Abstract
PML, a Ring-finger protein, participates in the disruption of normal myeloid differentiation when fused to the retinoic acid receptor alpha (RARα) by the translocation between Chromosomes (Chrs) 15 and 17 in acute promyelocytic leukemia (APL). As an initial step in the characterization of PML in species other than human, a murine cDNA clone of the PML gene was isolated and sequenced, and the intron/exon organization of the murine locus determined. The predicted amino acid sequence of the mouse PML protein shows 80% similarity to that of its human homolog. However, the mouse and human proteins show greater than 90% similarity in the proposed functional domains of the proteins. Despite its role in the etiology of APL, PML expression is not detectably altered during granulocytic differentiation in a murine in vitro system. Chromosomal localization of the Pml locus by somatic cell hybrids and by linkage analysis indicates that the gene maps to a region of mouse Chr 9 with known linkage homology to the region on human Chr 15q to which PML has been localized.
Similar content being viewed by others
References
Adamson, M.C., Silver, J., Kozak, C.A. (1991) The mouse homologue of the gibbon ape leukemia receptor: genetic mapping and a possible receptor function in rodents. Virology 183, 778–781.
Chen, S.J., Chen, Z., Chen, A., Tong, J.H., Dong, S., Wang, Z.Y., Waxman, S., Zelent, A. (1992). Occurrence of distinct PML-RAR-α fusion gene isoforms in patients with acute promyelocytic leukemia detected by reverse-transcriptase/polymerase chain-reaction. Oncogene 7, 1223–1232.
Church, G.M., Gilbert, W. (1984). Genomic sequencing. Proc. Natl. Acad. Sci. USA 81, 1991–1995.
Daniel, M.T., Koken, M., Romagné, O. Barbey, S., Bazarbachi, A., Stadler, M., Guillemin, M.C., Degos, L., Chomienne, C., de Thé, H. (1993). PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood 82, 1858–1867.
de Thé, 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.
Devereux, J., Haeberli, P., Smithies, O. (1984). A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 12, 387–395.
Donti, E., Longo, L., Pelicci, P.G. (1991). Chromosomal localization of the APL t(15;17) breakpoints by molecular cytogenetic analysis. Cancer Genet. Cytogenet. 54, 265–266.
Dyck, J.A., Maul, G.G., Miller, W.H.J., Chen, J.D., Kakizuka, A., Evans, R.M. (1994). A novel macromolecular structure is a target of the promyelocyte retinoic acid receptor oncoprotein. Cell 76, 333–343.
Eliopoulos, E.E., Geddes, A.J., Bretl, M., Pappin, D.J.C., Findley, J.B.C. (1982). A structural model of the chromopore binding domain of bovine rhodopsin. Int. J. Biol. Macromol. 4, 263–268.
Fagioli, M., Alcalay, M., Pandolfi, P.P., Venturini, L., Mencarelli, A., Simeone, A., Acampora, D., Grignani, F., Pelicci, P.G. (1992) Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms. Oncogene 7, 1083–1091.
Geng, J.P., Tong, J.H., Dong, S., Wang, Z.Y., Chen, S.J., Chen, Z., Zelent, A., Berger, R., Larsen, C.J. (1993) Localization of the chromosome 15 breakpoints and expression of multiple PML-RAR alpha transcripts in acute promyelocytic leukemia: a study of 28 Chinese patients. Leukemia 7, 20–26.
Goddard, A.D., Borrow, J., Freemont, P.S., Solomon, E. (1991) Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254, 1371–1374.
Heyworth, C.M., Dexter, T.M., Kan, O., Whetton, A.D. (1990). The role of hemopoietic growth factors in self-renewal and differentiation of IL-3-dependent stem cells. Growth Factors 2, 197–211.
Kakizuka, A., Miller, W.H.J., Umesono, K., Warrell, R.P.J., Frankel, S.R., Murty, V.V.V.S., Dmitrovsky, E., Evans, R.M. (1991). Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674.
Karasuyama, H., Melchers, F. (1988). Establishment of mouse cell lines which constitutively secrete quantities of interleukins 2, 3, 4 or 5 using modified cDNA expression vectors. Eur. J. Immunol. 18, 97–104.
Kastner, P., Perez, A., Lutz, Y., Rochetteegly, C., Gaub, M.P., Durand, B., Lanotte, M., Berger, R., Chambon, P. (1992). Structure, localization and transcriptional properties of two classes of retinoic acid receptor α fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 11, 629–642.
Kimura, S., Gonzalez, F.J., Nedert, D.W. (1984) The murine Ah locus. Comparison of the complete P1-450 and P3-450 cDNA nucleotide and amino acid sequences. J. Biol. Chem. 259, 10705–10713.
Koken, M.H.M., Puvion-Dutilleul, F., Guilleman, M.C., Vivon, 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 retinoic acid reversible fashion. EMBO J. 13, 1073–1083.
Lupas, A., Van Dyke, M., Stock, J. (1991). Predicting coiled coils from protein sequences. Science 252, 1162–1164.
Lyon, M.F., Searle, A.G. (1989) Genetic Variants and Strains of the Laboratory Mouse (Oxford: Oxford University Press).
Mercer, J.A., Seperack, P.K., Strobel, M.C., Copeland, N.G., Jenkins, N.A. (1991). Novel myosin heavy chain encoded by murine dilute coat colour locus. Nature 349, 709–713.
Miller, M., Reddy, B.A., Kloc M., Li, X.X., Dreyer, C., Etkin, L.D. (1991). The nuclear-cytoplasmic distribution of the Xenopus nuclear factor, xnf7, coincides with its state of phosphorylation during early development. Development 113, 569–575.
Miller, W.H., Kakizuka, A., Frankel, S.R., Warrell, R.P., Deblasio, A., Levine, K., Evans, R.M., Dmitrovsky, E. (1992) Reverse transcription polymerase chain-reaction for the rearranged retinoic acid receptor α clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 89, 2694–2698.
Pandolfi, P.P., Grignani, F., Alcalay, M., Mencarelli, A., Biondi, A., LoCoco, F., Grignani, F., Pelicci, P.G. (1991) Structure and origin of the acute promyelocytic leukemia myl/RARα cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 6, 1285–1292.
Reddy, B.A., Kloc, M., Etkin, L. (1991). The cloning and characterization of a maternally expressed novel zinc finger nuclear phosphoprotein (xnf7) in Xenopus laevis. Dev. Biol. 148, 107–116.
Regnier, D.C., Kozak, C.A., Kingsley, D.M., Jenkins, N.A., Copeland, N.G., Langdon, W.Y., Morse, H.C.I. (1989). Identification of two murine loci homologous to the v-cbl oncogene. J. Virol. 63, 3678–3682.
Sambrook, J., Fritsch, E.F., Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Press).
Spooncer, E., Heyworth, C.M., Dunn, A., Dexter, T.M. (1986). Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors. Differentiation 31, 111–118.
Sternberg, M.J.E. (1991) PROMOT: a FORTRAN program to scan protein sequences against a library of known motifs. Comput. Appl. Biosci. 7, 257–260.
Weis, K., Rambaud, S., Lavau, C., Jansen, J. Carvalho, T., Carmo-Fonseca, M., Lamond, A., Dejean, A. (1994). Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells. Cell 76, 345–356.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Goddard, A.D., Yuan, J.Q., Fairbairn, L. et al. Cloning of the murine homolog of the leukemia-associated PML gene. Mammalian Genome 6, 732–737 (1995). https://doi.org/10.1007/BF00354296
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00354296