TY - JOUR
T1 - Recurrent transcriptional responses in AML and MDS patients treated with decitabine
AU - Upadhyay, Pawan
AU - Beales, Jeremy
AU - Shah, Nakul M.
AU - Gruszczynska, Agata
AU - Miller, Christopher A.
AU - Petti, Allegra A.
AU - Ramakrishnan, Sai Mukund
AU - Link, Daniel C.
AU - Ley, Timothy J.
AU - Welch, John S.
N1 - Funding Information:
The study was supported by grants from the Specialized Program of Research Excellence in AML of the National Cancer Institute (P50 CA171963 to DCL), the Genomics of AML Program Project (P01 CA101937, to TJL), a Research Specialist Award (NCI R50 CA211782, to CAM), and by Janssen Pharmaceuticals. We thank Megan Haney and Jeff King for assistance in patient enrollment, sample collection, and data processing; Sharon Heath, Nicole Helton, and the Tissue Procurement Core for assistance in sample collection and processing; and the McDonnell Genome Institute at Washington University in St. Louis for support in sequencing.
Funding Information:
The study was supported by grants from the Specialized Program of Research Excellence in AML of the National Cancer Institute (P50 CA171963 to DCL), the Genomics of AML Program Project (P01 CA101937, to TJL), a Research Specialist Award (NCI R50 CA211782, to CAM), and by Janssen Pharmaceuticals. We thank Megan Haney and Jeff King for assistance in patient enrollment, sample collection, and data processing; Sharon Heath, Nicole Helton, and the Tissue Procurement Core for assistance in sample collection and processing; and the McDonnell Genome Institute at Washington University in St. Louis for support in sequencing.
Publisher Copyright:
© 2022 ISEH – Society for Hematology and Stem Cells
PY - 2022/7
Y1 - 2022/7
N2 - The molecular events responsible for decitabine responses in myelodysplastic syndrome and acute myeloid leukemia patients are poorly understood. Decitabine has a short serum half-life and limited stability in tissue culture. Therefore, theoretical pharmacologic differences may exist between patient molecular changes in vitro and the consequences of in vivo treatment. To systematically identify the global genomic and transcriptomic alterations induced by decitabine in vivo, we evaluated primary bone marrow samples that were collected during patient treatment and applied whole-genome bisulfite sequencing, RNA-sequencing, and single-cell RNA sequencing. Decitabine induced global, reversible hypomethylation after 10 days of therapy in all patients, which was associated with induction of interferon-induced pathways, the expression of endogenous retroviral elements, and inhibition of erythroid-related transcripts, recapitulating many effects seen previously in in vitro studies. However, at relapse after decitabine treatment, interferon-induced transcripts remained elevated relative to day 0, but erythroid-related transcripts now were more highly expressed than at day 0. Clinical responses were not correlated with epigenetic or transcriptional signatures, although sample size and interpatient variance restricted the statistical power required for capturing smaller effects. Collectively, these data define global hypomethylation by decitabine and find that erythroid-related pathways may be relevant because they are inhibited by therapy and reverse at relapse.
AB - The molecular events responsible for decitabine responses in myelodysplastic syndrome and acute myeloid leukemia patients are poorly understood. Decitabine has a short serum half-life and limited stability in tissue culture. Therefore, theoretical pharmacologic differences may exist between patient molecular changes in vitro and the consequences of in vivo treatment. To systematically identify the global genomic and transcriptomic alterations induced by decitabine in vivo, we evaluated primary bone marrow samples that were collected during patient treatment and applied whole-genome bisulfite sequencing, RNA-sequencing, and single-cell RNA sequencing. Decitabine induced global, reversible hypomethylation after 10 days of therapy in all patients, which was associated with induction of interferon-induced pathways, the expression of endogenous retroviral elements, and inhibition of erythroid-related transcripts, recapitulating many effects seen previously in in vitro studies. However, at relapse after decitabine treatment, interferon-induced transcripts remained elevated relative to day 0, but erythroid-related transcripts now were more highly expressed than at day 0. Clinical responses were not correlated with epigenetic or transcriptional signatures, although sample size and interpatient variance restricted the statistical power required for capturing smaller effects. Collectively, these data define global hypomethylation by decitabine and find that erythroid-related pathways may be relevant because they are inhibited by therapy and reverse at relapse.
UR - http://www.scopus.com/inward/record.url?scp=85129963722&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2022.04.002
DO - 10.1016/j.exphem.2022.04.002
M3 - Article
C2 - 35429619
AN - SCOPUS:85129963722
SN - 0301-472X
VL - 111
SP - 50
EP - 65
JO - Experimental Hematology
JF - Experimental Hematology
ER -