- Email: [email protected]
Acute promyelocytic leukemia with a PLZF-RARα fusion protein
Acute Promyelocytic Leukemia With a PLZF-RARcuFusion Protein Joop iFI. Jansea and Bob LtieBbeq In most cases of acute promyelocytic leukemia (APL), a fusion of the promyelocytic leukemia (PML) and the retinoic acid receptor-a (RARo) genes occurs, resulting in the expression of a PML-RARa chimeric protein. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found fusing RARcu with other genes. Four variant mutations have been described, and the t(lql7)(q2l;q23) translocation generating a promyelocyte leukemia zinc finger (PLZF)-RARa fusion gene is the most common. PLZF-RARa-positive APL forms a clinically distinct group because unlike PML-RARa-positive leukemia, it does not respond to retinoic acid with terminal granulocytic differentiation of the cells, and remissions cannot be achieved with retinoids alone. At the molecular level, this has been explained by the retinoic acid-insensitive binding of corepressor proteins to the PLZF part of the fusion protein, leading to sustained repression of target genes that are important for cellular differentiation. Targeting of the PLZF-RARa-bound corepressor complexes using a combination of all-frans retinoic acid (ATRA) and deacetylase inhibitors has shown that the repression of target genes can be relieved, allowing differentiation of the cells. In addition, when a combination of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) is applied, the cells may be forced to undergo terminal differentiation, both in vitro and in vivo. This suggests that signals from the activated G-CSF receptor may induce the release of corepressor proteins from PLZF. Together, these findings indicate that PLZF-RARa+positive leukemia is not completely resistant to differentiation induction if the proper costimuli are given. Semin Hematol38:37-41. Copyright @ 2001 by W.B. Saunders Company.
A
CUTI! PROMYELOCYTIC leukemia (APL) is characterized by mutations that &ect the retinoic acid receptor-4 @AR@, a ligand-inducible transcription factor. 29,34 In most cases, a t(l5; 17)(q2l;q22) translocation occurs, fusing the RARa! and the promyelocytic leukemia (PML) genes.26a7a9s19 Th’ is results in a PML-RARa and a reciprocal RARct-PML chimeric gene. In approximately 1% of cases of APL, variant chromosomal aberrations are found that fuse the same part of RARQ! to genes other than PML. So far, four additional partner genes have been described. The most common variant is a fusion of RARa! with the promyelocyte leukemia zinc finger (PLZF) gene.* Rare cases have been described in which the nucleophosmin (NPM),z7a2a the nuclearmitotic apparatus (NuMa),3> and the signal transducer and activator of transcription 5b (Stat5b)l serve as fusion partners. The consistent involvement of the same part of RARa! in these fusions suggests that abnormal regulation of retinoic acid receptor target genes plays an important role in the transformation of APL cells. It has been shown that the fusion proteins exhibit abnormal DNA-binding and Seminars
in Hematology,
transactivational properties.4~‘,17,19,20~26 In the case of PML-RARa, the differentiation block can be reversed by the application of nonphysiologic high concentrations of ligand, which has translated into a much better clinical outcome.3,152*,31,33
PLZF-RARcx-Positive Leukemia In a large survey of APL patients lacking the classical t( 15;17)(q22;q21) translocation,11~30 11 PLZF-RARa-positive cases were identified and compared with PML-RARa-positive cases. Morphologic review showed that PLZF-RARa
horn Rotter&m,
the institute of Hematology, The Netbevlands.
Erasmus
University,
Address yeprint requests to J. H. Jansen, PbD: Department of Hematology, University Medical Center St Radboud, PO Box 9101, 6SOO HB Nijmegen, The Netherlands. J.H‘J. is supported by the Royal Netherlands Academy of Arts and Sciences. Copyright 0 2001 by W.B. Saunders Company 0037-1963/0113801-0000$3>.00/0 doi:10.10~3ls~em.2001.20864
Vol 38, No 1 (January),
2001:
pp 37-41
37
38
Jansenaad Ltienberg
APL could be distinguished from PML-RARa APL by the appearance of blasts with regular nuclei, an increased number of Pelger-like cells, and expression of CD56. In vitro and in viva, PLZF-RARo+positive cells do not show terminal maturation upon treatment with retinoic acid. In addition, remission cannot be achieved using retinoic acid as a single agent in these patients.lzJ1
Corepressors In recent years, the molecular mechanisms by which retinoic acid receptors mediate their biological functions have been studied extensively. Retinoid receptors are ligand-dependent transcription factors that directly regulate the expression of target genes by binding to specific enhancer sequences in the DNA. Although various retinoic acid-responsive genes have been identified, the target genes that are crucially involved in leukemogenesis are not well known. Recent studies have provided insight into the mechanisms by which the PML-RARa and PLZF-RARct! fusion proteins may deregulate the expression of target genes.5,10J3,1*T22 Unliganded retinoic acid receptors inhibit gene expression by recruiting corepressor proteins like N-CoR/ SMRT and histone deacetylases to the DNA (Fig 1). The subsequent deacetylation of histones results in transcriptional silencing of the the target genes. Upon ligand binding, corepressor complex is released and replaced by a coactivator protein complex with histone acetylation activity, allowing transcriptional activation. The release of corepressor proteins from the PML-RARa fusion protein was shown to require much higher doses of ligand than the wild-type RARct receptor. This explains why supraphysiologic doses of ligand are necessary to induce differentiation of t( 15; 17)-positive leukemia cells. However, in the case of PLZFRARa promyelocytic leukemia, high doses of retinoic acid did not induce the complete release of corepressor proteins from the PLZFRARa fusion protein. This finding appears to be attributable to a second, retinoic acidinsensitive binding site for corepressor proteins in the PLZF part of the fusion protein. Therefore, incomplete corepressor release seems to
A
No gene expression Histom
Histone
deecety/ation
acetyhfion
1
Figure 1. Transcriptional activation by retinoic acid receptors. (A) In the absence of ligand, DNA-bound retinoic acid receptors recruit a corepressor complex of proteins such as N-CoR, SMRT, sin3, and HDACI to the DNA. The subsequent deacetylation of histones renders the chromatin inaccessible for transcription and silences the gene. (B) Upon ligand (ATRA) binding, the corepressor proteins are released and are replaced by coactivator proteins like CBP/p300 and proteins with histone acetyltransferase activity (HAT). The subsequent acetylation of histones opens up the chromatin structure, allowing transcription of the gene.
explain the insensitivity of t( 11; 17)-positive leukemia to retinoic acid. When ATRA was applied in combination with direct inhibitors of deacetylase activity such as trichostatin and sodium phenylbutyrate, synergistic induction of transcriptional activity by PLZF-RARa was observed, suggesting that both derepression and active transactivation are necessary for the induction of the differentiation regulating genes. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) on granulocytic differentiation of APL cells,16J5 we tested whether PLZF-RARa-positive leukemia cells would respond to the combination of ATRA and G-CSF.ls In vitro studies with the leukemic cells from a PLZF-RARct patient showed that ATRA and G-CSF were strongly synergistic with respect to differentiation (Fig 2). One patient was treated with the combination of ATRA and G-CSF, resulting in a complete remission. A possible explanation would be that signals from the activated G-CSF receptor induce the release of corepressor proteins from the PLZF part of the fusion protein, allowing the transactivation of relevant target genes by activated retinoic acid receptors.
PLZF-RARa-Podive
Figure 2. Granulocytic differentiation of PLZF-RARcx-positive leukemia cells in response to ATRA and G-CSF. (A) Freshly isolated PLZF-RARa-positive leukemia cells were cultured for 7 days in (6) medium, (C) 10-e mol/L ATRA, (D) 0.1 pg/mL G-CSF, or(E) a combination of ATRA and G-C.SF. Cytospin slides were stained with May-Grunwald Giemsa. Cells cultured with ATRA or G-CSF alone did not differentiate toward mature granulocytes. Cells cultured with the combination of ATRA and G-CSF showed profound granulocytic differentiation. Color reproduction supported in part by Roche Pharma AG (Schweiz).
APL
E
The efficacy of the combination of ATRA with trichostatin or ATRA with G-CSF indicates that PLZF-RARa-positive leukemia may be rendered sensitive to differentiation induction if the proper stimuli are given. The abnormal recruitment of corepressor complexes and silencing of crucial genes that are involved in differentiation may be a more general phenom-
enon in leukemia. For instance, it was shown that the ET0 protein, which is fused to AMLl in t(8;2I)-positive leukemia, recruits corepressor proteins to AMLl target genes.s,23J2 Investigations aiming at the reversal of abnormal gene silencing using combinations of growth factors, deacetylase inhibitors, and differentiation-inducing agents like retinoic acid may
40
allow ation
Jamn
expansion induction
and Liwenbq
of the use of forced differentito other types of leukemia. 14.
References 1. Arnould C, Philippe C, Bourdon V, et al: The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mel Genet 8:1741-1749, 1999 2. Borrow J, Goddard AD, Sheer D, et al: Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 249:15771580, 1990 3. Breitman T, Collins SJ, Keene BR: entiation of promyelocytic leukemia cultures in response to retinoic acid.
Terminal differcells in primary Blood 57:1000-
15.
16.
17.
1004, 1981 4.
5.
6.
7.
8.
Chen ZC, Brand a novel K+@-like
NJ,
Chen A, et al: Fusion between zinc finger gene and the retinoic
acid receptor-alpha locus due to a variant t(ll;l7) translocation associated with acute promyelocytic leukaemia. EMBO J 12:1161-1167, 1993 David G, Alland L, Hong SH, et al: Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 16:2549-2556, 1998 deThe H, Chomienne C, Lanotte M, et al: 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, 1990 deThe H, Lavau C, Marchio A, et al: The PML-RARalpha fusion mRNA generated by the t(l5;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66:675-684, 1991 Gelmetti V, Zhang J, Fanelli M, et al: Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mel Cell Biol 18:7185-
18.
19.
1991 20.
21.
7191, 1998 9.
10.
11.
Goddard AD, Borrow J, Freemont PS, et al: Characterization of a zinc-finger gene disrupted by the t(l5;17) in acute promyelocytic leukemia. Science 254:1371-1374, 1991 Grignani F, DeMatteis S, Nervi C, et al: Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815-818, 1998 Grimwade D, Biondi A, Mozziconacci MJ, et al: Characterisation of acute promyelocytic leukemia cases lacking the classical t(l5;17): Results of the European working party. Blood 96:1297-1308,
22.
23.
24.
2000 12.
13.
Guide2 F, Huang W, Tong JH, et al: Poor response to all-tnzzx retinoic acid therapy in a t(ll;l7) PLZF/ RARalpha patient. Leukemia 8:312-317, 1994 He LZ, Guide2 F, Tribioli C, et al: Distinct interac-
tions of PML-RARalpha and PLZF-RARalpha with corepressors determine differential responses to RA in APL. Nat Genet 18:126-135, 1998 Hong SH, David G, Wong CW, et al: SMRT corepressor interacts with PLZF and with the PMLretinoic acid receptor ct and PLZF-RARa oncoproteins associated with acute promyelocytic leukemia. Proc Nat1 Acad Sci USA 94:9028-9033, 1997 Huang ME, Ye YC, Chen SR, et al: Use of all-trazr retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567-572, 1988 Huang F, Zhao HP, Gao X2, et al: Recombinant human G-CSF and retinoic acid in synergistically inducing granulocyte differentiation of human promyelocytic leukemic cells. Chin Med J (Engl) 1992; 105:707-712 Jansen JH, Mahfoudi A, Rambaud S, et al: Multimerit complexes of the PML-RAR alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways. Proc Nat1 Acad Sci USA 92:7401-7405, 1995 Jansen JH, de Ridder MC, Geertsma WM, et al: Complete remission of t(ll;l7) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood 94:39-45, 1999 Kakizuka A, Miller WH, Umesono K, et al: Chromosomal translocation t(l5;17) in human acute promyelocytic leukemia fuses RAR-alpha with a novel putative transcription factor PML, Cell 66:663-674,
25.
Kastner P, Perez A, Lutz Y, et al: Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): Structural similarities with a new family of oncoproteins. EMBO J 11:629-642, 1992 Licht JD, Chomienne C, Goy A, et al: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85:1083-1094, 1995 Lin RJ, Nagy L, Inoue S, et al: Role of histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811-814, 1998 Lutterbach B, Westendorf JJ, Linggi B, et al: ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mel Cell Biol 18:7176-7184, 1998 Mandelli F, Diverio D, Avvisati G, et al: Molecular remission in PML/RARa-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 90:10141021, 1997 Nakamaki T, Sakashita A, Sane M, et al: Granulocyte-colony stimulating factor and retinoic acid cooperatively induce granulocyte differentiation of
PLZF-RARa-Positive
26.
27.
28.
29.
30.
acute promyelocytic leukemia cells in vitro. Jpn J Cancer Res 80:1077-1082, 1989 Perez A, Kastner P, Sethi S, et al: PML-RAR homodimers: Distinct DNA binding properties and heteromeric interactions with RXR. EMBO J 12: 3171-3182, 1993 Redner RL, Rush EA, Faas S, et al: The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87882886, 1996 Redner RL, Chen JD, Rush EA, et al: The t(5;17) acute promyelocytic leukemia fusion protein NPMRAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties. Blood 95:2683-2690, 2000 Rowley J, Golomb HM, Dougherty C: 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1:549-550, 1977 Sainty D, Liso V, Can&Rajnoldi A, et al: A new morphological classification system for acute promyelocytic leukemia distinguishes cases with underly-
APL
41
ing PJ~ZF-RARCY rearrangements. Blood 96:12871296, 2000 3 1. Sun GL, Huang YG, Chang XF, et al: Clinical study on all-t?aBJ retinoic acid in treatment of 544 cases of acute promyelocytic leukemia treated. Chin J Haematol 13:13S-137, 1992. 32. Wang J, Hoshino T, Redner RL, et al: ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/ mSin3/HDACl complex. Proc Nat1 Acad Sci USA 95:10860-10865, 1998 33. Warrell RP, Franked SR, Miller WH, et al: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-~~~z~ retinoic acid). N Engl J Med 34. 35.
324:1385-1393, 1991 Warrell RP, de The H, Wang ZY, et al: Acute promyelocytic leukemia. N Engl J Med 329:177-189, 1993 Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17: 109-113, 1997
A
CUTI! PROMYELOCYTIC leukemia (APL) is characterized by mutations that &ect the retinoic acid receptor-4 @AR@, a ligand-inducible transcription factor. 29,34 In most cases, a t(l5; 17)(q2l;q22) translocation occurs, fusing the RARa! and the promyelocytic leukemia (PML) genes.26a7a9s19 Th’ is results in a PML-RARa and a reciprocal RARct-PML chimeric gene. In approximately 1% of cases of APL, variant chromosomal aberrations are found that fuse the same part of RARQ! to genes other than PML. So far, four additional partner genes have been described. The most common variant is a fusion of RARa! with the promyelocyte leukemia zinc finger (PLZF) gene.* Rare cases have been described in which the nucleophosmin (NPM),z7a2a the nuclearmitotic apparatus (NuMa),3> and the signal transducer and activator of transcription 5b (Stat5b)l serve as fusion partners. The consistent involvement of the same part of RARa! in these fusions suggests that abnormal regulation of retinoic acid receptor target genes plays an important role in the transformation of APL cells. It has been shown that the fusion proteins exhibit abnormal DNA-binding and Seminars
in Hematology,
transactivational properties.4~‘,17,19,20~26 In the case of PML-RARa, the differentiation block can be reversed by the application of nonphysiologic high concentrations of ligand, which has translated into a much better clinical outcome.3,152*,31,33
PLZF-RARcx-Positive Leukemia In a large survey of APL patients lacking the classical t( 15;17)(q22;q21) translocation,11~30 11 PLZF-RARa-positive cases were identified and compared with PML-RARa-positive cases. Morphologic review showed that PLZF-RARa
horn Rotter&m,
the institute of Hematology, The Netbevlands.
Erasmus
University,
Address yeprint requests to J. H. Jansen, PbD: Department of Hematology, University Medical Center St Radboud, PO Box 9101, 6SOO HB Nijmegen, The Netherlands. J.H‘J. is supported by the Royal Netherlands Academy of Arts and Sciences. Copyright 0 2001 by W.B. Saunders Company 0037-1963/0113801-0000$3>.00/0 doi:10.10~3ls~em.2001.20864
Vol 38, No 1 (January),
2001:
pp 37-41
37
38
Jansenaad Ltienberg
APL could be distinguished from PML-RARa APL by the appearance of blasts with regular nuclei, an increased number of Pelger-like cells, and expression of CD56. In vitro and in viva, PLZF-RARo+positive cells do not show terminal maturation upon treatment with retinoic acid. In addition, remission cannot be achieved using retinoic acid as a single agent in these patients.lzJ1
Corepressors In recent years, the molecular mechanisms by which retinoic acid receptors mediate their biological functions have been studied extensively. Retinoid receptors are ligand-dependent transcription factors that directly regulate the expression of target genes by binding to specific enhancer sequences in the DNA. Although various retinoic acid-responsive genes have been identified, the target genes that are crucially involved in leukemogenesis are not well known. Recent studies have provided insight into the mechanisms by which the PML-RARa and PLZF-RARct! fusion proteins may deregulate the expression of target genes.5,10J3,1*T22 Unliganded retinoic acid receptors inhibit gene expression by recruiting corepressor proteins like N-CoR/ SMRT and histone deacetylases to the DNA (Fig 1). The subsequent deacetylation of histones results in transcriptional silencing of the the target genes. Upon ligand binding, corepressor complex is released and replaced by a coactivator protein complex with histone acetylation activity, allowing transcriptional activation. The release of corepressor proteins from the PML-RARa fusion protein was shown to require much higher doses of ligand than the wild-type RARct receptor. This explains why supraphysiologic doses of ligand are necessary to induce differentiation of t( 15; 17)-positive leukemia cells. However, in the case of PLZFRARa promyelocytic leukemia, high doses of retinoic acid did not induce the complete release of corepressor proteins from the PLZFRARa fusion protein. This finding appears to be attributable to a second, retinoic acidinsensitive binding site for corepressor proteins in the PLZF part of the fusion protein. Therefore, incomplete corepressor release seems to
A
No gene expression Histom
Histone
deecety/ation
acetyhfion
1
Figure 1. Transcriptional activation by retinoic acid receptors. (A) In the absence of ligand, DNA-bound retinoic acid receptors recruit a corepressor complex of proteins such as N-CoR, SMRT, sin3, and HDACI to the DNA. The subsequent deacetylation of histones renders the chromatin inaccessible for transcription and silences the gene. (B) Upon ligand (ATRA) binding, the corepressor proteins are released and are replaced by coactivator proteins like CBP/p300 and proteins with histone acetyltransferase activity (HAT). The subsequent acetylation of histones opens up the chromatin structure, allowing transcription of the gene.
explain the insensitivity of t( 11; 17)-positive leukemia to retinoic acid. When ATRA was applied in combination with direct inhibitors of deacetylase activity such as trichostatin and sodium phenylbutyrate, synergistic induction of transcriptional activity by PLZF-RARa was observed, suggesting that both derepression and active transactivation are necessary for the induction of the differentiation regulating genes. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) on granulocytic differentiation of APL cells,16J5 we tested whether PLZF-RARa-positive leukemia cells would respond to the combination of ATRA and G-CSF.ls In vitro studies with the leukemic cells from a PLZF-RARct patient showed that ATRA and G-CSF were strongly synergistic with respect to differentiation (Fig 2). One patient was treated with the combination of ATRA and G-CSF, resulting in a complete remission. A possible explanation would be that signals from the activated G-CSF receptor induce the release of corepressor proteins from the PLZF part of the fusion protein, allowing the transactivation of relevant target genes by activated retinoic acid receptors.
PLZF-RARa-Podive
Figure 2. Granulocytic differentiation of PLZF-RARcx-positive leukemia cells in response to ATRA and G-CSF. (A) Freshly isolated PLZF-RARa-positive leukemia cells were cultured for 7 days in (6) medium, (C) 10-e mol/L ATRA, (D) 0.1 pg/mL G-CSF, or(E) a combination of ATRA and G-C.SF. Cytospin slides were stained with May-Grunwald Giemsa. Cells cultured with ATRA or G-CSF alone did not differentiate toward mature granulocytes. Cells cultured with the combination of ATRA and G-CSF showed profound granulocytic differentiation. Color reproduction supported in part by Roche Pharma AG (Schweiz).
APL
E
The efficacy of the combination of ATRA with trichostatin or ATRA with G-CSF indicates that PLZF-RARa-positive leukemia may be rendered sensitive to differentiation induction if the proper stimuli are given. The abnormal recruitment of corepressor complexes and silencing of crucial genes that are involved in differentiation may be a more general phenom-
enon in leukemia. For instance, it was shown that the ET0 protein, which is fused to AMLl in t(8;2I)-positive leukemia, recruits corepressor proteins to AMLl target genes.s,23J2 Investigations aiming at the reversal of abnormal gene silencing using combinations of growth factors, deacetylase inhibitors, and differentiation-inducing agents like retinoic acid may
40
allow ation
Jamn
expansion induction
and Liwenbq
of the use of forced differentito other types of leukemia. 14.
References 1. Arnould C, Philippe C, Bourdon V, et al: The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mel Genet 8:1741-1749, 1999 2. Borrow J, Goddard AD, Sheer D, et al: Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 249:15771580, 1990 3. Breitman T, Collins SJ, Keene BR: entiation of promyelocytic leukemia cultures in response to retinoic acid.
Terminal differcells in primary Blood 57:1000-
15.
16.
17.
1004, 1981 4.
5.
6.
7.
8.
Chen ZC, Brand a novel K+@-like
NJ,
Chen A, et al: Fusion between zinc finger gene and the retinoic
acid receptor-alpha locus due to a variant t(ll;l7) translocation associated with acute promyelocytic leukaemia. EMBO J 12:1161-1167, 1993 David G, Alland L, Hong SH, et al: Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 16:2549-2556, 1998 deThe H, Chomienne C, Lanotte M, et al: 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, 1990 deThe H, Lavau C, Marchio A, et al: The PML-RARalpha fusion mRNA generated by the t(l5;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66:675-684, 1991 Gelmetti V, Zhang J, Fanelli M, et al: Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mel Cell Biol 18:7185-
18.
19.
1991 20.
21.
7191, 1998 9.
10.
11.
Goddard AD, Borrow J, Freemont PS, et al: Characterization of a zinc-finger gene disrupted by the t(l5;17) in acute promyelocytic leukemia. Science 254:1371-1374, 1991 Grignani F, DeMatteis S, Nervi C, et al: Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815-818, 1998 Grimwade D, Biondi A, Mozziconacci MJ, et al: Characterisation of acute promyelocytic leukemia cases lacking the classical t(l5;17): Results of the European working party. Blood 96:1297-1308,
22.
23.
24.
2000 12.
13.
Guide2 F, Huang W, Tong JH, et al: Poor response to all-tnzzx retinoic acid therapy in a t(ll;l7) PLZF/ RARalpha patient. Leukemia 8:312-317, 1994 He LZ, Guide2 F, Tribioli C, et al: Distinct interac-
tions of PML-RARalpha and PLZF-RARalpha with corepressors determine differential responses to RA in APL. Nat Genet 18:126-135, 1998 Hong SH, David G, Wong CW, et al: SMRT corepressor interacts with PLZF and with the PMLretinoic acid receptor ct and PLZF-RARa oncoproteins associated with acute promyelocytic leukemia. Proc Nat1 Acad Sci USA 94:9028-9033, 1997 Huang ME, Ye YC, Chen SR, et al: Use of all-trazr retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567-572, 1988 Huang F, Zhao HP, Gao X2, et al: Recombinant human G-CSF and retinoic acid in synergistically inducing granulocyte differentiation of human promyelocytic leukemic cells. Chin Med J (Engl) 1992; 105:707-712 Jansen JH, Mahfoudi A, Rambaud S, et al: Multimerit complexes of the PML-RAR alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways. Proc Nat1 Acad Sci USA 92:7401-7405, 1995 Jansen JH, de Ridder MC, Geertsma WM, et al: Complete remission of t(ll;l7) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood 94:39-45, 1999 Kakizuka A, Miller WH, Umesono K, et al: Chromosomal translocation t(l5;17) in human acute promyelocytic leukemia fuses RAR-alpha with a novel putative transcription factor PML, Cell 66:663-674,
25.
Kastner P, Perez A, Lutz Y, et al: Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): Structural similarities with a new family of oncoproteins. EMBO J 11:629-642, 1992 Licht JD, Chomienne C, Goy A, et al: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85:1083-1094, 1995 Lin RJ, Nagy L, Inoue S, et al: Role of histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811-814, 1998 Lutterbach B, Westendorf JJ, Linggi B, et al: ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mel Cell Biol 18:7176-7184, 1998 Mandelli F, Diverio D, Avvisati G, et al: Molecular remission in PML/RARa-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 90:10141021, 1997 Nakamaki T, Sakashita A, Sane M, et al: Granulocyte-colony stimulating factor and retinoic acid cooperatively induce granulocyte differentiation of
PLZF-RARa-Positive
26.
27.
28.
29.
30.
acute promyelocytic leukemia cells in vitro. Jpn J Cancer Res 80:1077-1082, 1989 Perez A, Kastner P, Sethi S, et al: PML-RAR homodimers: Distinct DNA binding properties and heteromeric interactions with RXR. EMBO J 12: 3171-3182, 1993 Redner RL, Rush EA, Faas S, et al: The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87882886, 1996 Redner RL, Chen JD, Rush EA, et al: The t(5;17) acute promyelocytic leukemia fusion protein NPMRAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties. Blood 95:2683-2690, 2000 Rowley J, Golomb HM, Dougherty C: 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1:549-550, 1977 Sainty D, Liso V, Can&Rajnoldi A, et al: A new morphological classification system for acute promyelocytic leukemia distinguishes cases with underly-
APL
41
ing PJ~ZF-RARCY rearrangements. Blood 96:12871296, 2000 3 1. Sun GL, Huang YG, Chang XF, et al: Clinical study on all-t?aBJ retinoic acid in treatment of 544 cases of acute promyelocytic leukemia treated. Chin J Haematol 13:13S-137, 1992. 32. Wang J, Hoshino T, Redner RL, et al: ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/ mSin3/HDACl complex. Proc Nat1 Acad Sci USA 95:10860-10865, 1998 33. Warrell RP, Franked SR, Miller WH, et al: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-~~~z~ retinoic acid). N Engl J Med 34. 35.
324:1385-1393, 1991 Warrell RP, de The H, Wang ZY, et al: Acute promyelocytic leukemia. N Engl J Med 329:177-189, 1993 Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17: 109-113, 1997