII-I and upstream stimulatory factor. FEBS J 274, 6065-73.
  48. Caraveo, G., van Rossum, D. B., Patterson, R. L., Snyder, S. H. & Desiderio, S. (2006). Action of TFII-I outside the nucleus as an inhibitor of agonist-induced calcium entry. Science 314, 122-5.
  49. Anantharaman, A., Lin, I. J., Barrow, J., Liang, S. Y., Masannat, J., Strouboulis, J., Huang, S. & Bungert, J. (2011). Role of helix- loop-helix proteins during differentiation of erythroid cells. Mol Cell Biol 31, 1332-43.
  50. Liu, K., Li, L., Nisson, P. E., Gruber, C., Jessee, J. & Cohen, S. N. (1999). Reversible tumorigenesis induced by deficiency of vasodilator- stimulated phosphoprotein. Mol Cell Biol 19, 3696-703.
  51. Puccetti, E., Zheng, X., Brambilla, D., Seshire, A., Beissert, T., Boehrer, S., Nürnberger, H., Hoelzer, D., Ottmann, O. G., Nervi, C. & Ruthardt, M. (2005). The integrity of the charged pocket in the BTB/POZ domain is essential for the phenotype induced by the leukemia- associated t(11;17) fusion protein PLZF/RARα. Cancer Res 65, 6080-8.
  52. Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1. Cancer Res 66, 2990-6.
  53. Wadhwa, M. & Thorpe, R. (2008). Haematopoietic growth factors and their therapeutic use. Thromb Haemost 99, 863-73.
  54. Le Beau, M. M., Davis, E. M., Patel, B., Phan, V. T., Sohal, J. & Kogan, S. C. (2003). Recurring chromosomal abnormalities in leuke- mia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia. Blood 102, 1072-4.
  55. Follo, M. Y., Finelli, C., Clissa, C., Mongiorgi, S., Bosi, C., Mar- tinelli, G., Baccarani, M., Manzoli, L., Martelli, A. M. & Cocco, L. (2009). Phosphoinositide-phospholipase Cβ1 mono-allelic deletion is as- sociated with myelodysplastic syndromes evolution into acute myeloid leu- kemia. J Clin Oncol 27, 782-90.
  56. The Ena/VASP enigma. J Cell Sci 115, 4721-6.
  57. Minogue, S., Waugh, M. G., De Matteis, M. A., Stephens, D. J., Berditchevski, F. & Hsuan, J. J. (2006). Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor. J Cell Sci 119, 571-81.
  58. Bear, J. E. & Gertler, F. B. (2009). Ena/VASP: towards resolving a pointed controversy at the barbed end. J Cell Sci 122, 1947-53.
  59. Benz, P. M., Blume, C., Seifert, S., Wilhelm, S., Waschke, J., Schuh, K., Gertler, F., Münzel, T. & Renné, T. (2009). Differential VASP phosphorylation controls remodeling of the actin cytoskeleton. J Cell Sci 122, 3954-65.
  60. Kondo, T., Mori, A., Darmanin, S., Hashino, S., Tanaka, J. & Asaka, M. (2008). The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. Haematologica 93, 1414-6.
  61. Shimakage, M., Inoue, N., Ohshima, K., Kawahara, K., Yama- moto, N., Oka, T., Tambe, Y., Yasui, K., Matsumoto, K., Yut- sudo, M. & Inoue, H. (2007). Downregulation of drs mRNA expression is associated with the progression of adult T-cell leukemia/lymphoma. Int J Oncol 30, 1343-8.
  62. Tao, Y., Chen, Y. C., Sang, J. R. & Xu, W. R. (2010). Phosphory- lation of vasodilator stimulated phosphoprotein is correlated with cell cycle progression in HeLa cells. Mol Med Report 3, 657-62.
  63. Lawrence, D. W. & Pryzwansky, K. B. (2001). The vasodilator- stimulated phosphoprotein is regulated by cyclic GMP-dependent protein kinase during neutrophil spreading. J Immunol 166, 5550-6.
  64. Metcalf, D. (2006). Loss of PU.1: one of the many roads to myeloid leukemia. Cell Cycle 5, 673-4.
  65. Schiffer, C. A. & Stone R. M. (2000). Acute myeloid leukemia in adults. Holland & Frei: Cancer Medicine Edition 5, B. C. Decker Inc.
  66. Koschmieder, S., Rosenbauer, F., Steidl, U., Owens, B. M. & Te- nen, D. G. (2005). Role of transcription factors C/EBPalpha and PU.1 in normal hematopoiesis and leukemia. Int J Hematol 81, 368-77.
  67. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet 36, 624-30.
  68. Sykes, S. M., Lane, S. W., Bullinger, L., Kalaitzidis, D., Yusuf, R., Saez, B., Ferraro, F., Mercier, F., Singh, H., Brumme, K. M., Acharya, S. S., Scholl, C., Tothova, Z., Attar, E. C., Fröhling, S., DePinho, R. A., Armstrong, S. A., Gilliland, D. G. & Scadden, D. T. (2011). AKT/FOXO signaling enforces reversible differentiation blo- ckade in myeloid leukemias. Cell 146, 697-708.
  69. Tambe, Y., Isono, T., Haraguchi, S., Yoshioka-Yamashita, A., Yut- sudo, M. & Inoue, H. (2004). A novel apoptotic pathway induced by the drs tumor suppressor gene. Oncogene 23, 2977-87.
  70. O'Carroll, S. J., Mitchell, M. D., Faenza, I., Cocco, L. & Gilmour, R. S. (2009). Nuclear PLC beta 1 is required for 3T3-L1 adipocyte differen- tiation and regulates expression of the cyclin D3-cdk4 complex. Cell Signal 21, 926-35.
  71. Holt, M. R., Critchley, D. R. & Brindle, N. P. (1998). The focal adhesion phosphoprotein, VASP. Int J Biochem Cell Biol 30, 307-11.
  72. Minucci, S., Maccarana, M., Cioce, M., De Luca, P., Gelmetti, V., Segalla, S., Di Croce, L., Giavara, S., Matteucci, C., Gobbi, A., Bianchini, A., Colombo, E., Schiavoni, I., Badaracco, G., Hu, X., Lazar, M. A., Landsberger, N., Nervi, C. & Pelicci, P. G. (2000). Oligomerization of RAR and AML1 Transcription Factors as a Novel Mechanism of Oncogenic Activation. Mol Cell 5, 811-20.
  73. Ruthardt, M., Orleth, A., Tomassoni, L., Puccetti, E., Riganelli, D., Alcalay, M., Mannucci, R., Nicoletti, I., Grignani, F., Fagioli, M. & Pelicci, P. G. (1998). The acute promyelocytic leukaemia specific PML and PLZF proteins localize to adjacent and functionally distinct nuclear bodies. Oncogene 16, 1945-53.
  74. Gene expression profiling of bone marrow endothelial cells in patients with multiple myeloma. Clin Cancer Res 15, 5369-78.
  75. Alemdehy, M. F. & Erkeland, S. J. (2012-1). MicroRNAs: key players of normal and malignant myelopoiesis. Curr Opin Hematol 19, 261-7.
  76. Wang, Z.-Y. & Chen, Z. (2008). Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111, 2505-15.
  77. Cheriyath, V. & Roy, A. L. (2000). Alternatively spliced isoforms of TFII-I. Complex formation, nuclear translocation, and differential gene re- gulation. J Biol Chem 275, 26300-8.
  78. Thiede, C., Steudel, C., Mohr, B., Schaich, M., Schäkel, U., Platz- becker, U., Wermke, M., Bornhäuser, M., Ritter, M., Neubauer, A., Ehninger, G. & Illmer, T. (2002). Analysis of FLT3-activating mu- tations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99, 4326-35.
  79. Barylko, B., Gerber, S. H., Binns, D. D., Grichine, N., Khvotchev, M., Südhof, T. C. & Albanesi, J. P. (2001). A novel family of phospha- tidylinositol 4-kinases conserved from yeast to humans. J Biol Chem 276, 7705-8.
  80. Michl, M. (2011). BASICS Hämatologie. München: Elsevier -Urban & Fischer 2. Auflage.
  81. Butt, E., Abel, K., Krieger, M., Palm, D., Hoppe, V., Hoppe, J. & Walter, U. (1994). cAMP-and cGMP-dependent protein kinase phos- phorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets. J Biol Chem 20, 14509-17.
  82. Duprez, E., Lillehaug, J. R., Naoe, T. & Lanotte, M. (1996). cAMP signalling is decisive for recovery of nuclear bodies (PODs) during maturation of RA-resistant t(15;17) promyelocytic leukemia NB4 cells expressing PML- RARα. Oncogene 12, 2451-9.
  83. Okuducu, A. F., Janzen, V., Ko, Y., Hahne, J. C., Lu, H., Ma, Z. L., Albers, P., Sahin, A., Wellmann, A., Scheinert, P. & Wernert, N. (2005). Cellular retinoic acid-binding protein 2 is down-regulated in prostate cancer. Int J Oncol 27, 1273-82.
  84. Lu, C., Shen, Q., DuPré, E., Kim, H., Hilsenbeck, S. & Brown, P. H. (2005). cFos is critical for MCF-7 breast cancer cell growth. Oncogene 24, 6516-24.
  85. Casteel, D. E., Zhuang, S., Gudi, T., Tang, J., Vuica, M., Desiderio, S. & Pilz, R. B. (2002). cGMP-dependent protein kinase Iβ physically and functionally interacts with the transcriptional regulator TFII-I. J Biol Chem 277, 32003-14.
  86. Nervi, C., Poindexter, E. C., Grignani, F., Pandolfi, P. P., Lo Coco, F., Avvisati, G., Pelicci, P. G., Jetten, A. M. (1992). Characteriza- tion of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation. Cancer Res 52, 3687-92.
  87. Benedetti, L., Levin, A. A., Scicchitano, B. M., Grignani, F., Al- lenby, G., Diverio, D., Lo Coco, F., Avvisati, G., Ruthardt, M., Adamo, S., Pelicci, P. G. & Nervi, C. (1997). Characterization of the Retinoid Binding Properties of the Major Fusion Products Present in Acute Promyelocytic Leukemia Cells. Blood 90, 1175-85.
  88. Cooperative interaction of an initiator-binding transcription initiation factor and the helix-loop-helix activator USF. Nature 354, 245-8.
  89. Bennett, J. M., Catovsky, D., Daniel, M.-T., Flandrin, G., Galton, D. A., Gralnick, H. R. & Sultan, C. (1985). Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French- American-British Cooperative Group. Ann Intern Med 103, 460-2.
  90. Eigenthaler, M., Ullrich, H., Geiger, J., Horstrup, K., Hönig-Liedl, P., Wiebecke, D. & Walter, U. (1993). Defective nitrovasodilator- stimulated protein phosphorylation and calcium regulation in cGMP- dependent protein kinase-deficient human platelets of chronic myelocytic leukemia. J Biol Chem 268, 13526-31.
  91. Seshire, A. (2006). Die Rolle der Makrokomplexe von PML/RARα und PLZF/RARα für die Pathogenese der akuten Promyelozyten Leukämie. Dis- sertation of the department of Pharmacy of the Johann Wolfgang Goethe- University Frankfurt (Main).
  92. Mao, C., Ray-Gallet, D., Tavitian, A. & Moreau-Gachelin, F. (1996). Differential phosphorylations of Spi-B and Spi-1 transcription fac- tors. Oncogene 12, 863-73.
  93. He, L.-Z., Guidez, F., Tribioli, C., Peruzzi, D., Ruthardt, M., Zelent, A. & Pandolfi, P. P. (1998). Distinct interactions of PML-RARα and PLZF-RARα with co-repressors determine differential responses to RA in APL. Nat Genet 18, 126-35.
  94. [121] Männich, J. (2011). Einfluss der Fusionsproteine PLZF-RARα und PML- RARα auf die Funktion der PI4KIIα. Diploma thesis of the department of Medicine of the Philipps-University Marburg.
  95. Grignani, F., Gelmetti, V., Fanelli, M., Rogaia, D., De Matteis, S., Ferrara, F. F., Bonci, D., Grignani, F., Nervi, C. & Pelicci, P. G. (1999). Formation of PML/RARα high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RARα-mediated retinoic acid response. Oncogene 18, 6313-21.
  96. Smith, C. (2003). Hematopoietic stem cells and hematopoiesis. Cancer Control 10, 9-16.
  97. Dalton, W. T. Jr., Ahearn, M. J., McCredie, K. B., Freireich, E. J., Stass, S. A. & Trujillo, J. M. (1988). HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3. Blood 71, 242-7.
  98. Mi, J.-Q., Li, J.-M., Shen, Z.-X., Chen, S.-J. & Chen, Z. (2012). How to manage acute promyelocytic leukemia. Leukemia 26, 1743-51.
  99. Misra, U. K., Mowery, Y. M., Gawdi, G. & Pizzo, S. V. (2011). Loss of cell surface TFII-I promotes apoptosis in prostate cancer cells stimulated with activated α 2 -macroglobulin. J Cell Biochem 112, 1685-95.
  100. Platanias, L. C. (2003). Map kinase signaling pathways and hematologic malignancies. Blood 101, 4667-79.
  101. Mitani, K. (2004). Molecular mechanisms of leukemogenesis by AML1/EVI-1. Oncogene 23, 4263-9.
  102. Beez, S. (2012). Molekulares Targeting von akuter Promyelozytenleukämie (APL)-assoziierter Fusionsproteine. Dissertation of the department of Medi- cine of the Philipps-University Marburg.
  103. Jansen, J. H., Mahfoudi, A., Rambaud, S., Lavau, C., Wahli, W. & Dejean, A. (1995). Multimeric complexes of the PML-retinoic acid receptor α fusion protein in acute promyelocytic leukemia cells and inter- ference with retinoid and peroxisome-proliferator signaling pathways. Proc Natl Acad Sci U S A 92, 7401-5.
  104. Mesa, R. (2008). Myeloproliferative disorder-associated massive splenome- galy. Clin Adv Hematol Oncol 6, 278, 281-2.
  105. Sakamuro, D. & Prendergast, G. C. (1999). New Myc-interacting pro- teins: a second Myc network emerges. Oncogene 18, 2942-54.
  106. Passegué, E., Jamieson, C. H., Ailles, L. E. & Weissman, I. L. (2003). Normal and leukemic hematopoiesis: are leukemias a stem cell di- sorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A 100, 11842-9.
  107. Follo, M. Y., Mongiorgi, S., Finelli, C., Clissa, C., Ramazzotti, G., Fiume, R., Faenza, I., Manzoli, L., Martelli, A. M. & Cocco, L. (2010). Nuclear inositide signaling in myelodysplastic syndromes. J Cell Biochem 109, 1065-71.
  108. Wang, P. Y., Weng, J. & Anderson, R. G. (2005). OSBP is a cholesterol-regulated scaffolding protein in control of ERK 1/2 activation. Science 307, 1472-6.
  109. Balla, A. & Balla, T. (2006). Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol 16, 351-61.
  110. Phosphoinositide signaling disorders in human diseases. FEBS Lett 546, 25-31.
  111. Prestwich, G. D. (2004). Phosphoinositide signaling; from affinity probes to pharmaceutical targets. Chem Biol 11, 619-37.
  112. Di Paolo, G. & De Camilli, P. (2006). Phosphoinositides in cell regula- tion and membrane dynamics. Nature 443, 651-7.
  113. Tussié-Luna, M. I., Bayarsaihan, D., Seto, E., Ruddle, F. H. & Roy, A. L. (2002). Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxβ. Proc Natl Acad Sci U S A 99, 12807-12.
  114. Frech, M., Männich, J. & Puccetti, E. (Submitted). PI4KIIα nuclear sequester by oncogenic transcription factors lead to ERK1/2 inactivation.
  115. Bennett, J. M., Catovsky, D., Daniel, M.-T., Flandrin, G., Galton, D. A., Gralnick, H. R. & Sultan, C. (1991). Proposal for the recogni- tion of minimally differentiated acute myeloid leukaemia (AML-MO). Br J Haematol 78, 325-9.
  116. Bennett, J. M., Catovsky, D., Daniel, M.-T., Flandrin, G., Galton, D. A., Gralnick, H. R. & Sultan, C. (1976). Proposals for the classifi- cation of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33, 451-8.
  117. Licht, J. D., Shaknovich, R., English, M. A., Melnick, A., Li, J. Y., Reddy, J. C., Dong, S., Chen, S. J., Zelent, A. & Waxman, S. (1996). Reduced and altered DNA-binding and transcriptional proper- ties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11;17)- associated acute promyelocytic leukemia. Oncogene 12, 323-36.
  118. Regulation of human endothelial cell focal adhesion sites and migration by cGMP-dependent protein kinase I. J Biol Chem 275, 25723-32.
  119. Zhu, J., Gianni, M., Kopf, E., Honoré, N., Chelbi-Alix, M., Koken, M., Quignon, F., Rochette-Egly, C. & de Thé, H. (1999). Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins. Proc Natl Acad Sci U S A 96, 14807-12.
  120. Steelman, L. S., Franklin, R. A., Abrams, S. L., Chappell, W., Kempf, C. R., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., Nicoletti, F., Libra, M., Ruvolo, P., Ruvolo, V., Evange- listi, C., Martelli, A. M. & McCubrey, J. A. (2011). Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 25, 1080-94.
  121. Moreau-Gachelin, F., Tavitian, A. & Tambourin, P. (1988). Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature 331, 277-80.
  122. Gianni, M., Terao, M., Fortino, I., LiCalzi, M., Viggiano, V., Bar- bui, T., Rambaldi, A. & Garattini, E. (1997). Stat1 is induced and activated by all-trans retinoic acid in acute promyelocytic leukemia cells. Blood 89, 1001-12.
  123. Halbrügge, M., Friedrich, C., Eigenthaler, M., Schanzenbächer, P. & Walter, U. (1990). Stoichiometric and reversible phosphorylation of a 46-kDa protein in human platelets in response to cGMP-and cAMP- elevating vasodilators. J Biol Chem 265, 3088-93.
  124. Brown, P. H., Alani, R., Preis, L. H., Szabo, E. & Birrer, M. J. (1993). Suppression of oncogene-induced transformation by a deletion mutant of c-jun. Oncogene 8, 877-86.
  125. Mano H. (1999). Tec family of protein-tyrosine kinases: an overview of their structure and function. Cytokine Growth Factor Rev 10, 267-80.
  126. Peterson, L. F. & Zhang, D. E. (2004). The 8;21 translocation in leu- kemogenesis. Oncogene 23, 4255-62.
  127. [27] Buitenhuis, M. & Coffer, P. J. (2009). The role of the PI3K-PKB signaling module in regulation of hematopoiesis. Cell Cycle 8, 560-6.
  128. Zelent, A., Guidez, F., Melnick, A., Waxman, S. & Licht, J. D. (2001). Translocations of the RARα gene in acute promyelocytic leukemia. Oncogene 20, 7186-203.
  129. Lengfelder, E., Gnad, U., Büchner, T. & Hehlmann, R. (2003). Treatment of relapsed acute promyelocytic leukemia. Onkologie 26, 373-9.
  130. Wei, Y. J., Sun, H. Q., Yamamoto, M., Wlodarski, P., Kunii, K., Martinez, M., Barylko, B., Albanesi, J. P. & Yin, H. L. (2002). Type II phosphatidylinositol 4-kinase β is a cytosolic and peripheral membrane protein that is recruited to the plasma membrane and activated by Rac- GTP. J Biol Chem 277, 46586-93.
  131. Lee, G. R., Foerster, J., Lukens, J., Paraskevas, F., Green, J. P. & Rodgers, G. M. (1998). Wintrobe's Clinical Hematology. Baltimore: Williams & Wilkins 10 Edition, P. W., ed.
  132. Adolfsson, J., Månsson, R., Buza-Vidas, N., Hultquist, A., Liuba, K., Jensen, C. T., Bryder, D., Yang, L., Borge, O. J., Thoren, L. A., Anderson, K., Sitnicka, E., Sasaki, Y., Sigvardsson, M. & Jacobsen, S. E. (2005). Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295-306.
  133. Till, J. E. & McCulloch, E. A. (1961). A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14, 213-22.
  134. Chimge, N. O., Mungunsukh, O., Ruddle, F. & Bayarsaihan, D. (2007). Gene expression analysis of TFII-I modulated genes in mouse em- bryonic fibroblasts. J Exp Zool B Mol Dev Evol 308, 225-35.
  135. Abel, K., Mieskes, G. & Walter, U. (1995). Dephosphorylation of the focal adhesion protein VASP in vitro and in intact human platelets. FEBS Lett 370, 184-8.
  136. Pan, J., Nakanishi, K., Yutsudo, M., Inoue, H., Li, Q., Oka, K., Yoshioka, N. & Hakura, A. (1996). Isolation of a novel gene down- regulated by v-src. FEBS Lett 383, 21-5.
  137. Hasle, H., Alonzo, T. A., Auvrignon, A., Behar, C., Chang, M., Creutzig, U., Fischer, A., Forestier, E., Fynn, A., Haas, O. A., Har- bott, J., Harrison, C. J., Heerema, N. A., van den Heuvel-Eibrink, M. M., Kaspers, G. J., Locatelli, F., Noellke, P., Polychronopou- lou, S., Ravindranath, Y., Razzouk, B., Reinhardt, D., Savva, N. N., Stark, B., Suciu, S., Tsukimoto, I., Webb, D. K., Wojcik, D., Woods, W. G., Zimmermann, M., Niemeyer, C. M. & Raimondi, S. C. (2007). Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study. Blood 109, 4641-7.
  138. Zhu, J. & Emerson, S. G. (2002). Hematopoietic cytokines, transcription factors and lineage commitment. Oncogene 21, 3295-313.
  139. Yamashita, A., Hakura, A. & Inoue, H. (1999). Suppression of anchorage-independent growth of human cancer cell lines by the drs gene. Oncogene 18, 4777-87.
  140. Resh, M. D. (2006). Palmitoylation of ligands, receptors, and intracellular signaling molecules. Sci STKE 2006, re14.
  141. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood 101, 270-7.
  142. Catalano, A., Dawson, M. A., Somana, K., Opat, S., Schwarer, A., Campbell, L. J. & Iland, H. (2007). The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood 110, 4073-6.
  143. Raelson, J. V., Nervi, C., Rosenauer, A., Benedetti, L., Monczak, Y., Pearson, M., Pelicci, P. G. & Miller, W. H. Jr. (1996). The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood 88, 2826-32.
  144. Melnick, A. & Licht, J. D. (1999). Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93, 3167-215.
  145. Hakimi, M. A., Dong, Y., Lane, W. S., Speicher, D. W. & Shie- khattar, R. (2003). A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem 278, 7234-9.
  146. Lodie, T. A., Savedra, R. Jr., Golenbock, D. T., Van Beveren, C. P., Maki, R. A. & Fenton, M. J. (1997). Stimulation of macrophages by lipopolysaccharide alters the phosphorylation state, conformation, and function of PU.1 via activation of casein kinase II. J Immunol 158, 1848-56.
  147. Ashworth, T. & Roy, A. L. (2007). Cutting Edge: TFII-I controls B cell proliferation via regulating NF-κB. J Immunol 178, 2631-5.
  148. Dry, K. L., Aldred, M. A., Edgar, A. J., Brown, J., Manson, F. D., Ho, M.-F., Prosser, J., Hardwick, L. J., Lennon, A. A., Thomson, K., Van Keuren, M., Kurnit, D. M., Bird, A. C., Jay, M., Monaco, A. P. & Wright, A. F. (1995). Identification of a novel gene, ETX1, from Xp21.1, a candidate gene for X-linked retintis pigmentosa (RP3). Hum Mol Genet 4, 2347-53.
  149. Fiume, R., Keune, W. J., Faenza, I., Bultsma, Y., Ramazzotti, G., Jones, D. R., Martelli, A. M., Somner, L., Follo, M. Y., Divecha, N. & Cocco, L. (2012). Nuclear phosphoinositides: location, regulation and function. Subcell Biochem 59, 335-61.
  150. Mackarehtschian, K., Hardin, J. D., Moore, K. A., Boast, S., Goff, S. P. & Lemischka, I. R. (1995). Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3, 147-61.
  151. Grignani, F., De Matteis, S., Nervi, C., Tomassoni, L., Gelmetti, V., Cioce, M., Fanelli, M., Ruthardt, M., Ferrara, F. F., Zamir, I., Seiser, C., Grignani, F., Lazar, M. A., Minucci, S. & Pelicci, P. G. (1998). Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815-8.
  152. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature 414, 105-11.
  153. Watamoto, K., Towatari, M., Ozawa, Y., Miyata, Y., Okamoto, M., Abe, A., Naoe, T. & Saito, H. (2003). Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation. Oncogene 22, 9176-84.
  154. Okuno, Y., Huang, G., Rosenbauer, F., Evans, E. K., Radomska, H. S., Iwasaki, H., Akashi, K., Moreau-Gachelin, F., Li, Y., Zhang, P., Göttgens, B. & Tenen, D. G. (2005). Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol Cell Biol 25, 2832-45.
  155. TFII-I enhances activation of the c-fos promoter through interactions with upstream elements. Mol Cell Biol 18, 3310-20.
  156. Inoue, H., Pan, J. & Hakura, A. (1998). Suppression of v-src transfor- mation by the drs gene. J Virol 72, 2532-7.
  157. Zheng, P. Z., Wang, K. K., Zhang, Q. Y., Huang, Q. H., Du, Y. Z., Zhang, Q. H., Xiao, D. K., Shen, S. H., Imbeaud, S., Eveno, E., Zhao, C. J., Chen, Y. L., Fan, H. Y., Waxman, S., Auffray, C., Jin, G., Chen, S. J., Chen, Z. & Zhang, J. (2005). Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A 102, 7653-8.
  158. Chen, R. H., Corbalan-Garcia, S. & Bar-Sagi, D. (1997). The role of the PH domain in the signal-dependent membrane targeting of Sos. EMBO J 16, 1351-9.
  159. PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A 99, 8283-8.
  160. Budhu, A. S. & Noy, N. (2002). Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Recep- tor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest. Mol Cell Biol 22, 2632-41.
  161. Melnick, A., Carlile, G., Ahmad, K. F., Kiang, C.-L., Corcoran, C., Bardwell, V., Prive, G. G. & Licht, J. D. (2002). Critical resi- dues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol Cell Biol 22, 1804-18.
  162. Chen, L., Daum, G., Chitaley, K., Coats, S. A., Bowen-Pope, D. F., Eigenthaler, M., Thumati, N. R., Walter, U. & Clowes, A. W. (2004). Vasodilator-stimulated phosphoprotein regulates proliferation and growth inhibition by nitric oxide in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 24, 1403-8.
  163. Rajaiya, J., Nixon, J. C., Ayers, N., Desgranges, Z. P., Roy, A. L. & Webb, C. F. (2006). Induction of immunoglobulin heavy-chain trans- cription through the transcription factor Bright requires TFII-I. Mol Cell Biol 26, 4758-68.
  164. Crusselle-Davis, V. J., Vieira, K. F., Zhou, Z., Anantharaman, A. & Bungert, J. (2006). Antagonistic regulation of β-globin gene expression by helix-loop-helix proteins USF and TFII-I. Mol Cell Biol 26, 6832-43.
  165. Chan, I. T., Kutok, J. L., Williams, I. R., Cohen, S., Moore, S., Shigematsu, H., Ley, T. J., Akashi, K., Le Beau, M. M. & Gilliland, D. G. (2006). Oncogenic K-ras cooperates with PML-RARα to induce an acute promyelocytic leukemia-like disease. Blood 108, 1708-15.
  166. Mueller, B. U., Pabst, T., Fos, J., Petkovic, V., Fey, M. F., Asou, N., Buergi, U. & Tenen, D. G. (2006). ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 107, 3330-8.
  167. Peterson, L. F., Boyapati, A., Ahn, E. Y., Biggs, J. R., Okumura, A. J., Lo, M. C., Yan, M. & Zhang, D. E. (2007). Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts. Blood 110, 799-805.
  168. Zhu, J., Koken, M. H., Quignon, F., Chelbi-Alix, M. K., Degos, L., Wang, Z. Y., Chen, Z. & de Thé, H. (1997). Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci U S A 94, 3978-83.
  169. Friedman, A. D. (2007). C/EBPα induces PU.1 and interacts with AP-1 and NF-κB to regulate myeloid development. Blood Cells Mol Dis 39, 340-3.
  170. Roy, A. L. (2007). Signal-induced functions of the transcription factor TFII-I. Biochim Biophys Acta 1769, 613-21.
  171. Koken, M. H., Reid, A., Quignon, F., Chelbi-Alix, M. K., Da- vies, J. M., Kabarowski, J. H., Zhu, J., Dong, S., Chen, S., Chen, Z., Tan, C. C., Licht, J., Waxman, S., de Thé, H. & Zelent, A. (1997). Leukemia-associated retinoic acid receptor α fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies. Proc Natl Acad Sci U S A 94, 10255-60.
  172. Zhou, W., Grandis, J. R. & Wells, A. (2006). STAT3 is required but not sufficient for EGF receptor-mediated migration and invasion of human prostate carcinoma cell lines. Br J Cancer 95, 164-71.
  173. Gureasko, J., Galush, W. J., Boykevisch, S., Sondermann, H., Bar- Sagi, D., Groves, J. T. & Kuriyan, J. (2008). Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol 15, 452-61.
  174. Chimge, N. O., Makeyev, A. V., Ruddle, F. H. & Bayarsaihan, D. (2008). Identification of the TFII-I family target genes in the vertebrate genome. Proc Natl Acad Sci U S A 105, 9006-10.
  175. Gupta, P., Ho, P. C., Huq, M. M., Ha, S. G., Park, S. W., Khan, A. A., Tsai, N. P. & Wei, L. N. (2008). Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression. Proc Natl Acad Sci U S A 105, 11424-9.
  176. Grant, S. (2008). Cotargeting survival signaling pathways in cancer. J Clin Invest 118, 3003-6.
  177. Orkin, S. H. & Zon, L. I. (2008). Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631-44.
  178. Barylko, B., Mao, Y. S., Wlodarski, P., Jung, G., Binns, D. D., Sun, H. Q., Yin, H. L. & Albanesi, J. P. (2009). Palmitoylation controls the catalytic activity and subcellular distribution of phosphatidyli- nositol 4-kinase IIα. J Biol Chem 284, 9994-10003.
  179. Chesarone, M. A. & Goode, B. L. (2009). Actin nucleation and elon- gation factors: mechanisms and interplay. Curr Opin Cell Biol 21, 28-37.
  180. Dominguez, R. (2009). Actin filament nucleation and elongation factors– structure-function relationships. Crit Rev Biochem Mol Biol 44, 351-66.
  181. Wang, J., Hoshino, T., Redner, R. L., Kajigaya, S., Liu, J. M. (1998). ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 com- plex. Proc Natl Acad Sci U S A 95, 10860-5.
  182. Rice, K. L., Hormaeche, I., Doulatov, S., Flatow, J. M., Grimwade, D., Mills, K. I., Leiva, M., Ablain, J., Ambardekar, C., McConnell, M. J., Dick, J. E. & Licht, J. D. (2009). Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC. Blood 114, 5499-511.
  183. Mulloy, J. C., Cancelas, J. A., Filippi, M.-D., Kalfa, T. A., Guo, F. & Zheng, Y. (2010). Rho GTPases in hematopoiesis and hemopathies. Blood 115, 936-47.
  184. Lin, W. H., Nelson, S. E., Hollingsworth, R. J. & Chung, C. Y. (2010). Functional roles of VASP phosphorylation in the regulation of che- motaxis and osmotic stress response. Cytoskeleton (Hoboken) 67, 259-71.
  185. Yedjou, C. G. & Tchounwou, P. B. (2009). Modulation of p53, c-fos, RARE, cyclin A, and cyclin D1 expression in human leukemia (HL-60) cells exposed to arsenic trioxide. Mol Cell Biochem 331, 207-14.
  186. Cuiffo, B. & Ren, R. (2010). Palmitoylation of oncogenic NRAS is es- sential for leukemogenesis. Blood 115, 3598-605.
  187. Szentpetery, Z., Várnai, P. & Balla, T. (2010). Acute manipulation of Golgi phosphoinositides to assess their importance in cellular trafficking and signaling. Proc Natl Acad Sci U S A 107, 8225-30.
  188. Malhotra, S. & Kincade, P. W. (2009). Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell 4, 27-36.
  189. Swartling, F. J., Ferletta, M., Kastemar, M., Weiss, W. A. & Wes- termark, B. (2009). Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines. Oncogene 28, 3121-31.
  190. [23] Breitsprecher, D., Kiesewetter, A. K., Linkner, J., Vinzenz, M., Stradal, T. E., Small, J. V., Curth, U., Dickinson, R. B. & Faix, J. (2011). Molecular mechanism of Ena/VASP-mediated actin-filament elon- gation. EMBO J 30, 456-67.
  191. Graham, T. R. & Burd, C. G. (2011). Coordination of Golgi functions by phosphatidylinositol 4-kinases. Trends Cell Biol 21, 113-21.
  192. Welch, J. S., Yuan, W. & Ley, T. J. (2011). PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice. J Clin Invest 121, 1636-45.
  193. Stone, J. C. (2011). Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells. Genes Cancer 2, 320-34.
  194. Inducible production of c-fos antisense RNA inhibits 3T3 cell proli- feration. Proc Natl Acad Sci U S A 83, 4794-8.
  195. Roy, A. L. (2012). Biochemistry and biology of the inducible multifunc- tional transcription factor TFII-I: 10 years later. Gene 492, 32-41.
  196. Resh, M. D. (2012). Targeting protein lipidation in disease. Trends Mol Med 18, 206-14.
  197. Bearer, E. L., Prakash, J. M. & Li, Z. (2002). Actin dynamics in platelets. Int Rev Cytol 217, 137-82.
  198. Liu, M., Bi, F., Zhou, X. & Zheng, Y. (2012). Rho GTPase regulation by miRNAs and covalent modifications. Trends Cell Biol 22, 365-73.
  199. Suliman, B. A., Xu, D. & Williams, B. R. (2012). The promyelocytic leukemia zinc finger protein: two decades of molecular oncology. Front Oncol 2, 74.
  200. Tao, Y., Gu, Y. J., Cao, Z. H., Bian, X. J., Lan, T., Sang, J. R., Jiang, L., Wang, Y., Qian, H. & Chen, Y. C. (2012). Endogenous cGMP-dependent protein kinase reverses EGF-induced MAPK/ERK signal transduction through phosphorylation of VASP at Ser239. Oncol Lett 4, 1104-8.
  201. Pylayeva-Gupta, Y., Grabocka, E. & Bar-Sagi, D. (2011). RAS on- cogenes: weaving a tumorigenic web. Nat Rev Cancer 11, 761-74.
  202. McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Montalto, G., Cervello, M., Nicoletti, F., Fagone, P., Malaponte, G., Mazzarino, M. C., Candido, S., Libra, M., Bäsecke, J., Mijato- vic, S., Maksimovic-Ivanic, D., Milella, M., Tafuri, A., Cocco, L., Evangelisti, C., Chiarini, F. & Martelli, A. M. (2012). Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cas- cades. Oncotarget 3, 954-87.
  203. Perez, A., Kastner, P., Sethi, S., Lutz, Y., Reibel, C. & Chambon, P. (1993). PMLRAR homodimers: distinct DNA binding properties and heteromeric interactions with RXR. EMBO J 12, 3171-82.
  204. PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis. J Cell Mol Med 13, 4349-63.
  205. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epi- dermal growth factor receptor family. Proc Natl Acad Sci U S A 90, 1746-50.
  206. [43] Christensen, J. L. & Weissman, I. L. (2001). Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A 98, 14541-6.
  207. Melnick, A., Ahmad, K. F., Arai, S., Polinger, A., Ball, H., Borden, K. L., Carlile, G. W., Prive, G. G. & Licht, J. D. (2000). In-depth mutational analysis of the promyelocytic leukemia zinc finger BTB/POZ domain reveals motifs and residues required for biological and transcriptional functions. Mol Cell Biol 20, 6550-67.
  208. Parker, R., Phan, T., Baumeister, P., Roy, B., Cheriyath, V., Roy, A. L. & Lee, A. S. (2001). Identification of TFII-I as the endoplasmic reticulum stress response element binding factor ERSF: its autoregulation by stress and interaction with ATF6. Mol Cell Biol 21, 3220-33.
  209. Degos, L. & Wang, Z. Y. (2001). All trans retinoic acid in acute pro- myelocytic leukemia. Oncogene 20, 7140-5.
  210. Dong, S., Zhu, J., Reid, A., Strutt, P., Guidez, F., Zhong, H. J., Wang, Z. Y., Licht, J., Waxman, S., Chomienne, C., Chen, Z., Zelent, A. & Chen, S. J. (1996). Amino-terminal protein-protein inter- action motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-α fusion protein. Proc Natl Acad Sci U S A 93, 3624-9.
  211. Rohr, S. S., Pelloso, L. A., Borgo, A., De Nadai, L. C., Yamamoto, M., Rego, E. M., de Lourdes L. F. Chauffaille, M. (2012). Acute promyelocytic leukemia associated with the PLZF-RARA fusion gene: two additional cases with clinical and laboratorial peculiar presentations. Med Oncol 29, 2345-7.
  212. Franke, T. F., Yang, S. I., Chan, T. O., Datta, K., Kazlauskas, A., Morrison, D. K., Kaplan, D. R. & Tsichlis, P. N. (1995). The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727-36.
  213. Klette, K. L. & Wanda, P. E. (1991). Inositol lipid metabolism accom- panies erythroid differentiation of K562 human leukemic cells. Leuk Res 15, 453-6.
  214. & Hu, Z. B. (1995). Leukemia cell lines: in vitro models for the study of acute promyelocytic leukemia. Leuk Res 19, 681-91.
  215. Chardin, P. (1988). The ras superfamily proteins. Biochimie 70, 865-68.
  216. Faucheux, C., Ulysse, F., Bareille, R., Reddi, A. H. & Amédée, J. (1997). Opposing actions of BMP3 and TGFβ1 in human bone marrow stromal cell growth and differentiation. Biochem Biophys Res Commun 241, 787-93.
  217. Machesky, L. M. (2000). Putting on the brakes: a negative regulatory function for Ena/VASP proteins in cell migration. Cell 101, 685-8.
  218. Mrózek, K., Heerema, N. A. & Bloomfield, C. D. (2004). Cytogene- tics in acute leukemia. Blood Rev 18, 115-36.
  219. Tambe, Y., Okuyama, N., Nakagawa, T., Muramoto, A., Hasebe, M., Chano, T. & Inoue, H. (2012). Suppression of viral replication by drs tumor suppressor via mTOR dependent pathway. Cancer Lett 314, 82-91.
  220. Kastner, P. & Chan, S. (2008). PU.1: a crucial and versatile player in hematopoiesis and leukemia. Int J Biochem Cell Biol 40, 22-7.
  221. Alemdehy, M. F. & Erkeland, S. J. (2012-2). Stop the dicing in hema- topoiesis: what have we learned? Cell Cycle 11, 2799-807.
  222. Chung, E. & Kondo, M. (2011). Role of Ras/Raf/MEK/ERK signaling in physiological hematopoiesis and leukemia development. Immunol Res 49, 248-68.
  223. Heilmeyer, L. M., Jr., Vereb, G., Jr., Vereb, G., Kakuk, A. & Szivák, I. (2003). Mammalian phosphatidylinositol 4-kinases. IUBMB Life 55, 59-65.
  224. [28] Burnicka-Turek, O., Kata, A., Buyandelger, B., Ebermann, L., Kramann, N., Burfeind, P., Hoyer-Fender, S., Engel, W. & Adham, I. M. (2010). Pelota interacts with HAX1, EIF3G and SRPX and the resulting protein complexes are associated with the actin cytoskeleton. BMC Cell Biol 11, 28.
  225. Grimwade, D., Biondi, A., Mozziconacci, M. J., Hagemeijer, A., Berger, R., Neat, M., Howe, K., Dastugue, N., Jansen, J., Radford- Weiss, I., Lo Coco, F., Lessard, M., Hernandez, J. M., Delabesse, E., Head, D., Liso, V., Sainty, D., Flandrin, G., Solomon, E., Birg, F. & Lafage-Pochitaloff, M. (2000). Characterization of acute promye- locytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action " Molecular Cytogene- tic Diagnosis in Haematological Malignancies " . Blood 96, 1297-308.
  226. Mistry, A. R., Pedersen, E. W., Solomon, E. & Grimwade, D. (2003). The molecular pathogenesis of acute promyelocytic leukaemia: im- plications for the clinical management of the disease. Blood Rev 17, 71-97.
  227. Libura, M., Asnafi, V., Tu, A., Delabesse, E., Tigaud, I., Cym- balista, F., Bennaceur-Griscelli, A., Villarese, P., Solbu, G., Ha- gemeijer, A., Beldjord, K., Hermine, O. & Macintyre, E. (2003). FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. Blood 102, 2198-204.
  228. Gorman, A. M., Healy, S. J., Jäger, R. & Samali, A. (2012). Stress management at the ER: regulators of ER stress-induced apoptosis. Pharma- col Ther 134, 306-16.

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