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Gene Review

PRDM16  -  PR domain containing 16

Homo sapiens

Synonyms: CMD1LL, KIAA1675, LVNC8, MDS1/EVI1-like gene 1, MEL1, ...
 
 
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Disease relevance of PRDM16

  • Integrations are located in intron 1 or 2, where they promote expression of truncated proteins lacking the PRDI-BF1-RIZ1 homologous (PR) domain, similar to what is observed in human leukemias with EVI1 or PRDM16 mutations [1].
  • Overexpression of PRDM16 in the presence and absence of the RUNX1/PRDM16 fusion gene in myeloid leukemias [2].
  • Microarray analysis demonstrated the majority of the neural crest-selected 852 ESTs (Mel1 array) were differentially expressed in melanoma cell lines compared with a non-neural crest kidney epithelial cell line (P < 1 x 10(-8)) [3].
  • Antiproliferative studies in vitro suggested that the growth of three human breast carcinomas (MCF-7, MDA-MB-231, and MDA-MB-468), an ovarian carcinoma (NIH-OVCAR-3), and a malignant melanoma (SK-MEL-1) was inhibited to a greater degree by combination treatment with human IFN-beta and RA compared to single agents [4].
  • In contrast, no similar correlation could be established in nude mice, as all 3 cell lines, including the non-adherent SK-MEL-1 cells, were tumorigenic when injected s.c., while only HT-144 consistently produced experimental lung metastasis [5].
  • We demonstrated that transcriptional co-repressors of TGF-beta signaling, SKI and MDS1/EVI1-like gene 1 (MEL1), were aberrantly expressed in MKN28 gastric cancer cells by chromosomal co-amplification of 1p36.32 [6].
 

High impact information on PRDM16

  • Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals [7].
  • The DNA regions identified contained MEL1, CACNA1H, and Nogo receptor genes [8].
  • Among them, MEL1S, an alternatively spliced form of MEL1 lacking the PR (positive regulatory domain I binding factor 1 and retinoblastoma-interacting zinc finger protein) domain, was frequently transcribed in ATL cells, and the transcriptional initiation sites were identified upstream from exons 4 and 6 [8].
  • Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells [9].
  • MEL1 has been reported to be expressed in leukemia cells with t(1;3) and in the normal uterus and fetal kidney, but neither in bone marrow (BM) nor in other tissues, suggesting that this gene is specific to t(1;3)-positive MDS/AML [9].
 

Chemical compound and disease context of PRDM16

 

Biological context of PRDM16

 

Anatomical context of PRDM16

  • The unmodified and PEGylated proteins were tested for their ability to inhibit the formation of radially oriented blood vessels entering the periphery of human SK-MEL-1 melanoma tumors in athymic nude homozygous (nu/nu) mice [17].
  • MATERIALS AND METHODS: Using real-time polymerase chain reaction, we measured MEL1 expression levels, normal bone marrow, and distinct blood cell fractions in 162 de novo AML patients [15].
 

Associations of PRDM16 with chemical compounds

  • Heterogeneity in integrin expression, such as elevated levels in alpha(v)beta3 in SK-MEL-1 and SK-MEL-2 cells and low expression in HT-144 cells, correlated with their in vitro invasiveness, since only the adherent HT-144 and SK-MEL-2 cells were able to invade Matrigel, and in addition, secreted a 72-kDa gelatinase [5].
  • Previous treatment with AZA of B16F10 reinforced the effect of melphalan (2.5 times), CCNU (10 times), and fotemustine (14 times); whereas for SK-MEL-28 and SK-MEL-1, only the cytotoxicity of CCNU and fotemustine increased [11].
  • In all the tissues assayed, the power of the ligands to inhibit [125I]Mel binding decreased in the following order: melatonin>>4-P-PDOT>luzindole> or =N-acetylserotonin, which points to the presence of Mel1-like receptors [18].
 

Other interactions of PRDM16

  • In two of them, the PRDM16 reading frame is maintained in the fusion with RUNX1, suggesting that the RUNX1-PRDM16 gene fusion results in the production of a protein that is highly homologous to the RUNX1-MDS1/EVI1 chimeric protein [19].
  • Recently, the two genes involved in this translocation have been identified: the MEL1 gene at 1p36.3, and the RPN1 gene at 3q21 [20].
 

Analytical, diagnostic and therapeutic context of PRDM16

  • With fluorescence in situ hybridization analysis by use of BAC/PAC probes, we identified the breakpoint at 1p36.3 in three MDS/AML patients with t(1;3)(p36;q21): within the first intron of the MEL1 gene (one patient) or within a 29-kb region located in the 5' region of MEL1 (two other patients) [20].

References

  1. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Du, Y., Jenkins, N.A., Copeland, N.G. Blood (2005) [Pubmed]
  2. Overexpression of PRDM16 in the presence and absence of the RUNX1/PRDM16 fusion gene in myeloid leukemias. Hazourli, S., Chagnon, P., Sauvageau, M., Fetni, R., Busque, L., Hébert, J. Genes Chromosomes Cancer (2006) [Pubmed]
  3. Informatic selection of a neural crest-melanocyte cDNA set for microarray analysis. Loftus, S.K., Chen, Y., Gooden, G., Ryan, J.F., Birznieks, G., Hilliard, M., Baxevanis, A.D., Bittner, M., Meltzer, P., Trent, J., Pavan, W. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  4. Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Lindner, D.J., Borden, E.C., Kalvakolanu, D.V. Clin. Cancer Res. (1997) [Pubmed]
  5. Up-regulated expression of the beta3 integrin and the 92-kDa gelatinase in human HT-144 melanoma cell tumors grown in nude mice. Gouon, V., Tucker, G.C., Kraus-Berthier, L., Atassi, G., Kieffer, N. Int. J. Cancer (1996) [Pubmed]
  6. SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells. Takahata, M., Inoue, Y., Tsuda, H., Imoto, I., Koinuma, D., Hayashi, M., Ichikura, T., Yamori, T., Nagasaki, K., Yoshida, M., Matsuoka, M., Morishita, K., Yuki, K., Hanyu, A., Miyazawa, K., Inazawa, J., Miyazono, K., Imamura, T. J. Biol. Chem. (2009) [Pubmed]
  7. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Ott, M.G., Schmidt, M., Schwarzwaelder, K., Stein, S., Siler, U., Koehl, U., Glimm, H., Kühlcke, K., Schilz, A., Kunkel, H., Naundorf, S., Brinkmann, A., Deichmann, A., Fischer, M., Ball, C., Pilz, I., Dunbar, C., Du, Y., Jenkins, N.A., Copeland, N.G., Lüthi, U., Hassan, M., Thrasher, A.J., Hoelzer, D., von Kalle, C., Seger, R., Grez, M. Nat. Med. (2006) [Pubmed]
  8. Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells. Yoshida, M., Nosaka, K., Yasunaga, J., Nishikata, I., Morishita, K., Matsuoka, M. Blood (2004) [Pubmed]
  9. Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells. Lahortiga, I., Agirre, X., Belloni, E., Vázquez, I., Larrayoz, M.J., Gasparini, P., Lo Coco, F., Pelicci, P.G., Calasanz, M.J., Odero, M.D. Oncogene (2004) [Pubmed]
  10. Induction of G(1) cell cycle arrest and p27(KIP1) increase by panaxydol isolated from Panax ginseng. Moon, J., Yu, S.J., Kim, H.S., Sohn, J. Biochem. Pharmacol. (2000) [Pubmed]
  11. Azelaic acid was sensitizing effect in the chemotherapeutic treatment of several melanoma cell lines. Rodriguez-Vicente, J., Vicente-Ortega, V., Canteras-Jordana, n.u.l.l. Pigment Cell Res. (1996) [Pubmed]
  12. Relationship between 4-hydroxyanisole toxicity and dopa oxidase activity for three melanoma cell lines. Rodriguez-Vicente, J., Vicente-Ortega, V., Canteras-Jordana, M., Calderon-Rubiales, F. Melanoma Res. (1997) [Pubmed]
  13. The effects of different antineoplastic agents and of pretreatment by modulators on three melanoma lines. Rodriguez-Vicente, J., Vicente-Ortega, V., Canteras-Jordana, M. Cancer (1998) [Pubmed]
  14. Immunohistochemical detection of melanoma-specific antigens in spontaneous canine melanoma. Sulaimon, S., Kitchell, B., Ehrhart, E. J. Comp. Pathol. (2002) [Pubmed]
  15. Low expression of MDS1-EVI1-like-1 (MEL1) and EVI1-like-1 (EL1) genes in favorable-risk acute myeloid leukemia. Barjesteh van Waalwijk van Doorn-Khosrovani, S., Erpelinck, C., Löwenberg, B., Delwel, R. Exp. Hematol. (2003) [Pubmed]
  16. Effects of several flavonoids on the growth of B16F10 and SK-MEL-1 melanoma cell lines: relationship between structure and activity. Rodriguez, J., Yáñez, J., Vicente, V., Alcaraz, M., Benavente-García, O., Castillo, J., Lorente, J., Lozano, J.A. Melanoma Res. (2002) [Pubmed]
  17. N-terminally PEGylated human interferon-beta-1a with improved pharmacokinetic properties and in vivo efficacy in a melanoma angiogenesis model. Baker, D.P., Lin, E.Y., Lin, K., Pellegrini, M., Petter, R.C., Chen, L.L., Arduini, R.M., Brickelmaier, M., Wen, D., Hess, D.M., Chen, L., Grant, D., Whitty, A., Gill, A., Lindner, D.J., Pepinsky, R.B. Bioconjug. Chem. (2006) [Pubmed]
  18. Binding characteristics and daily rhythms of melatonin receptors are distinct in the retina and the brain areas of the European sea bass retina (Dicentrarchus labrax). Bayarri, M.J., Iigo, M., Muñoz-Cueto, J.A., Isorna, E., Delgado, M.J., Madrid, J.A., Sánchez-Vázquez, F.J., Alonso-Gómez, A.L. Brain Res. (2004) [Pubmed]
  19. Novel RUNX1-PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22). Sakai, I., Tamura, T., Narumi, H., Uchida, N., Yakushijin, Y., Hato, T., Fujita, S., Yasukawa, M. Genes Chromosomes Cancer (2005) [Pubmed]
  20. Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1. Xinh, P.T., Tri, N.K., Nagao, H., Nakazato, H., Taketazu, F., Fujisawa, S., Yagasaki, F., Chen, Y.Z., Hayashi, Y., Toyoda, A., Hattori, M., Sakaki, Y., Tokunaga, K., Sato, Y. Genes Chromosomes Cancer (2003) [Pubmed]
 
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