medigraphic.com
ISSN 0016-3813 (Print)

2006, Number 2

<< Back Next >>

Gac Med Mex 2006; 142 (2)

Molecular hemato-oncology and new specific treatment strategies for leukemia.

Martínez-Mancilla M, Zafra-de la Rosa G, Reynoso-Gómez E, Astudillo-de la Vega H, Nambo-Lucio MJ, Benítez-Bribiesca L, Martínez-Avalos A, Rivera-Luna R, Gariglio P

Language: Spanish
References: 56
Page: 145-150
PDF size: 493.04 Kb.


ABSTRACT

Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins such as Pml-Rara, have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could constitute an important target for new therapeutic agents. Alternatively, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways normally involved in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway.
In this review, we shed some light on our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction pathway. In addition, the administration of low molecular weight drugs for human leukemia treatment based on this knowledge brings about a significant long-term clinical remission and an acceptable risk of toxic effects that should increase the cure rate.


REFERENCES

  1. Graf T. Differentiation plasticity of hematopoietic cells. Blood 2002;99:3089-3101.

  2. Hoffman B, Leibermann D. Hematopoiesis. Oncogene 2002;21:3260-3261.

  3. Look A. Oncogenic transcription factors in the human acute leukemias.Science 1997;278:1059-1064.

  4. Rabbitts T, Stocks M. Chromosomal translocations products engender newintracellular therapeutic technologies. Nat Med 2003;9:383-386.

  5. Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C.CEBPA point mutations in hematological malignancies. Leukemia 2005;19:329-334.

  6. Lund A, Van Lohuizen M. Epigenetics and cancer. Genes Dev 2004;18:2315-2335.

  7. Krause D, Van Etten R. Tyrosine kinases as targets for cancer therapy.N Engl J Med 2005;353:172-187.

  8. Carroll W. On target for advances in the treatment of childhood acutelymphoblastic leukemia. Blood 2005;105:438-439.

  9. Callens C, Chevret S, Cayuela J, Cassinat B, Raffoux E, de Botton S, etal. Prognostic implication of FLT3 and Ras gene mutations in patients withacute promyelocytic leukemia (APL): a retrospective study from theEuropean APL Group. Leukemia 2005;19:1153-1160.

  10. Melnick A. Predicting the effect of transcription therapy in hematologicmalignancies. Leukemia 2005;19:1109-1117.

  11. Towatari M, Yanada M, Usui N, Takeuchi J, Sugiura I, Takeuchi M, et al.Combination of intensive chemotherapy and imatinib can rapidly inducehigh-quality complete remission for a majority of patients with newlydiagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood 2004;104:3507-3512.

  12. Okuno M, Kojima S, Matsushima-Nishiwaki R, Tsurumi H, Muto Y,Friedman SL, et al. Retinoids in cancer chemoprevention. Curr Cancer DrugTargets 2004;4:285-298.

  13. Testi A, Biondi A, Coco F, Moleti M, Giona F, Vignetti M, et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocyticleukemia (APL) in children. Blood 2005;106:447-453.

  14. Speck N, Stacy T, Wang Q, et al. Core-binding factor: a central player inhematopoiesis and leukemia. Cancer Res 1999;59:1789-1793.

  15. Rowley J, Golomb H, Dougherty C. 15/17 translocation a consistentchromosomal change in acute promyelocytic. Lancet 1977;1:549-550.

  16. de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17)translocations of acute promyelocytic leukaemia fases the retinoic acidreceptor alpha gene to a novel transcribed locus. Nature 1990;347:558-561.

  17. Collins S. The role of retinoids and retinoic acid receptors in normal hemato-poiesis. Leukemia 2002;16:1896-1905.

  18. Kakizuka A, Miller W, Umesono K, et al. Chromosomal translocationt(15;17) in human acute promyelocytic leukemia fuses RAR alpha with anovel putative transcription factor. Cell 1991;66:663-674.

  19. Kastner P, Perez A, Lutz Y, et al. Structure, localization and transcriptionalproperties of two classes of retinoic acid receptor alpha fusion proteins inacute promyelocytic leukemia (APL): structural similarities with a new familyof oncoproteins. Embo J 1992;11:629-642.

  20. Pandolfi P, Alcalay M, Longo L, et al. Molecular genetics of the t(15;17) ofacute promyelocytic leukemia (APL). Leukemia 1992; 6 (Suppl 3): 120S-122S.

  21. Zelent A, Guidez F, Melnick A, Waxman S, Licht J. Translocations of theRARalpha gene in acute promyelocytic leukemia. Oncogene 2001;20:7186-7203.

  22. Melnick A, Licht J. Deconstructing a disease: RARalpha, its fusion partners,and their roles in the pathogenesis of acute promyelocytic leukemia. Blood1999;93:3167-3215.

  23. Huang M, Ye Y, Chen S, et al. Use of all-trans retinoic acid in the treatmentof acute promyelocytic leukemia. Blood 1988;72:567-572.

  24. Lin R, Nagy L, Inoue S, et al. Role of the histone deacetylase complex inacute promyelocytic leukaemia. Nature 1998;391:811-814.

  25. Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoicacid receptor-α recruit histone deacetylase in promyelocytic leukaemia.Nature 1998;391:815-818.

  26. Guidez F, Huang W, Tong J, et al. Poor response to all-trans retinoic acidtherapy in a t(11;17) PLZF/RARalpha patient. Leukemia 1994;8:312-317.

  27. Chen Z, Guidez F, Rousselot P, et al. PLZF-RARalpha fusion proteinsgenerated from the variant t(11;17)(q23;q21) translocation in acutepromyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Proc Nat Acad Sci USA 1994;91:1178-1182.

  28. Licht J, Shaknovitch R, English M, et al. Reduced and alterated DNA-binding and transcriptional properties of the PLZP-retinoic acid receptor-αchimera generated in t(11;17)-associated acute promyelocytic leukemia.Oncogene 1996;12:323-336.

  29. Licht J, Chomienne C, Goy A, et al. Clinical and molecular characterizationof a rare syndrome of acute promyelocytic leukemia associated withtranslocation (11;17). Blood 1995;85:1083-1094.

  30. He L-Z, Guidez F, Tribioli C, et al. Distinct interactions of PML-RARα andPLZF-RARα with co-repressors determine differential responses to RA inAPL. Nature Genet 1998;18:126-135.

  31. Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A. Reducedretinoic acid-sensitivities of nuclear receptor co-repressor binding to PML-and PLZF-RARalpha underlie molecular pathogenesis and treatment ofacute promyelocytic leukemia. Blood 1998;91:2634-2642.

  32. Tallman M, Andersen J, Schiffer C, et al. All-trans-retinoic acid in acutepromyelocytic leukemia. N Engl J Med 1997;337:1021-1028.

  33. Imaizumi M, Suzuki H, Yoshinari M, et al. Mutations in the E-domain ofRAR? portion of the PML/RARα chimeric gen may confer clinical resistanceto all-trans retinoic acid in acute promyelocytic leukemia. Blood 1998;92:374-382.

  34. Miller W, Waxman S. Differentiation induction as treatment for hematologicmalignancies. Oncogene 2002;21:3496-3506.

  35. Cote S, Rosenauer A, Bianchini A, et al. Response to histone deacetylaseinhibition of novel PML/RARα mutants detected in retinoic acid-resistantAPL cells. Blood 2002;100:2586-2596.

  36. Batova A, Shao L, Diccianni M, et al. The histone deacetylase inhibitorAN-9 has selective toxicity to acute leukemia and drug-resistant primaryleukemia and cancer cell lines. Blood 2002;100:3319-3324.

  37. Lutterbach B, Westendolf J, Linggi B, et at. ETO a target of t(8;21) in acuteleukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol1998;18:7176-7184.

  38. Ferrera F, Fazi F, Bianchimi A, et al. Histone deacetylase-targeted treatmentrestores retinoic acid signalling and differentiation in acute myeloid leukemia.Cancer Res 2001;61:2-7.

  39. Redner R, Wang J, Liu J. Chromatin remodeling and leukemia: newtherapeutic paradigms. Blood 2001;94:417-428.

  40. Rowley J. A new consistent chromosomal abnormality in chronic myelogenousleukaemia identified by quinacrine fluorescence and giemsa staining.Nature 1973;243:290-293.

  41. Deininger M, Goldman J, Melo J. The molecular biology of chronic myeloidleukemia. Blood 2000;96:3343-3356.

  42. Faderl S, Talpaz M, Estrov Z, Kantarjian H. Chronic myelogenousleukemia: biology and therapy. Ann Intern Med 1999;131:207-219.

  43. Sawyers C. Chronic myeloid leukemia. N Engl J Med 1999;340:1330-1340.

  44. Drucker B. Can we cure CML. Blood 2004;103:2865-2866.

  45. Shet A, Jahagirdar B, Verfaillie C. Chronic myelogenous leukemia:mechanisms underlying disease progression. Leukemia 2002;16:1402-1411.

  46. Goldman J, Druker B. Chronic myeloid leukemia: current treatmentoptions. Blood 2001;98:2039-2042.

  47. Druker B, Tamura S, Buchdunger E, et al. Effects of a selective inhibitorof the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. NatureMed 1996;2:561-566.

  48. le Coutre P, Mologni L, Cleris L, et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Nat Cancer Inst1999;91:163-168.

  49. Ross D, Hughert T. Cancer treatment with kinase inhibitors: what have welearn from imatinib. Brith J Cancer 2004;90:12-19.

  50. Druker B, Talpaz M, Resta D, et al. Efficacy and safety of a specific inhibitorof the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med2001;344:1031-1037.

  51. Ottmann O, Druker B, Sawyers C, et al. A phase 2 study of imatinib inpatients with relapsed or refractory Philadelphia chromosome-positiveacute lymphoid leukemias. Blood 2002; 100:1965-1971.

  52. Sawyers C, Hochhaus A, Feldman E, et al. Imatinib induces hematologicand cytogenetic response in patients with chronic myelogenous leukemiain myeloid blast crisis: results of a phase II study. Blood 2002;99:3530-3539.

  53. Talpaz M, Silver R, Druker B, et al. Imatinib induces durable hematologicand cytogenetic response in patients with accelerated phase chronicmyeloid leukemia: results of a phase 2 study. Blood 2002;99:1928-1937.

  54. Hoover R, Mahon F, Melo J, Daley G. Overcoming STI571 resistance withthe farnesyl transferase inhibitor SCH66336. Blood 2002;100:1068-1071.

  55. Kuroda J, Kimura S, Segawa H, et al. The third-generation bisphosphonatezoledronate synergistically augments the anti-Ph+ leukemia activity ofimatinib mesylate. Blood 2003;102:2229-2235.

  56. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasomeinhibitor bortezomib interacts synergistically with histone deacetylase inhibitorsto induce apoptosis in Bcr-Abl + cells sensitive and resistant to STI571. Blood2003;102:3765-3774.




2020     |     www.medigraphic.com