TY - JOUR
T1 - Txnip Enhances Fitness of Dnmt3a-Mutant Hematopoietic Stem Cells via p21
AU - Zhang, Christine R.
AU - Ostrander, Elizabeth L.
AU - Kukhar, Ostap
AU - Mallaney, Cates
AU - Sun, Jiameng
AU - Haussler, Emily
AU - Celik, Hamza
AU - Koh, Won Kyun
AU - King, Katherine Y.
AU - Gontarz, Paul
AU - Challen, Grant A.
N1 - Funding Information:
We thank all members of the Challen laboratory for ongoing contributions and critical discussion. We thank the Alvin J. Siteman Cancer Center at Washington University for use of the Siteman Flow Cytometry Core, supported in part by NCI Grant CA91842 and NIH WLC6313040077. We thank the Genome Technology Access Center and McDonnell Genome Institute at Washington University for genomic analysis, partially supported by NCI Grant CA91842 and by ICTS/CTSA NIH Grant UL1TR000448. This work was supported by the NIH (DK102428 and DK124883 to G.A. Challen; HL136333 and, HL134880 to K.Y. King), the Edward P. Evans Foundation, Gabrielle’s Angel Foundation, Gabrielle’s Angel Foundation, and
Funding Information:
We thank all members of the Challen laboratory for ongoing contributions and critical discussion. We thank the Alvin J. Siteman Cancer Center at Washington University for use of the Siteman Flow Cytometry Core, supported in part by NCI Grant CA91842 and NIH WLC6313040077. We thank the Genome Technology Access Center and McDonnell Genome Institute at Washington University for genomic analysis, partially supported by NCI Grant CA91842 and by ICTS/CTSA NIH Grant UL1TR000448. This work was supported by the NIH (DK102428 and DK124883 to G.A. Challen; HL136333 and, HL134880 to K.Y. King), the Edward P. Evans Foundation, Gabrielle’s Angel Foundation, Gabrielle’s Angel Foundation, and The Longer Life Foundation (to G.A. Challen). C.R. Zhang was supported by an American Society of Hematology post-doctoral scholar award and Edward P. Evans Center for MDS Post-Doctoral Fellowship. E.L. Ostrander was supported by NIH 5T32CA113275 and NIH F31DK114951. C. Mallaney was supported by NIH T32HL007088, and NIH DK111058. H. Celik was supported by an Edward P. Evans Foundation Young Investigator Award. G.A. Challen is a scholar of the Leukemia and Lymphoma Society.
Funding Information:
The Longer Life Foundation (to G.A. Challen). C.R. Zhang was supported by an American Society of Hematology post-doctoral scholar award and Edward P. Evans Center for MDS Post-Doctoral Fellowship. E.L. Ostrander was supported by NIH 5T32CA113275 and NIH F31DK114951. C. Mallaney was supported by NIH T32HL007088, and NIH DK111058. H. Celik was supported by an Edward P. Evans Foundation Young Investigator Award. G.A. Challen is a scholar of the Leukemia and Lymphoma Society.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress. We found Dnmt3a-mutant HSCs resist IFNγ-mediated depletion, and IFNγ-signaling is required for clonal expansion of Dnmt3a-mutant HSCs in vivo. Mechanistically, DNA hypomethylation–associated overexpression of Txnip in Dnmt3a-mutant HSCs leads to p53 stabilization and upregulation of p21. This preserves the functional potential of Dnmt3a-mutant HSCs through increased quiescence and resistance to IFNγ-induced apoptosis. These data identify a previously undescribed mechanism to explain increased fitness of DNMT3A-mutant clones under hematopoietic stress.
AB - Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress. We found Dnmt3a-mutant HSCs resist IFNγ-mediated depletion, and IFNγ-signaling is required for clonal expansion of Dnmt3a-mutant HSCs in vivo. Mechanistically, DNA hypomethylation–associated overexpression of Txnip in Dnmt3a-mutant HSCs leads to p53 stabilization and upregulation of p21. This preserves the functional potential of Dnmt3a-mutant HSCs through increased quiescence and resistance to IFNγ-induced apoptosis. These data identify a previously undescribed mechanism to explain increased fitness of DNMT3A-mutant clones under hematopoietic stress.
UR - http://www.scopus.com/inward/record.url?scp=85130866682&partnerID=8YFLogxK
U2 - 10.1158/2643-3230.BCD-21-0132
DO - 10.1158/2643-3230.BCD-21-0132
M3 - Article
C2 - 35394496
AN - SCOPUS:85130866682
SN - 2643-3230
VL - 3
SP - 220
EP - 239
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 3
ER -