Local radiotherapy induces homing of hematopoietic stem cells to the irradiated bone marrow.
Local breast radiation therapy (RT) is associated with a 3-fold increased risk of secondary acute myeloid leukemia. As a first step in determining the mechanism(s) underlying this observation, we investigated the role of RT in mediating the active recruitment of hematopoietic stem cells (HSC) to the site of RT. Our results show in a mouse model that local RT delivered to the left leg causes preferential accumulation of bone marrow mononuclear cells to the irradiated site, with maximum signal intensity observed at 7 days post-RT. This is associated with a 4-fold higher number of donor-derived HSC present in the left leg, demonstrating recruitment of HSC to the site of RT. SDF-1, matrix metalloproteinase 2 (MMP-2), and MMP-9 expression is significantly increased in the irradiated bone marrow, and their inhibition significantly reduced HSC recruitment to the irradiated bone marrow. Our data show that local RT has significant systemic effects by recruiting HSC to the irradiated bone marrow site, a process mediated by SDF-1, MMP-2, and MMP-9. These results raise the possibility that the exposure of increased numbers of HSC at a local site to fractionated irradiation may increase the risk of leukemogenesis. Our data also suggest some opportunities for leukemia prevention in breast cancer patients undergoing RT.
Bastianutto
Carlo
C
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Mian
Asim
A
Symes
Julie
J
Mocanu
Joseph
J
Alajez
Nehad
N
Sleep
Gillian
G
Shi
Wei
W
Keating
Armand
A
Crump
Michael
M
Gospodarowicz
Mary
M
Medin
Jeff
J
Minden
Mark
M
Liu
Fei-Fei
FF
D000818:Animals; D001854:Bone Marrow Cells / Q000528:radiation effects*; D002465:Cell Movement / Q000528:radiation effects; D054377:Chemokine CXCL12 / Q000235:genetics; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D007953:Leukemia, Radiation-Induced / Q000209:etiology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011878:Radiotherapy / Q000009:adverse effects*
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9