Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms.

Abstract

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.

• Authors: Adam S Sperling, Veronica A Guerra, James A Kennedy, Yuanqing Yan, Joanne I Hsu, Feng Wang, Andrew T Nguyen, Peter G Miller, Marie E McConkey, Vanessa A Quevedo Barrios, Ken Furudate, Linda Zhang, Rashmi Kanagal-Shamanna, Jianhua Zhang, Latasha Little, Curtis Gumbs, Naval Daver, Courtney D DiNardo, Tapan Kadia, Farhad Ravandi, Hagop Kantarjian, Guillermo Garcia-Manero, P Andrew Futreal, Benjamin L Ebert, Koichi Takahashi
• Journal: Blood (Blood) Vol. 140 Issue 16 Pg. 1753-1763 (10 20 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 35512188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Lenalidomide
• Thalidomide
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Humans
• Lenalidomide (pharmacology)
• Thalidomide (adverse effects)
• Hematopoietic Stem Cells (metabolism)
• Genes, p53
• Mutation
• Neoplasms, Second Primary (etiology, genetics)
• Tumor Suppressor Protein p53 (genetics, metabolism)