Investigation of the genetic and epigenetic alterations in the promotor region of sFRP1 gene in chronic myeloid leukemia (CML) patients

The first description of deregulated Wnt signaling in a hematological malignancy wasreported in chronic myeloid leukemia (CML). The Wnt signaling antagonists, secretedfrizzled related proteins (sFRPs), are able to inhibit the activity of Wnt proteins. Epigeneticsilencing of sFRP genes lead to constitutive activation of the canonical Wnt-signalingpathway.In this present study we investigated genetics and epigenetics alteration in promotor region of the sFRP1 gene in 48 chronic phase CML patients. Bi-directional sequencing show that the variation is an inframe deletion of nucleotides 38, 39 and 40 (CAG). This three-nucleotide deletion affects codons 13 and 14, and both encoding for consecutive alanin residues. The resulting just in-frame codon also encodes for alanin.When investigated methylation status of the sFRP1 promotor in 48 chronic phase CML patients show that it?s fully methylated in 1, hemi-methylated in 6 and unmethylated in 41 patients. Albeit observed infrequently in chronic phase CML, sFRP1 promoter methylation correlates with therapy resistance and disease progression. Forty-one patients that were unmethylated at the sFRP1 promoter all achieved major or complete cytogenetic remission; while five of the six hemi-methylated patients have only achieved partial cytogenetic remission or no cytogenetic remission. The full-methylated patient has shown cytogenetic progression with additional chromosomal abnormalities.sFRP1 promoter methylation may indicate a genetically more unstable form of disease resistant to therapy and provide a key biological difference in therapy resistant patients. In addition to a possible mechanism for the observed activation of canonical Wnt signaling in CML.