@article{e572d0c5bbe74d0f95b3a385a6eac572,
title = "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.",
author = "Sperling, {Adam S.} and Guerra, {Veronica A.} and Kennedy, {James A.} and Yuanqing Yan and Hsu, {Joanne I.} and Feng Wang and Nguyen, {Andrew T.} and Miller, {Peter G.} and McConkey, {Marie E.} and {Quevedo Barrios}, {Vanessa A.} and Ken Furudate and Linda Zhang and Rashmi Kanagal-Shamanna and Jianhua Zhang and Latasha Little and Curtis Gumbs and Naval Daver and DiNardo, {Courtney D.} and Tapan Kadia and Farhad Ravandi and Hagop Kantarjian and Guillermo Garcia-Manero and Futreal, {P. Andrew} and Ebert, {Benjamin L.} and Koichi Takahashi",
note = "Funding Information: The authors thank D. Sykes and D. Scadden for the kind gift of the Hoxb8 viral vector and CHO-SCF cells. The authors also thank Koji Sasaki for helping chart review. This study was supported by the National Institutes of Health (NIH), National Cancer Institute grants K12CA087723 and K08CA252174 (A.S.S.); an Evans Foundation Young Investigator Award (P.G.M.); an American Society of Hematology Research Training Award for Fellows (P.G.M.); NIH National Heart, Lung, and Blood Institute grant R01HL082945 (B.L.E.); NIH National Cancer Institute grants R01CA237291 (K.T.), P01CA265748 (K.T.), and P01CA066996 (B.L.E.); the Howard Hughes Medical Institute grant (B.L.E.); the Edward P. Evans Foundation grant (B.L.E.); the Leukemia and Lymphoma Society grant (B.L.E. and K.T.); the Adelson Medical Research Foundation grant (B.L.E.); the Cancer Prevention and Research Institute of Texas grant R120501 (P.A.F.); the Welch Foundation grant G-0040 (P.A.F.); the University of Texas System STARS award (grant PS100149) (P.A.F.); Physician Scientist Program at MD Anderson (K.T.); Andrew Sabin Family Foundation award (K.T.); American Society of Hematology Scholar Award (K.T.); Dresner Foundation Early Investigator award (K.T.); Lyda Hill Foundation grant (P.A.F.); the Charif Souki Cancer Research fund (H.K.); the MD Anderson Cancer Center Leukemia SPORE grant (NIH P50 CA100632) (H.K. and K.T.); the MD Anderson Cancer Center Support grant (NIH/NCI P30 CA016672); and generous philanthropic contributions to MD Anderson Moon Shot Program grant (P.A.F. K.T. G.G.-M. and H.K.). Contribution: A.S.S. J.A.K. A.T.N. P.G.M. M.E.M. V.A.Q.B. and B.L.E. designed and performed in vitro and in vivo experiments; V.A.G. collected data and wrote the manuscript; Y.Y. performed statistical analysis; J.I.H. and L.Z. collected data; F.W. K.F. and J.Z. performed bioinformatics analysis; L.L. and C.G. performed DNA sequencing; N.D. R.K.-S. C.D.D. T.K. F.R. H.K. and G.G.-M. collected samples and data; A.S.S. P.G.M. B.L.E. and K.T. wrote the manuscript; A.S.S. B.L.E. P.A.F. and K.T. provided leadership and managed the study team; and all authors read and approved the manuscript. Funding Information: B.L.E. received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL and serves on the scientific advisory board for and is a shareholder in Neomorph Therapeutics, Skyhawk Therapeutics, TenSixteen Bio, and Exo Therapeutics. P.G.M. received consulting fees from Foundation Medicine, Inc. F.R. received honoraria from Celgene and BMS as an advisory board member. C.D.D. received research support (to institution) from AbbVie, Agios, Bayer, Calithera, Cleave, BMS/Celgene, Daiichi-Sankyo, and ImmuneOnc and is a consultant/advisory board member at AbbVie, Agios, Celgene/BMS, Daiichi-Sankyo, ImmuneOnc, Novartis, Takeda, and Notable Labs. H.K. received research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer, and Sanofi and honoraria from AbbVie, Actinium, Adaptive Biotechnologies, Amgen, Apptitude Health, BioAscend, Daiichi-Sankyo, Delta Fly, Janssen Global, Novartis, Oxford Biomedical, Pfizer and, Takeda. K.T. received consulting fees from Celgene, GSK, and Novartis; received honoraria from Mission Bio and Illumina; and serves on the scientific advisory board for Symbio Pharmaceuticals. The remaining authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2022 The American Society of Hematology",
year = "2022",
month = oct,
day = "20",
doi = "10.1182/blood.2021014956",
language = "English (US)",
volume = "140",
pages = "1753--1763",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "16",
}