Deletion of proapoptotic Puma selectively protects hematopoietic stem and progenitor cells against high-dose radiation.
Bone marrow injury is a major adverse side effect of radiation and chemotherapy. Attempts to limit such damage are warranted, but their success requires a better understanding of how radiation and anticancer drugs harm the bone marrow. Here, we report one pivotal role of the BH3-only protein Puma in the radiosensitivity of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Puma deficiency in mice confers resistance to high-dose radiation in a hematopoietic cell-autonomous manner. Unexpectedly, loss of one Puma allele is sufficient to confer mice radioresistance. Interestingly, null mutation in Puma protects both primitive and differentiated hematopoietic cells from damage caused by low-dose radiation but selectively protects HSCs and HPCs against high-dose radiation, thereby accelerating hematopoietic regeneration. Consistent with these findings, Puma is required for radiation-induced apoptosis in HSCs and HPCs, and Puma is selectively induced by irradiation in primitive hematopoietic cells, and this induction is impaired in Puma-heterozygous cells. Together, our data indicate that selective targeting of p53 downstream apoptotic targets may represent a novel strategy to protecting HSCs and HPCs in patients undergoing intensive cancer radiotherapy and chemotherapy.
Shao
Lijian
L
COBRE in Stem Biology and Regenerative Medicine Center for Molecular Medicine, Maine Medical Center Research Institute, Maine Medical Center, Scarborough, ME, USA.
Sun
Yan
Y
Zhang
Zhonghui
Z
Feng
Wei
W
Gao
Yongxing
Y
Cai
Zailong
Z
Wang
Zack Z
ZZ
Look
A Thomas
AT
Wu
Wen-Shu
WS
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011836:Radiation Tolerance / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins