All trans retinoic acid as a targeting drug for differentiation therapy in acute promyelocytic leukemia

  • Laurent Degos
Part of the Cancer Treatment and Research book series (CTAR, volume 64)


Acute promyelocytic leukemia (APL) is a clonal expansion created by a specific translocation t(15;17) (q22;qll.21) [1] of malignant myeloid cells arrested at a specific step of maturation, leading to a characteristic morphological feature—the M3 type in the FAB (French, American, British) cytological classification [2].


Retinoic Acid Acute Promyelocytic Leukemia Retinoic Acid Receptor Acute Promyelocytic Leukemia Patient Retinoic Acid Receptor Alpha 
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  1. 1.
    Larson RA, Kondo K, Vardunab JW, Butler AE, Golomb HM, Rowley JD (1984). Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am J Med 76: 827–841.PubMedCrossRefGoogle Scholar
  2. 2.
    Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1976). Proposals for the classification of the acute leukemias. Br J Haematol 33: 451–458.CrossRefGoogle Scholar
  3. 3.
    Sachs L (1978). Control of normal differentiation and the phenotypic reversion of malignancy in myeloid leukemia cells. Nature 274: 535–539.PubMedCrossRefGoogle Scholar
  4. 4.
    Housset M, Daniel MT, Degos L (1982). Small doses of ARA-C in the treatment of acute myeloid leukemia. Differentiation of myeloid leukaemic cells? Br J Haematol 51: 125–139.PubMedCrossRefGoogle Scholar
  5. 5.
    Castaigne S, Daniel MT, Tilly H, Herait P, Degos L (1983). Does treatment with ARA-C in low dosage cause differentiation of leukemic cells? Blood 62: 85–86.PubMedGoogle Scholar
  6. 6.
    Fearon ER, Burke PJ, Schiffer CA, Zehnbauer BA, Vogelstein B (1986). Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. N Engl J Med 315: 15–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Lotan R (1980). Effect of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochem Biophys Acta 605: 33–91.PubMedGoogle Scholar
  8. 8.
    Douer D, Koeffler HP (1982). Retinoic acid enhances colony-stimulating factor-induced clonal growth of normal human myeloid progenitor cells in vitro. Exp Cell Res 138: 193–201.PubMedCrossRefGoogle Scholar
  9. 9.
    Douer D, Koeffler HP (1982). Retinoic acid: inhibition of the clonal growth of human myeloid leukemia cells. J Clin Invest 69: 277–283.PubMedCrossRefGoogle Scholar
  10. 10.
    Chomienne C, Balitrand N, Cost H, Degos L, Abita JP (1986). Structure-activity relationships of the aromatic retinoids on the differentiation of the human histiocytic lymphoma cell line U-937. Leuk Res 10: 1301–1306.PubMedCrossRefGoogle Scholar
  11. 11.
    Breitman TR, Collins SJ, Keene BR (1981). Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 6: 1000–1004.Google Scholar
  12. 12.
    Chomienne C, Ballerini P, Balitrand N, Amar M, Bernard JF, Boivin P, Daniel MT, Berger R, Castaigne S, Degos L (1989). Retinoic acid therapy for promyelocytic leukemia. Lancet 1: 746–747.CrossRefGoogle Scholar
  13. 13.
    Chomienne C, Ballerini P, Balitrand N, Daniel MT, Fenaux P, Castaigne S, Degos L (1990). All trans retinoic acid in acute promyelocytic leukemia. II. In vitro studies: structure function relationship. Blood 76: 1710–1717.PubMedGoogle Scholar
  14. 14.
    Huang ME, Ye YC, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY (1988). Use of all trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72: 567–572.PubMedGoogle Scholar
  15. 15.
    Degos L, Chomienne C, Daniel MT, Berger R, Dombret H, Fenaux P, Castaigne S (1990). Treatment of first relapse in acute promyelocytic leukemia with all trans retinoic acid. Lancet 336: 1440–1441.PubMedCrossRefGoogle Scholar
  16. 16.
    Warrell RM, Frankel SR, Miller WH, Scheinberg DA, Itri LM, Hittleman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gobrilove J, Gordon MS, Dimitrovsky E (1991). Differentiation therapy of acute promyelocytic leukemia with tretinoin (All trans retinoic acid). N Engl J Med 324: 1385–1393.PubMedCrossRefGoogle Scholar
  17. 17.
    Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L (1990). All trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76: 1704–1709.Google Scholar
  18. 18.
    Frankel S, Weiss M, Warrell RP (1991). A retinoic acid syndrome in acute promyelocytic leukemia: reversal by corticosteroids. Blood (ASH Abstract): Abst 1511, p. 380a.Google Scholar
  19. 19.
    Fenaux P, Castaigne S, Dombret H, Chomienne C, Duarte M, Archimbaud E, Lamy T, Tibeghien P, Tilly H, Dufour P, Cransac M, Guerci A, Sadoun A, Degos L (1991). All trans retinoic acid in newly diagnosed acute promyelocytic leukemia: A pilot study. Blood (ASH Abstract): Abst 305 (plenary session), p. 79a.Google Scholar
  20. 20.
    Dombret H, Sutton L, Duarte M, Daniel MT, Leblond V, Castaigne S, Degos L (1992). Combined therapy with all trans retinoic acid and high-dose chemotherapy in patients with hyperleukocytic acute promyelocytic leukemia and severe visceral hemorrhage. Leukemia.Google Scholar
  21. 21.
    Avvisati G, Tencate JW, Sturk A, Lamping R, Petti MC, Mandelli F (1988). Acquired alpha2 antiplasmin deficiency in acute promyelocytic leukemia. Br J Haemat 70: 43–48.CrossRefGoogle Scholar
  22. 22.
    Sakata Y, Murakami T, Noro A, Mori K, Matsuda M (1991). The specific activity of plasminogen activator inhibitor 1 in disseminated intra vascular coagulation with acute promyelocytic leukemia. Blood 77: 1949–1957.PubMedGoogle Scholar
  23. 23.
    Scrobohaci ML, Dombret H, Ghorra P, Baurmann H, Castaigne S, Daniel MT, Boffa MC, Amiral J, Degos L (1991). Disseminated intravascular coagulation (DIC) and/or primary fibrinolysis in acute promyelocytic leukemia. Effect of all trans retinoic acid treatment. Blood (ASH Abstract): Abst 183, p. 48a.Google Scholar
  24. 24.
    Chen ZX, Xue YQ, Zhang R, Tao RF, Xia XM, Li C, Wang W, Zu WY, Yao XZ, Ling BJ (1991). A clinical and experimental study on all trans retinoic acid treated acute promyelocytic leukemia patients. Blood 78: 1413–1419.PubMedGoogle Scholar
  25. 25.
    Muindi J, Frankel SR, Jakubowski A, Dmitrovsky E, Miller WH, Warrell RP (1991). Continuous treatment with all trans retinoic acid progressively decreases plasma drug concentrations: implications for relapse and resistance in acute promyelocytic leukemia. Blood (ASH abstract): Abst 1063, p. 268a.Google Scholar
  26. 26.
    Lefebvre P, Thomas G, Gourmel B, Agadir A, Castaigne S, Dreux C, Degos L, Chomienne C (1991). Pharmacokinetics of oral all trans retinoic acid in patients with acute promyelocytic leukemia. Leukemia 5: 1054–1058.PubMedGoogle Scholar
  27. 27.
    Cornic M, Delva L, Guidez F, Balitrand N, Degos L, Chomienne C (1992). Induction of retinoic acid binding protein in normal and malignant human myeloid cells by retinoic acid in AML3 patients. Cancer Res. 52: 3329–3334.PubMedGoogle Scholar
  28. 28.
    Mattei MG, Petkovich M, Mattei JF, Band N, Chambon P (1988). Mapping of the human retinoic acid receptor to the q21 band of chromosome 17. Human Genet 80: 186–188.CrossRefGoogle Scholar
  29. 29.
    Chomienne C, Ballerini P, Balitrand N, Huang ME, Krawice I, Castaigne S, Fenaux P, Tiollais P, Dejean A, Degos L, DeThe H (1990). The retinoic acid receptor alpha gene is rearranged in retinoic acid sensitive promyelocytic leukemia. Leukemia 4: 802–807.PubMedGoogle Scholar
  30. 30.
    Wang C, Curtis JE, Minden MD, McCullogh EA (1988). Expression of a retinoic acid receptor gene in myeloid cells. Leukemia 3: 264–269.Google Scholar
  31. 31.
    Largman C, D’Temer K, Corral JC, Hack FM, Lawrence HJ (1989). Expression of retinoic acid receptor alpha mRNA in human leukemic cells. Blood 74: 99–102.PubMedGoogle Scholar
  32. 32.
    Gallagher RE, Said F, Pua I, Papenhausen PR, Paietta E, Wiernick PH (1989). Expression of retinoic acid receptor alpha MRNA in human leukemic cells with variable responsiveness to retinoic acid. Leukemia 3: 789–795.PubMedGoogle Scholar
  33. 33.
    De The H, Chomienne C, Lanotte M, Degos L, Dejean A (1990). The t(15;17) translocation of acute promyelocytic leukemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347: 558–561.PubMedCrossRefGoogle Scholar
  34. 34.
    Longo L, Pandolfi PP, Biondi A, Rambaldi A, Mencarelli A, Lococo F, Diverio D, Pegoraro L, Avanzi G, Tabilio A, Zangrilli D, Alcalay M, Donti E, Grignani F, Pelici PG (1990). Rearrangements and aberrant expression in the RAR alpha gene in acute promyelocytic cells. J Exp Med 172: 1571–1575.PubMedCrossRefGoogle Scholar
  35. 35.
    Miller WH, Warrell RP, Frankel SR, Jakubowski A, Gabrilove JG, Muindi H, Dimitrowsky E (1990). A novel retinoic acid receptor alpha transcripts in acute promyelocytic leukemia patients, responding to all trans retinoic acid. J Natl Cancer Inst 82: 1932–1933.PubMedCrossRefGoogle Scholar
  36. 36.
    Chang KS, Trujillo JM, Ogura T, Castiglione CM, Kidd DD, Zhao S, Freiriech EJ, Stass SA (1991). Rearrangement of the retinoic acid receptor gene in acute promyelocytic leukemia. Leukemia 5: 200–204.PubMedGoogle Scholar
  37. 37.
    Chen SJ, Zhu YJ, Tong JH, Dong S, Huang W, Chen Y, Xiang WM, Zhang L, Li XS, Qian GQ, Wang ZY, Chen Z, Larsen CJ, Berger R (1991). Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid induced leukemic cell differentiation. Blood 78: 2696–2701.PubMedGoogle Scholar
  38. 38.
    Lanotte M, Thouvenin MV, Najman S, Ballerini P, Valensi F, Berger R (1991). NB4, a maturation inducible cell line with t(15;17) marker from a human acute promyelocytic leukemia M3. Blood 77: 1080–1086.PubMedGoogle Scholar
  39. 39.
    Borrows T, Goddard AD, Sheer D, Solomon E (1990). Molecular analysis of APL breakpoint cluster region on chromosome 17. Science 249: 1577–1580.CrossRefGoogle Scholar
  40. 40.
    Alcalay M, Zangilli D, Pandolfi PP, Longo L, Mencarelli A, Giacomucci A, Rocchi A, Biondi A, Rambaldi A, Lococo F, Diverio D, D'Znti E, Grignani F, Pelicci PG (1991). Translocation breakpoint of acute promyelocytic leukemia lies within retinoic acid receptor alpha locus. Proc Natl Acad Sci USA 88: 1977–1981.PubMedCrossRefGoogle Scholar
  41. 41.
    Castaigne S, Balitrand N, DeThe H, Dejean A, Degos L, Chomienne C (in press). A PML/RAR alpha fusion transcript is constantly detected by RNA-based polymerase chain reaction in acute promyelocytic leukemia. Blood.Google Scholar
  42. 42.
    Miller WH, Kakizuka A, Frankel SR, Warrell RP, Levine K, Arlin Z, Evans R, D'Mitrovky E (1991). Reverse transcriptase polymerase chain reaction (RT-PCR) for the rearranged retinoic acid receptor alpha of acute promyelocytic leukemia clarifies diagnosis and detects minimal residual disease in clinical remission. Blood (ASH Abstract): Abst 1075, p. 271a.Google Scholar
  43. 43.
    Petkovitch M, Brand NJ, Krust A, Chambon P (1987). A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330: 444–450.CrossRefGoogle Scholar
  44. 44.
    DeThe H, Marchio A, Tiollais P, Dejean A (1989). A novel steroid thyroid hormone receptor related gene inappropriately expressed in human hepatocellular carcinoma. Nature 330: 667–670.CrossRefGoogle Scholar
  45. 45.
    Giguere V, Ong ES, Segui P, Evans RM (1987). Identification of a receptor for morphogen retinoic acid. Nature 330: 624–629.PubMedCrossRefGoogle Scholar
  46. 46.
    Krust A, Kastner P, Petkovich M, Zelent A, Chambon P (1989). A third human retinoic acid receptor, HRAR gamma. Proc Natl Acad Sci USA 86: 5310–5314.PubMedCrossRefGoogle Scholar
  47. 47.
    DeThe H, Marchio A, Tiollais P, DeJean A (1989). Differential expression and ligand regulation of the retinoic acid receptor alpha and beta gene. EMBO J 8: 429–433.PubMedGoogle Scholar
  48. 48.
    Chambon P, Zelent A, Petrovitch M, Mendelsohn C, Leroy P, Krust A, Kastner P, Band N (1991). The family of retinoic acid receptor. In Saurat JH (ed). Retinoics: 10 Years On, Karger: Basel, pp. 10–27.Google Scholar
  49. 49.
    Goddard A, Borrow J, Freemont PS, Solomon E (1991). Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254: 1371–1374.PubMedCrossRefGoogle Scholar
  50. 50.
    Kakizuka A, Miller WH, Umesono K, Warrell RP, Frankel SR, Murty VS, Dimitrovsky E, Evans RM (1991). Chromosomal transklocation t(15;17) in human acute promyelocytic leukemia fuses RARa with a novel putative transcription factor, PML. Cell 66: 663–674.PubMedCrossRefGoogle Scholar
  51. 51.
    Freemont PS, Hawson IM, Ttowsdale T (1991). A novel cystein rich sequence motif. Cell 64: 483–484.PubMedCrossRefGoogle Scholar
  52. 52.
    Kastner P (1991). Communication at the Retinoid Symposium, Palermo.Google Scholar
  53. 53.
    Biondi A, Rambaldi A, Pandolfi PP, Alcalay M, Rossi V, Giudici G, Lococo F, Diverio D, Zanguilli D, Mandelli F, Grignani F, Masera G, Barbecci T, Pelici PG (1992). Molecular monitoring of the PML-RAR alpha fusion gene in acute promyelocytic leukemia by polymerase chain reaction. Abstract book, Leukemia symposium, Munster.Google Scholar
  54. 54.
    DeThe H, Lavau C, Marchio A, Chomienne C, Degos L, DeJean A (1991). The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66: 675–684.PubMedCrossRefGoogle Scholar
  55. 55.
    Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, Lococo F, Pelicci PG (1991). Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoic binding and transactivation properties. Oncogene 6: 1285–1292.PubMedGoogle Scholar
  56. 56.
    Chang KS, Stass SA, Chu DT, Deaven LL, Trujillo JM, Freireich EJ (1991). Molecular characterization of the t(15;17) translocation breakpoint in APL. Blood (ASH Abstract): Abst. 1504, p. 378a.Google Scholar
  57. 57.
    Mangelsforf DJ, Ong ES, Dyck JA, Evans RM (1990). Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345: 224–227.CrossRefGoogle Scholar
  58. 58.
    Chomienne C, Balitrand N, Ballerini P, Castaigne S, DeThe H, Degos L (1991). All trans retinoic acid modulates the retinoic receptor alpha in promyelocytic cells. J Clin Invest 88: 2150–2154.PubMedCrossRefGoogle Scholar
  59. 59.
    Leroy P, Krust A, Zelent A, Mendelsohn C, Gamier JM, Kastner P, Dierich A, Chambon P (1991). Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J 10: 59–69.PubMedGoogle Scholar
  60. 60.
    Chomienne C, Barbey S, Balitrand N, Degos L, Sachs L (1992). Regulation of Bcl-2 and cell death by all trans retinoic acid in acute promyelocytic leukemic cells. AACR Abstract.Google Scholar

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© Springer Science+Business Media New York 1993

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  • Laurent Degos

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