4.7 Article

Gene Methylation and Silencing of WIF1 Is a Frequent Genetic Abnormality in Mantle Cell Lymphoma

Journal

Publisher

MDPI
DOI: 10.3390/ijms22020893

Keywords

mantle cell lymphoma; Wnt canonical pathway; Wnt inhibitory factor-1; gene methylation

Funding

  1. Deanship of Scientific Research at Taibah University [442/80]

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The constitutive activation of the Wnt canonical pathway (WCP) in mantle cell lymphoma (MCL) is mainly due to gene methylation/silencing of WIF1, which promotes cell growth. Gene transfection of WIF1 into cells significantly reduces cell growth and results in downregulation of various proteins in WCP.
We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/silencing of WIF1 (Wnt inhibitory factor-1), a physiologic inhibitor of WCP, contributes to the deregulation of WCP and promotes cell growth in MCL. In support of this hypothesis, we found that the expression of WIF1 was detectable in none of the 4 MCL cell lines, and in only 2 of 5 tumors (40%) examined. Using methylation-specific PCR, we found evidence of gene methylation of WIF1 in 4 of 5 cell lines (80%) and in 24 of 29 (82%) tumors. The addition of the demethylation agent 5-aza-2 '-deoxycytidine to Mino and JeKo-1, two WIF1-negative cell lines, restored the expression of WIF1 mRNA in these cells. Gene transfection of WIF1 into JeKo-1 and Mino cells significantly reduced cell growth, and this finding correlated with substantial downregulations of various proteins in WCP, such as beta-catenin and pGSK-3 beta. In conclusion, our results support the concept that gene methylation/silencing of WIF1 is a frequent event in MCL, and this abnormality contributes to the aberrant activation of WCP. These results have provided further evidence that aberrant Wnt signaling is pathogenetically important in MCL and it may represent a potential therapeutic target.

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