Skip to main content
SpringerLink
Log in
Book cover

Targeted Therapy of Acute Myeloid Leukemia pp 461–475Cite as

PML/RARA as the Master Driver of APL Pathogenesis and Therapy Response

  • Chapter
  • First Online:

  • 2220 Accesses

Part of the book series: Current Cancer Research ((CUCR))

Abstract

Acute promyelocytic leukemia (APL) is a model disease for targeted therapy. APL is caused by a variety of fusion proteins, all implicating the retinoic acid receptor alpha (RARA). The promyelocytic gene (PML)/RARA fusion is by far the most frequent, present in 99 % of patients. Two unconventional drugs, retinoic acid (RA) and arsenic trioxide were first shown to exhibit extraordinary clinical activity and later found to directly target PML/RARA. RA binds PML/RARA via its RARA moiety, activates transcription and degrades PML/RARA. Arsenic only degrades the fusion protein by targeting its PML part. Mouse modeling in APL has allowed an unprecedented level of understanding of the disease pathogenesis and basis for therapy response, highlighting the key role of PML/RARA degradation in the latter. The combination of RA and arsenic definitively eradicate the disease in mice and in most patients. APL thus represents a paradigm for oncoprotein-targeted cures.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Ablain J, de The H (2011) Revisiting the differentiation paradigm in acute promyelocytic leukemia. Blood 117(22):5795–5802. doi:10.1182/blood-2011-02-329367

    Article  CAS  PubMed  Google Scholar 

  • Ablain J, Nasr R, Bazarbachi A, de The H (2011) Oncoprotein proteolysis, an unexpected Achille’s Heel of cancer cells? Cancer Discov 1:117–127

    Article  CAS  PubMed  Google Scholar 

  • Akagi T, Shih LY, Kato M, Kawamata N, Yamamoto G, Sanada M, Okamoto R, Miller CW, Liang DC, Ogawa S, Koeffler HP (2009) Hidden abnormalities and novel classification of t(15;17) acute promyelocytic leukemia (APL) based on genomic alterations. Blood 113 (8):1741–1748. doi:blood-2007-12-130260 [pii] 10.1182/blood-2007-12-130260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen Z, Brand N, Chen A, Chen S, Tong J, Wang Z, Waxman S, Zelent A (1993) Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor a locus due to a variant t(11,17) translocation in acute promyelocytic leukemia. EMBO J 12:1161–1167

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen SJ, Zhou GB, Zhang XW, Mao JH, de The H, Chen Z (2011) From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood 117(24):6425–6437. doi:10.1182/blood-2010-11-283598

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • de The H, Chen Z (2010) Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer 10(11):775–783. doi:nrc2943 [pii] 10.1038/nrc2943

    Article  PubMed  Google Scholar 

  • de Thé H, Vivanco-Ruiz MdM, Tiollais P, Stunnenberg H, Dejean A (1990) Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 343:177–180

    Article  Google Scholar 

  • de The H, Le Bras M, Lallemand-Breitenbach V (2012) The cell biology of disease: acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol 198(1):11–21. doi:10.1083/jcb.201112044

    Article  PubMed Central  PubMed  Google Scholar 

  • Degos L, Dombret H, Chomienne C, Daniel MT, Miclea JM, Chastang C, Castaigne S, Fenaux P (1995) All-trans retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 85(10):2643–2653.

    CAS  PubMed  Google Scholar 

  • Dos Santos GA, Abreu ELRS, Pestana CR, Lima AS, Scheucher PS, Thome CH, Gimenes-Teixeira HL, Santana-Lemos BA, Lucena-Araujo AR, Rodrigues FP, Nasr R, Uyemura SA, Falcao RP, de The H, Pandolfi PP, Curti C, Rego EM (2011) (+)alpha-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo. Leukemia: Off Leukemia Soc Am, Leukemia Res Fund, UK 26(3):451–460. doi:10.1038/leu.2011.216

    Article  Google Scholar 

  • Dyck JA, Warrell RP, Evans RM, Miller WH (1995) Rapid diagnosis of acute promyelocytic leukemia by immunohistochemical localization of PML/RAR alpha protein. Blood 86:862–867

    CAS  PubMed  Google Scholar 

  • Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H (2006) Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 107(9):3469–3473

    Article  CAS  PubMed  Google Scholar 

  • Farboud B, Hauksdottir H, Wu Y, Privalsky ML (2003) Isotype-restricted corepressor recruitment: a constitutively closed helix 12 conformation in retinoic acid receptors beta and gamma interferes with corepressor recruitment and prevents transcriptional repression. Mol Cell Biol 23(8):2844–2858

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gallagher RE (2002) Retinoic acid resistance in acute promyelocytic leukemia. Leukemia: Off Leukemia Soc Am, Leukemia Res Fund, UK 16(10):1940–1958. doi:10.1038/sj.leu.2402719

    Article  CAS  Google Scholar 

  • Gallagher RE, Schachter-Tokarz EL, Zhou DC, Ding W, Kim SH, Sankoorikal BJ, Bi W, Livak KJ, Slack JL, Willman CL (2006) Relapse of acute promyelocytic leukemia with PML-RARalpha mutant subclones independent of proximate all-trans retinoic acid selection pressure. Leukemia: Off Leukemia Soc Am, Leukemia Res Fund, UK 20(4):556–562. doi:10.1038/sj.leu.2404118

    Article  CAS  Google Scholar 

  • Geoffroy MC, Hay RT (2009) An additional role for SUMO in ubiquitin-mediated proteolysis. Nat Rev Mol Cell Biol 10(8):564–568. doi:nrm2707 [pii] 10.1038/nrm2707

    Article  CAS  PubMed  Google Scholar 

  • Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T (2011) Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment. Blood 118(6):1600–1609 doi:10.1182/blood-2011-01-329433

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z (2009) Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 106(9):3342–3347. doi:10.1073/pnas.0813280106

    Google Scholar 

  • Hua S, Kittler R, White KP (2009) Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 137(7):1259–1271. doi:10.1016/j.cell.2009.04.043

    Article  PubMed Central  PubMed  Google Scholar 

  • Huang M, Ye Y, Chen R, Chai J, Lu J, Zhoa L, Gu L, Wang Z (1988) Use of all trans retinoic acid in the treatment of acute promyelocytic leukaemia. Blood 72:567–572

    CAS  PubMed  Google Scholar 

  • Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J, Pandolfi PP (2008) PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453(7198):1072–1078. doi:nature07016 [pii] 10.1038/nature07016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ito K, Bernardi R, Pandolfi PP (2009) A novel signaling network as a critical rheostat for the biology and maintenance of the normal stem cell and the cancer-initiating cell. Curr Opin Genet Dev 19(1):51–59. doi:S0959-437X(09)00017-3 [pii]10.1016/j.gde.2009.01.004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jeanne M, Lallemand-Breitenbach V, Ferhi O, Koken M, Le Bras M, Duffort S, Peres L, Berthier C, Soilihi H, Raught B, de The H (2010) PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 18(1):88–98. doi:S1535-6108(10)00241-2 [pii] 10.1016/j.ccr.2010.06.003

    Article  CAS  PubMed  Google Scholar 

  • Kamashev DE, Vitoux D, De Thé H (2004) PML/RARA-RXR oligomers mediate retinoid- and rexinoid-/cAMP in APL cell differentiation. J Exp Med 199:1–13

    Article  Google Scholar 

  • Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83(6):859–869

    Article  CAS  PubMed  Google Scholar 

  • Kastner P, Lawrence HJ, Waltzinger C, Ghyselinck NB, Chambon P, Chan S (2001) Positive and negative regulation of granulopoiesis by endogenous RARalpha. Blood 97(5):1314–1320

    Article  CAS  PubMed  Google Scholar 

  • Kogan SC (2009) Curing APL: differentiation or destruction? Cancer Cell 15 (1):7–8. doi:S1535-6108(08)00413-3 [pii] 10.1016/j.ccr.2008.12.012

    Article  CAS  PubMed  Google Scholar 

  • Koken MHM, Puvion-Dutilleul F, Guillemin MC, Viron A, Linares-Cruz G, Stuurman N, de Jong L, Szostecki C, Calvo F, Chomienne C, Degos L, Puvion E, de Thé H (1994) The t(15;17) translocation alters a nuclear body in a RA-reversible fashion. EMBO J 13:1073–1083

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, de The H (2010) PML nuclear bodies. Cold Spring Harb Perspect Biol 2:a000661

    Article  PubMed Central  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Guillemin M-C, Janin A, Daniel M-T, Degos L, Kogan SC, Bishop JM, de The H (1999) Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med 189:1043–1052

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honore N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de The H (2001) Role of Promyelocytic Leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As(2)O(3)-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 193(12):1361–1372

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Zhu J, Kogan S, Chen Z, de The H (2005) Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia. Nat Rev Cancer 5(10):821–827

    Article  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de The H (2008) Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 10(5):547–555. doi:ncb1717 [pii] 10.1038/ncb1717

    Article  CAS  PubMed  Google Scholar 

  • Lallemand-Breitenbach V, Zhu J, Chen Z, de The H (2012) Mechanisms of APL cure through PML/RARA degradation by As2O3. Trends Mol Med 18:36–42

    Article  CAS  PubMed  Google Scholar 

  • Leiva M, Moretti S, Soilihi H, Pallavicini I, Peres L, Mercurio C, Dal Zuffo R, Minucci S, de The H (2012) Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL. Leukemia: Off Leukemia Soc Am, Leukemia Res Fund, UK 26(7):1630–1637. doi:10.1038/leu.2012.39

    Article  CAS  Google Scholar 

  • Licht JD (2006) Reconstructing a disease: what essential features of the retinoic acid receptor fusion oncoproteins generate acute promyelocytic leukemia? Cancer Cell 9(2):73–74

    Article  CAS  PubMed  Google Scholar 

  • Martens JH, Brinkman AB, Simmer F, Francoijs KJ, Nebbioso A, Ferrara F, Altucci L, Stunnenberg HG (2010) PML-RARalpha/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell 17(2):173–185. doi:S1535-6108(10)00005-X [pii] 10.1016/j.ccr.2009.12.042

    Article  CAS  PubMed  Google Scholar 

  • Melnick A, Licht JD (1999) Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93:3167–3215

    CAS  PubMed  Google Scholar 

  • Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B, Parry A, Walz C, Wiemels JL, Segal MR, Ades L, Blair IA, Osheroff N, Peniket AJ, Lafage-Pochitaloff M, Cross NC, Chomienne C, Solomon E, Fenaux P, Grimwade D (2005) DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 352(15):1529–1538

    Article  CAS  PubMed  Google Scholar 

  • Muindi J, Frankel SR, Miller WH Jr, Jakubowski A, Scheinberg DA, Young CW, Dmitrovsky E, Warrell RP, Jr. (1992) Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood 79(2):299–303

    CAS  PubMed  Google Scholar 

  • Muto A, Kizaki M, Kawamura C, Matsushita H, Fukuchi Y, Umezawa A, Yamada T, Hata J, Hozumi N, Yamato K, Ito M, Ueyama Y, Ikeda Y (2001) A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF. Leukemia 15(8):1176–1184

    Article  CAS  PubMed  Google Scholar 

  • Nardella C, Lunardi A, Patnaik A, Cantley LC (2011) The APL paradigm and the co-clinical trial project. Cancer Discov 1:108–116

    Article  PubMed  Google Scholar 

  • Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C, Rousselot P, Robledo-Sarmiento M, Lallemand-Breitenbach V, Gourmel B, Vitoux D, Pandolfi PP, Rochette-Egly C, Zhu J, de The H (2008) Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 14(12):1333–1342. doi:nm.1891 [pii] 10.1038/nm.1891

    Article  CAS  PubMed  Google Scholar 

  • Occhionorelli M, Santoro F, Pallavicini I, Gruszka A, Moretti S, Bossi D, Viale A, Shing D, Ronzoni S, Muradore I, Soncini M, Pruneri G, Rafaniello P, Viale G, Pelicci PG, Minucci S (2011) The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha. Leukemia: Off Leukemia Soc Am, Leukemia Res Fund, UK 25(5):814–820. doi:10.1038/leu.2011.18

    Article  CAS  Google Scholar 

  • Piazza F, Gurrieri C, Pandolfi PP (2001) The theory of APL. Oncogene 20(49):7216–7222

    Article  CAS  PubMed  Google Scholar 

  • Quignon F, Chen Z, de Thé H (1997) Retinoic acid and arsenic: towards oncogene targeted treatments of acute promyelocytic leukaemia. Biochim Biophys Acta 1333:M53–M61

    Google Scholar 

  • Regad T, Bellodi C, Nicotera P, Salomoni P (2009) The tumor suppressor Pml regulates cell fate in the developing neocortex. Nat Neurosci 12(2):132–140. doi:nn.2251 [pii] 10.1038/nn.2251

    Article  CAS  PubMed  Google Scholar 

  • Rego EM, He LZ, Warrell RP Jr, Wang ZG, Pandolfi PP (2000) Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins. Proc Natl Acad Sci U S A 97:10173–10178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shao W, Fanelli M, Ferrara FF, Riccioni R, Rosenauer A, Davison K, Lamph WW, Waxman S, Pelicci PG, Lo Coco F, Avvisati G, Testa U, Peschle C, Gambacorti-Passerini C, Nervi C, Miller WHJ (1998) Arsenic trioxide as an inducer of apoptosis and loss of PML/RARalpha protein in acute promyelocytic leukemia cells. J Natl Cancer Inst 90:124–133

    Article  CAS  PubMed  Google Scholar 

  • Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF et al (2004) All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101:5328–5335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • So CW, Cleary ML (2004) Dimerization: a versatile switch for oncogenesis. Blood 104(4):919–922

    Article  CAS  PubMed  Google Scholar 

  • Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP (2008) The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455(7214):813–817. doi:nature07290 [pii] 10.1038/nature07290

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sternsdorf T, Phan VT, Maunakea ML, Ocampo C, Sohal J, Siletto A, Galimi F, Le Beau MM, Evans R, Kogan S (2006) Forced retinoic acid receptor a homodimer prime mice for APL-like leukemia. Cancer Cell 9:81–94

    Article  CAS  PubMed  Google Scholar 

  • Strickland S, Mahdavi V (1978) The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 15(2):393–403. doi:0092-8674(78)90008-9 [pii]

    Article  CAS  PubMed  Google Scholar 

  • Tallman MS, Altman JK (2009) How I treat acute promyelocytic leukemia. Blood 114 (25):5126–5135. doi:blood-2009-07-216457 [pii] 10.1182/blood-2009-07-216457

    Article  CAS  PubMed  Google Scholar 

  • Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT (2008) RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 10(5):538–546. doi:ncb1716 [pii] 10.1038/ncb1716

    Article  CAS  PubMed  Google Scholar 

  • Tsimberidou AM, Tirado-Gomez M, Andreeff M, O’Brien S, Kantarjian H, Keating M, Lopez-Berestein G, Estey E (2006) Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk Lymphoma 47(6):1062–1068. doi:K54M427781W6874X [pii] 10.1080/10428190500463932

    Article  CAS  PubMed  Google Scholar 

  • Verger A, Perdomo J, Crossley M (2003) Modification with SUMO. A role in transcriptional regulation. EMBO Rep 4(2):137–142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vickers M, Jackson G, Taylor P (2000) The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation. Leukemia 14 (4):722–726

    Article  CAS  PubMed  Google Scholar 

  • Wang ZY, Chen Z (2008) Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111(5):2505–2515. doi:111/5/2505 [pii] 10.1182/blood-2007-07-102798

    Article  CAS  PubMed  Google Scholar 

  • Warrell R, de Thé H, Wang Z, Degos L (1993) Acute promyelocytic leukemia. New Engl J Med 329:177–189

    Article  CAS  PubMed  Google Scholar 

  • Welch JS, Yuan W, Ley TJ (2011) PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice. J Clin Invest 121(4):1636–1645. doi:10.1172/JCI42953

    Article  PubMed Central  PubMed  Google Scholar 

  • Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O’Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, Dipersio JF, Ding L, Mardis ER, Wilson RK (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150(2):264–278. doi:10.1016/j.cell.2012.06.023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zeisig BB, Kwok C, Zelent A, Shankaranarayanan P, Gronemeyer H, Dong S, So CW (2007) Recruitment of RXR by homotetrameric RARalpha fusion proteins is essential for transformation. Cancer Cell 12(1):36–51. doi:S1535-6108(07)00175-4 [pii] 10.1016/j.ccr.2007.06.006

    Article  CAS  PubMed  Google Scholar 

  • Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de The H, Chen SJ, Chen Z (2010) Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328(5975):240–243. doi:328/5975/240 [pii] 10.1126/science.1183424

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Lallemand-Breitenbach V, de The H (2001) Pathways of retinoic acid- or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission. Oncogene 20(49):7257–7265

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Chen Z, Lallemand-Breitenbach V, de Thé H (2002) How acute promyelocytic leukemia revived arsenic. Nat Rev Cancer 2:705–713

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Zhou J, Peres L, Riaucoux F, Honore N, Kogan S, de The H (2005) A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell 7(2):143–153

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Nasr R, Peres L, Riaucoux-Lormiere F, Honore N, Berthier C, Kamashev D, Zhou J, Vitoux D, Lavau C, de The Hs (2007) RXR is an essential component of the oncogenic PML/RARA complex in vivo. Cancer Cell 12(1):23–35

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis 1, Avenue Claude Vellefaux, 75475, Paris cedex 10, France

    Hugues de Thé, Jun Zhu, Julien Ablain & Valérie Lallemand-Breittenbach

  2. INSERM UMR 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d’Hématologie, Hôpital St. Louis 1, Avenue Claude Vellefaux, 75475, Paris cedex 10, France

    Hugues de Thé, Jun Zhu, Julien Ablain & Valérie Lallemand-Breittenbach

  3. CNRS UMR 7212, Hôpital St. Louis 1, Avenue Claude Vellefaux, 75475, Paris cedex 10, France

    Hugues de Thé, Jun Zhu, Julien Ablain & Valérie Lallemand-Breittenbach

  4. Pole Sino-Francais des Sciences du Vivant et de Génomique de l’Hôpital Rui Jin, Rui-Jin Hospital affiliated with Jiao Tong University, 197 Rui Jin Road, 200025, Shanghai, China

    Hugues de Thé & Jun Zhu

  5. Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon

    Rihab Nasr

  6. Department Molecular Pathology and Virology, INSERM U 944 et CNRS UMR 7212, Institut Universitaire d’Hématologie, l’Université Paris VII, 75475, Paris Cedex 10, France

    Hugues de Thé

Authors
  1. Hugues de Thé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rihab Nasr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julien Ablain
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valérie Lallemand-Breittenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hugues de Thé .

Editor information

Editors and Affiliations

  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag New York

About this chapter

Cite this chapter

de Thé, H., Zhu, J., Nasr, R., Ablain, J., Lallemand-Breittenbach, V. (2015). PML/RARA as the Master Driver of APL Pathogenesis and Therapy Response. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1393-0_23

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-1392-3

  • Online ISBN: 978-1-4939-1393-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation