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

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 RavandiHagop Kantarjian, Guillermo Garcia-Manero, P. Andrew Futreal, Benjamin L. Ebert*, Koichi Takahashi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1753-1763
Number of pages11
JournalBlood
Volume140
Issue number16
DOIs
StatePublished - Oct 20 2022

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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