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

Table 18

SLIT/ROBO signaling and nervous system development.

Gene names	Related pathway	Findings in CLL	Ref.
SLIT2	Nervous system development; regulation of SLIT/ROBO and VEGF signaling pathways	Frequent promoter methylation was reported in high-risk CLL cases	[98, 153, 154]
ROBO 1	Nervous system development, SLIT/ROBO signaling pathways	The expression of ROBO1 was significantly lower compared to healthy control samples; when DNA sequencing of the promoter region was performed, in most CLL samples, a higher level of methylation than the healthy individuals was identified	[155]
ID4	Signaling by NTRKs nuclear events (kinase and transcription factor activation)	Shortened patient survival is associated with high levels of promoter; methylation ID4 promoter methylation is generally methylated in varying levels in CLL cells; ID4 mRNA and protein expression are both silenced in CLL cells, a phenomenon independent of ID4 promoter methylation status	[156–158]
PTPRO	Signaling by the NTRKs PAK pathway	PTPRO gene promoter was methylated and expression was suppressed compared to normal B cells, with overall expression of PTPRO being lower in CLL lymphocytes than in normal samples	[51, 159–161]

CLL: chronic lymphocytic leukemia, Ref.: reference, SLIT2: slit glycoprotein 2, ROBO1: roundabout receptor 1, ID4: inhibitor of differentiation 4, PTPRO: protein tyrosine phosphatase type O, SLIT/ROBO: slit glycoprotein/roundabout receptor, VEGF: vascular endothelial growth factor, NTRK: neurotrophic tyrosine receptor kinase, PAK: p21 activated kinase, IGVH: immunoglobulin variable heavy chain gene.