Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
08
05
2019
accepted:
03
11
2019
revised:
04
10
2019
pubmed:
16
11
2019
medline:
2
9
2020
entrez:
16
11
2019
Statut:
ppublish
Résumé
Accumulation of DNA damage and myeloid-skewed differentiation characterize aging of the hematopoietic system, yet underlying mechanisms remain incompletely understood. Here, we show that aging hematopoietic progenitor cells particularly of the myeloid branch exhibit enhanced resistance to bulky DNA lesions-a relevant type of DNA damage induced by toxins such as cancer drugs or endogenous aldehydes. We identified aging-associated activation of the Hedgehog (Hh) pathway to be connected to this phenotype. Inhibition of Hh signaling reverts DNA damage tolerance and DNA damage-resistant proliferation in aged hematopoietic progenitors. Vice versa, elevating Hh activity in young hematopoietic progenitors is sufficient to impair DNA damage responses. Altogether, these findings provide experimental evidence for aging-associated increases in Hh activity driving DNA damage tolerance in myeloid progenitors and myeloid-skewed differentiation. Modulation of Hh activity could thus be explored as a therapeutic strategy to prevent DNA damage tolerance, myeloid skewing, and disease development in the aging hematopoietic system.
Identifiants
pubmed: 31728056
doi: 10.1038/s41375-019-0641-3
pii: 10.1038/s41375-019-0641-3
pmc: PMC7214262
doi:
Substances chimiques
Hedgehog Proteins
0
Veratrum Alkaloids
0
cyclopamine
ZH658AJ192
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1125-1134Références
Kapp FG, Perlin JR, Hagedorn EJ, Gansner JM, Schwarz DE, O’Connell LA, et al. Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature. 2018;558:445–8.
pubmed: 29899448
pmcid: 6093292
Burkhalter MD, Rudolph KL, Sperka T. Genome instability of ageing stem cells-Induction and defence mechanisms. Ageing Res Rev. 2015;23(Pt A):29–36.
pubmed: 25668152
pmcid: 4504031
Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447:686–90.
pubmed: 17554302
Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JH, Touw IP, et al. Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice. EMBO J. 2005;24:861–71.
pubmed: 15692571
pmcid: 549615
Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447:725–9.
pubmed: 17554309
Zhang S, Yajima H, Huynh H, Zheng J, Callen E, Chen HT, et al. Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J Cell Biol. 2011;193:295–305.
pubmed: 21482716
pmcid: 3080267
Rube CE, Fricke A, Widmann TA, Furst T, Madry H, Pfreundschuh M, et al. Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PLoS ONE. 2011;6:e17487.
pubmed: 21408175
pmcid: 3049780
Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature. 2014;512:198–202.
pubmed: 25079315
pmcid: 4456040
Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.
pubmed: 25931582
pmcid: 4624443
Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44:1179–81.
pubmed: 23001125
pmcid: 3483435
Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.
pubmed: 25426838
pmcid: 4290021
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.
pubmed: 25426837
pmcid: 4306669
Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.
pubmed: 25326804
pmcid: 4313872
Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci USA. 2010;107:5465–70.
pubmed: 20304793
Cho RH, Sieburg HB, Muller-Sieburg CE. A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood. 2008;111:5553–61.
pubmed: 18413859
pmcid: 2424153
Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000;192:1273–80.
pubmed: 11067876
pmcid: 2193349
Morita Y, Ema H, Nakauchi H. Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J Exp Med. 2010;207:1173–82.
pubmed: 20421392
pmcid: 2882827
Gutierrez-Martinez P, Hogdal L, Nagai M, Kruta M, Singh R, Sarosiek K, et al. Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat Cell Biol. 2018;20:413–21.
pubmed: 29531308
pmcid: 6067675
Wang J, Morita Y, Han B, Niemann S, Loffler B, Rudolph KL. Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nat Cell Biol. 2016;18:480–90.
pubmed: 27088856
Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 2012;148:1001–14.
pubmed: 22385964
Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature. 2012;489:571–5.
pubmed: 22922648
Gillet LC, Scharer OD. Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem Rev. 2006;106:253–76.
pubmed: 16464005
Batty D, Rapic’-Otrin V, Levine AS, Wood RD. Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites. J Mol Biol. 2000;300:275–90.
pubmed: 10873465
Hess MT, Schwitter U, Petretta M, Giese B, Naegeli H. Bipartite substrate discrimination by human nucleotide excision repair. Proc Natl Acad Sci USA. 1997;94:6664–9.
pubmed: 9192622
Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, et al. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998;2:223–32.
pubmed: 9734359
Sugasawa K, Okamoto T, Shimizu Y, Masutani C, Iwai S, Hanaoka F. A multistep damage recognition mechanism for global genomic nucleotide excision repair. Genes Dev. 2001;15:507–21.
pubmed: 11238373
pmcid: 312644
Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194–9.
pubmed: 15967997
Blair HJ, Tompson S, Liu YN, Campbell J, MacArthur K, Ponting CP, et al. Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus. BMC Biol. 2011;9:14.
pubmed: 21356043
pmcid: 3052239
Dorn KV, Hughes CE, Rohatgi R. A smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev Cell. 2012;23:823–35.
pubmed: 22981989
pmcid: 3586260
Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12:413–25.
pubmed: 23415915
Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14:673–88.
pubmed: 24792119
pmcid: 4070311
Takahashi R, Yamagishi M, Nakano K, Yamochi T, Fujikawa D, Nakashima M, et al. Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia. Cancer Sci. 2014;105:1160–9.
pubmed: 24996003
pmcid: 4462393
Bersenev A, Rozenova K, Balcerek J, Jiang J, Wu C, Tong W. Lnk deficiency partially mitigates hematopoietic stem cell aging. Aging Cell. 2012;11:949–59.
pubmed: 22812478
pmcid: 3500428
Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 2007;5:e201.
pubmed: 17676974
pmcid: 1925137
Norddahl GL, Pronk CJ, Wahlestedt M, Sten G, Nygren JM, Ugale A, et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell. 2011;8:499–510.
pubmed: 21549326
Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013;14:416–29.
pubmed: 23719536
Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA. 2003;100:7331–6.
pubmed: 12777630
Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004;64:7724–31.
pubmed: 15520176
Avila AI, Illing A, Becker F, Maerz LD, Morita Y, Philipp M, et al. Xpg limits the expansion of haematopoietic stem and progenitor cells after ionising radiation. Nucl Acids Res. 2016;44:6252–61.
pubmed: 27137888
Curtiss JH. On the distribution of the quotient of two chance variables. Ann Math Stat. 1941;12:409–21.
Abe Y, Oda-Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K, et al. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci USA. 2008;105:4838–43.
pubmed: 18359851
Leonard JM, Ye H, Wetmore C, Karnitz LM. Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability. J Cell Biol. 2008;183:385–91.
pubmed: 18955550
pmcid: 2575780
Li ZJ, Mack SC, Mak TH, Angers S, Taylor MD, Hui CC. Evasion of p53 and G2/M checkpoints are characteristic of Hh-driven basal cell carcinoma. Oncogene. 2014;33:2674–80.
pubmed: 23752195
Mazumdar T, DeVecchio J, Shi T, Jones J, Agyeman A, Houghton JA. Hedgehog signaling drives cellular survival in human colon carcinoma cells. Cancer Res. 2011;71:1092–102.
pubmed: 21135115
Tripathi K, Mani C, Barnett R, Nalluri S, Bachaboina L, Rocconi RP, et al. Gli1 protein regulates the S-phase checkpoint in tumor cells via Bid protein, and its inhibition sensitizes to DNA topoisomerase 1 inhibitors. J Biol Chem. 2014;289:31513–25.
pubmed: 25253693
pmcid: 4223349
Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–54.
pubmed: 18813320
pmcid: 4457317
Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9.
pubmed: 22670903
pmcid: 5278761
Gao J, Graves S, Koch U, Liu S, Jankovic V, Buonamici S, et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell. 2009;4:548–58.
pubmed: 19497283
pmcid: 2914688
Hofmann I, Stover EH, Cullen DE, Mao J, Morgan KJ, Lee BH, et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell. 2009;4:559–67.
pubmed: 19497284
pmcid: 3065323
Trowbridge JJ, Scott MP, Bhatia M. Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration. Proc Natl Acad Sci USA. 2006;103:14134–9.
pubmed: 16968775
Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14:238–49.
pubmed: 18772113
Klein C, Zwick A, Kissel S, Forster CU, Pfeifer D, Follo M, et al. Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression. J Exp Med. 2016;213:273–90.
pubmed: 26834157
pmcid: 4749921
Lim Y, Gondek L, Li L, Wang Q, Ma H, Chang E, et al. Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci Transl Med. 2015;7:291ra96.
pubmed: 26062848
pmcid: 4644635
Mondal BC, Mukherjee T, Mandal L, Evans CJ, Sinenko SA, Martinez-Agosto JA, et al. Interaction between differentiating cell- and niche-derived signals in hematopoietic progenitor maintenance. Cell. 2011;147:1589–600.
pubmed: 22196733
pmcid: 4403793
Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458:776–9.
pubmed: 19169242
pmcid: 2946231
Waters LS, Minesinger BK, Wiltrout ME, D’Souza S, Woodruff RV, Walker GC. Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance. Microbiol Mol Biol Rev. 2009;73:134–54.
pubmed: 19258535
pmcid: 2650891
Shachar S, Ziv O, Avkin S, Adar S, Wittschieben J, Reissner T, et al. Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO J. 2009;28:383–93.
pubmed: 19153606
pmcid: 2646147
Albertella MR, Green CM, Lehmann AR, O’Connor MJ. A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res. 2005;65:9799–806.
pubmed: 16267001
Xie K, Doles J, Hemann MT, Walker GC. Error-prone translesion synthesis mediates acquired chemoresistance. Proc Natl Acad Sci USA. 2010;107:20792–7.
pubmed: 21068378
Choi JS, Kim S, Motea E, Berdis A. Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents. Oncotarget. 2017;8:40804–16.
pubmed: 28489578
pmcid: 5522278