Growing data suggested that under the positive selection pressure of chemo- and radiation treatments, therapy-related myeloid neoplasms (t-MNs) with driver gene mutations develop in the context of clonal hematopoiesis (CH). Understanding the pathophysiology and etiology of t-MNs depended on identifying the exposure interactions that provide particular CH mutations a selection advantage.
Researchers discovered that TP53 mutations were substantially related to past treatment with thalidomide analogs, most especially lenalidomide, in a methodical investigation of 416 individuals with t-MN and a complete prior exposure history. They used experiments to show that lenalidomide medication benefits hematopoietic stem and progenitor cells (HSPCs) with the Trp53 mutation both in vitro and in vivo. The effect was only demonstrated in HSPCs with the Trp53 mutation; it was not seen in HSPCs with other CH mutations.
Pomalidomide therapy did not confer the same degree of selective advantage to Trp53-mutant HSPCs due to variations in CK1α degradation, giving a biological justification for its usage in individuals at high risk for t-MN.
The results demonstrated the function of lenalidomide therapy in promoting TP53-mutated t-MNs and provided a potential substitute approach to reduce the likelihood of t-MN formation.
