Key signaling pathways involved in genetic methylation of lymphoid malignancies. In WNT pathway, WNT binds to Frizzled and LRP to phosphorylate Dvl and downstream degrades complex containing APC, AXIN, CK1α, PPP2R4 and GSK-3β. β-catenin is then released and translocated into the nucleus, activating target gene expression. In JAK-STAT pathway, cytokines bind to transmembrane receptors and activate JAKs, who then activate transcription factors STATs. STATs then translocate into the nucleus and initiate target gene transcription. P53 is an important tumor suppressor, and functions through both transcription dependent and independent ways. MDM2 is the main negative regulator of p53. In lymphoid malignancies, important negative regulatory genes (indicated in yellow) are found hypermethylated and down-regulated, resulting in aberrantly activated signaling in tumor cells. Targeted therapies for specific WNT and JAK-STAT signaling pathways under preclinical and clinical evaluations are listed.