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

• In this study, we first showed that panaxydol decreased markedly the proliferation, and to a lesser extent, the number of cells in a human melanoma cell line, SK-MEL-1 [10].
• We carried out MTT assays to evaluate the cytotoxicity of melphalan, lomustine (CCNU), fotemustine, and 4-Hydroxyanisole (4-HA) on three melanoma lines (B16F10, SK-MEL-28, and SK-MEL-1), and the modulating effect of pretreatment with AZA (1 mM) [11].
• We studied the response of mouse B16F10 and SK-MEL-28 and SK-MEL-1 human melanoma cell lines to treatment with 4-hydroxyanisole (4-HA), and attempted to relate the response to the dopa oxidase levels and the morphological characteristics of each cell line [12].
• METHODS: The authors used mouse (B16F10) and human (SK-MEL-28 and SK-MEL-1) melanoma lines for in vitro treatment with melphalan, lomustine, fotemustine, and 4-hydroxyanisole (4-HA) alone, combined and after pretreatment with buthionine sulfoximine (BSO), ethacrynic acid (EA), and azelaic acid (AZA) [13].
• HMB-45 and MEL-1 reacted with 22/25 (88%) and 18/25 (72%) of canine melanomas, respectively, but only after microwave antigen retrieval and pretreatment with potassium permanganate and oxalic acid (KMnO(4)/OA) [14].

Biological context of PRDM16

• Cell cycle analysis revealed that panaxydol inhibited cell cycle progression of a human malignant melanoma cell line, SK-MEL-1, at G(1)-S transition [10].
• MEL1 (at chromosome band 1p36.3) is thought to be transcriptionally activated as a result of juxtaposition to the RPN1 gene at 3q21 [15].
• CONCLUSION: Our data suggest that simultaneous low MEL1/EL1 expression in AML is abnormal and that favorable disease is highly associated with this abnormal phenotype [15].
• Tangeretin was the most effective of the flavonoids in inhibiting B16F10 and SK-MEL-1 cell growth, showing a clear dose-response curve after 72 h [16].

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