Paradoxical Effect of Caesin Kinase Inhibition in Deletion 5q Myelodysplastic Syndrome

 Caesin Kinase (CK1) is common to the Wnt-beta catenin pathway and the Hedgehog pathway. Along with other kinases, it acts as an inhibitor in both pathways to reduce the transcription of genes in response to wnt and hedgehog proteins respectively. 

Myelodysplastic syndrome (MDS) due to deletion of 5q (5q del) has an unique phenotype which can be explained by the differential action of CK1 on the wnt-beta catenin pathway. 

Subjects with 5q del have macrocytic anaemia, mild thrombocytosis with dysplastic, hypolobated megakaryocytes. MDS in 5q del is uniquely responsive to immunomodulators such as lenalidomide, although the anaemia does relapse after 2-3 years due to new mutations in other genes such as RUNX1.

Deletion of 5q leads to haploinsufficiency of the CK1A1 gene located on 5q.32. Lenalidomide inhibits the remaining CK1A1 allele and reverses the phenotype of MDS. This is admittedly non-intuitive, as there seems to be an abrogation of the dose-response effect here. If haploinsufficiency leads to a phenotype, how can suppressing the remaining normal allele reverse that phenotype (rather than worsen it)?

This apparent paradox is explained by the effect of CK1 on the wnt-beta catenin pathway. Haploinsufficiency of CK1 removes some of the inhibition exercised on the wnt-beta catenin pathway. The latter leads to enhanced survival and proliferation of the neoplastic clone, causing MDS.

However, genetic knockdown in mice or pharmacological inhibition of the remaining CK1A1 allele by lenalidomide in 5q del MDS sufferers leads to complete disinhibition of the wnt-beta catenin pathway. While this initially stimulates the haemopoetic progenitors of the neoplastic clone, continued stimulation soon leads to stem cell exhaustion and death of the progenitor cells now bereft of any CK1 activity.