The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review

Table 11

NOTCH signaling.

Gene name	Related pathway	Findings in CLL	Ref.
CREBBP	Regulation of activated PAK-2, NOTCH	Genome-wide methylation profiling identified CREBBP gene body to be differentially methylated	[130]
HDAC4/HDAC9	Notch signaling gene expression (transcription)	Gene promoter was differentially methylated between prognostic CLL subgroups	[14, 131]
RASF10, RASF6, and KIBRA	Notch signaling regulator of the Hippo/SWH pathway	RASF10 gene promoter was frequently methylated, followed by RASF6 KIBRA gene promoter was recurrently methylated and associated with the IGVH-unmutated status and CD38 expression	[132]
FABP7	PKC, MAPK-Erk, triglyceride metabolism, notch signaling	Methylated gene body was observed in IGVH-mutated cases	[26, 133]
NOTCH1	Notch signaling regulation of activated PAK-2	Gene promoter methylation was associated with aggressive clinical types such as Richter’s transformation and chemorefractoriness independent predictor of poor prognosis	[14, 134]

CLL: chronic lymphocytic leukemia, Ref.: reference, NOTCH1: neurogenic locus, notch homolog protein 1, HDAC4/HDAC9: histone deacetylases 4 and 9, RASF6/RASF10: rat sarcoma-associated domain family member 6 and 10, KIBRA: kidney and brain expressed protein, FABP7: fatty acid-binding protein 7, CREBBP: cAMP response element-binding protein binding protein, PAK-2: p21 activated kinase 2, SWH: Salvador-Warts-Hippo, PKC: protein kinase C, MAPK-Erk: mitogen-activated protein kinase-extracellular signal-regulated kinase, CD38: cluster of differentiation 38, IGVH: immunoglobulin variable heavy chain gene.