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Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia

Oncogene volume 27, pages 4666–4677 (2008)Cite this article

Abstract

Acute promyelocytic leukemia (APL) is characterized by reciprocal balanced chromosomal translocations involving retinoic acid receptor-α (RARα). RARα heterodimerizes with the retinoid X receptor-α (RXRα) and transcriptionally regulates myeloid differentiation in response to ATRA (all-trans retinoic acid). Several lines of evidence suggest that APL fusion proteins interact with RXRα. To elucidate the role of RXRα in APL, we conditionally knocked out RXRα in the hCG-NuMA-RARα APL mouse model. Phenotype analysis of NuMA-RARα+ mice demonstrated that these mice developed a myeloproliferative disease-like myeloid leukemia within 4 months of birth. While hemizygous and homozygous RXRα conditional knockout mice were phenotypically normal as late as 12 months of age, we observed that the leukemic phenotype in NuMA-RARα+ mice was dependent on the presence of functional RXRα. Bone marrow promyelocyte counts were significantly reduced in NuMA-RARα+ mice with RXRα knocked down. Significant differences in the accumulations of Gr-1+ and Mac-1+ cells were also seen. We further observed that genes previously identified to be cooperating events in APL were also regulated in an RXRα-dependent manner. We therefore propose that the APL fusion protein NuMA-RARα cooperates with RXRα in the development of leukemia in hCG-NuMA-RARα transgenic mice and suggest a novel role for RXRα in the pathogenesis of APL.

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References

  • Arnould C, Philippe C, Bourdon V, Gr goire MJ, Berger R, Jonveaux P . (1999). The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mol Genet 8: 1741–1749.

    Article  CAS  PubMed  Google Scholar 

  • Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. (1976). Proposals for the classification of the acute leukaemias. French–American–British (FAB) Co-operative Group. Br J Haematol 33: 451–458.

    Article  CAS  PubMed  Google Scholar 

  • Bugge TH, Pohl J, Lonnoy O, Stunnenberg HG . (1992). RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO J 11: 1409–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P et al. (1990). All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76: 1704–1709.

    CAS  PubMed  Google Scholar 

  • Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ et al. (2007). The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood 110: 4073–4076.

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Kubalak SW, Chien KR . (1998). Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development 125: 1943–1949.

    CAS  PubMed  Google Scholar 

  • Chen Z, Brand NJ, Chen A, Chen SJ, Tong JH, Wang ZY et al. (1993). Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J 12: 1161–1167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Thé H, Chomienne C, Lanotte M, Degos L, Dejean A . (1990). The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347: 558–561.

    Article  PubMed  Google Scholar 

  • Dong S, Stenoien DL, Qiu J, Mancini MA, Tweardy DJ . (2004). Reduced intranuclear mobility of APL fusion proteins accompanies their mislocalization and results in sequestration and decreased mobility of retinoid X receptor alpha. Mol Cell Biol 24: 4465–4475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hummel JL, Wells RA, Dube ID, Licht JD, Kamel-Reid S . (1999). Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia. Oncogene 18: 633–641.

    Article  CAS  PubMed  Google Scholar 

  • Hummel JL, Zhang T, Wells RA, Kamel-Reid S . (2002). The Retinoic acid receptor alpha (RARalpha) chimeric proteins PML-, PLZF-, NPM-, and NuMA-RARalpha have distinct intracellular localization patterns. Cell Growth Differ 13: 173–183.

    CAS  PubMed  Google Scholar 

  • Imai T, Jiang M, Kastner P, Chambon P, Metzger D . (2001). Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity. Proc Natl Acad Sci USA 98: 4581–4586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamashev D, Vitoux D, De The H . (2004). PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med 199: 1163–1174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamel-Reid S, Zhang T, Wells RA . (2003). Expression of the NPM-RARα fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis. Oncogene 22: 6424–6435.

    Article  CAS  PubMed  Google Scholar 

  • Kastner P, Grondona JM, Mark M, Gansmuller A, LeMeur M, Decimo D et al. (1994). Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78: 987–1003.

    Article  CAS  PubMed  Google Scholar 

  • Kogan SC, Brown DE, Shultz DB, Truong BT, Lallemand-Breitenbach V, Guillemin MC et al. (2001). BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. J Exp Med 193: 531–543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kogan SC, Ward JM, Anver MR, Berman JJ, Brayton C, Cardiff RD et al. (2002). Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. Blood 100: 238–245.

    Article  CAS  PubMed  Google Scholar 

  • Li M, Chiba H, Warot X, Messaddeq N, Gerard C, Chambon P et al. (2001). RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development 128: 675–688.

    CAS  PubMed  Google Scholar 

  • Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S et al. (2000). Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 407: 633–636.

    Article  CAS  PubMed  Google Scholar 

  • Licht JD, Shaknovich R, English MA, Melnick A, Li JY, Reddy JC et al. (1996). Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11;17)-associated acute promyelocytic leukemia. Oncogene 12: 323–336.

    CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD . (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  • Loonstra A, Vooijs M, Beverloo HB, Al Allak B, van Drumen E, Kanaar R et al. (2001). Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells. Proc Natl Acad Sci USA 98: 9209–9214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Macedo Silva ML, Land M, Heller A, Abdelhay E, do Socorro Pombo-de-Oliveira M, Ribeiro R et al. (2005). New rearrangement t(3;l7)(q26.3;ql2) in an AML patient with a poor outcome. Oncol Rep 14: 663–666.

    PubMed  Google Scholar 

  • Minucci S, Maccarana M, Cioce M, De Luca P, Gelmetti V, Segalla S et al. (2000). Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell 5: 811–820.

    Article  CAS  PubMed  Google Scholar 

  • 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: 3171–3182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ . (1996). The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87: 882–886.

    CAS  PubMed  Google Scholar 

  • Reis PP, Rogatto SR, Kowalski LP, Nishimoto IN, Montovani JC, Corpus G et al. (2002). Quantitative real-time PCR identifies a critical region of deletion on 22ql3 related to prognosis in oral cancer. Oncogene 21: 6480–6487.

    Article  CAS  PubMed  Google Scholar 

  • Ricote M, Snyder CS, Leung HY, Chen J, Chien KR, Glass CK . (2006). Normal hematopoiesis after conditional targeting of RXRalpha in murine hematopoietic stem/progenitor cells. J Leukoc Biol 4: 850–861.

    Article  Google Scholar 

  • Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML et al. (1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376: 62–66.

    Article  CAS  PubMed  Google Scholar 

  • So CW, Dong S, So CK, Cheng GX, Huang QH, Chen SJ et al. (2000). The impact of differential binding of wild-type RARalpha, PML-, PLZF- and NPM-RARalpha fusion proteins towards transcriptional co-activator, RIP-140, on retinoic acid responses in acute promyelocytic leukemia. Leukemia 14: 77–83.

    Article  CAS  PubMed  Google Scholar 

  • Stephensen CB, Borowsky AD, Lloyd KC . (2007). Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance. Immunology 121: 484–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sukhai MA, Wu X, Xuan Y, Zhang T, Reis PP, Dube K et al. (2004). Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Oncogene 23: 665–678.

    Article  CAS  PubMed  Google Scholar 

  • Taschner S, Koesters C, Platzer B, Jörgl A, Ellmeier W, Benesch T et al. (2007). Down-regulation of RXRalpha expression is essential for neutrophil development from granulocyte/monocyte progenitors. Blood 109: 971–979.

    Article  CAS  PubMed  Google Scholar 

  • Truong BT, Lee YJ, Lodie TA, Park DJ, Perrotti D, Watanabe N et al. (2003). CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101: 1141–1148.

    Article  CAS  PubMed  Google Scholar 

  • Wells RA, Catzavelos C, Kamel-Reid S . (1997). 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.

    Article  CAS  PubMed  Google Scholar 

  • Zeisig BB, Kwok C, Zelent A, Shankaranarayanan P, Gronemeyer H, Dong S et al. (2007). Recruitment of RXR by homotetrameric RARalpha fusion proteins is essential for transformation. Cancer Cell 12: 36–51.

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Nasr R, Peres L, Riaucoux-Lormiere F, Honore N, Berthier C et al. (2007). RXR is an essential component of the oncogenic PML/RARA complex in vivo. Cancer Cell 12: 23–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge Dr RS Goswami and Dr PP Reis for their careful editing of the manuscript. This work was supported by grants from the National Cancer Institute of Canada (SK-R, Grant no. 013087) and the Canadian Institutes of Health Research (RAW, MOP 42420). MAS held a CIHR Canada Graduate Scholarship during the period in which the research described herein was carried out. Disability-related accommodations support for MAS was provided by the University of Toronto, Offices of Accessibility Services, and Admissions and Awards. The authors have no competing financial interests. MAS and MT designed and performed research; collected, interpreted and analyzed data; and drafted the manuscript. YX performed research and collected data. SAH, TZ, RRB and LSAC performed research as part of this project. ACS contributed Flk1Cre mice use in the study; RAW contributed the murine RαG and RαGC cell lines and assisted with manuscript preparation. SK-R designed the experiments, oversaw the research and drafted the manuscript.

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    M A Sukhai, M Thomas, L S A Chan, A C Schuh, R A Wells & S Kamel-Reid

  2. Division of Applied Molecular Oncology, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    M A Sukhai, M Thomas, Y Xuan, S A Hamadanizadeh, T Zhang, R R Bharadwaj, A C Schuh & S Kamel-Reid

  3. Crashley Myelodysplastic Syndrome Research Laboratory, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

    L S A Chan & R A Wells

  4. Institute for Medical Sciences, University of Toronto, Toronto, Ontario, Canada

    S A Hamadanizadeh & S Kamel-Reid

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    S Kamel-Reid

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  1. M A Sukhai
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Correspondence to S Kamel-Reid.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Sukhai, M., Thomas, M., Xuan, Y. et al. Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia. Oncogene 27, 4666–4677 (2008). https://doi.org/10.1038/onc.2008.106

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