TY - JOUR
T1 - p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita
AU - Fok, Wilson Chun
AU - Niero, Evandro Luis de Oliveira
AU - Dege, Carissa
AU - Brenner, Kirsten Ann
AU - Sturgeon, Christopher Michael
AU - Batista, Luis Francisco Zirnberger
N1 - Funding Information:
W.C.F. and C.D. were supported by an NHLBI T32 Training Grant in Molecular Hematology (HL007088-41). E.L.d.O.N. was supported by CNPq, Brazil. K.A.B. was supported by the National Fellowship Foundation. L.F.Z.B. is supported by the NHLBI (4R00HL114732-03) and grants from the V Foundation for Cancer Research, Edward Mallinckrodt Jr. Foundation, the Concern Foundation, and the AA&MDS International Foundation. Part of this project was also supported by the Washington University DDRCC grant (NIDDK P30 DK052574) to L.F.Z.B.
Publisher Copyright:
© 2017 The Authors
PY - 2017/8/8
Y1 - 2017/8/8
N2 - Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients.
AB - Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients.
KW - bone marrow failure
KW - disease modeling
KW - dyskeratosis congenita
KW - embryonic stem cells
KW - hematopoiesis
KW - telomerase
KW - telomere damage
KW - telomeres
UR - http://www.scopus.com/inward/record.url?scp=85026235808&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2017.06.015
DO - 10.1016/j.stemcr.2017.06.015
M3 - Article
C2 - 28757166
AN - SCOPUS:85026235808
VL - 9
SP - 409
EP - 418
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 2
ER -