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

Author:

Sperling Adam S.12,Guerra Veronica A.3,Kennedy James A.1456,Yan Yuanqing7,Hsu Joanne I.8,Wang Feng9,Nguyen Andrew T.1,Miller Peter G.1,McConkey Marie E.1,Quevedo Barrios Vanessa A.2,Furudate Ken310,Zhang Linda8,Kanagal-Shamanna Rashmi11,Zhang Jianhua9,Little Latasha9,Gumbs Curtis9,Daver Naval3,DiNardo Courtney D.3,Kadia Tapan3,Ravandi Farhad3,Kantarjian Hagop3,Garcia-Manero Guillermo3,Futreal P. Andrew9,Ebert Benjamin L.112,Takahashi Koichi39

Affiliation:

1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

2. 2Division of Hematology, Brigham and Women’s Hospital, Boston, MA

3. 3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

4. 4Department of Medicine, University of Toronto, Toronto, Canada

5. 5Division of Hematology and Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

6. 6Division of Hematology and Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada

7. 7Department of Neurosurgery, University of Northwestern, Chicago, IL

8. 8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

9. 9Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

10. 10Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

11. 11Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX

12. 12Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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