Transmission of clonal chromosomal abnormalities in human hematopoietic stem and progenitor cells surviving radiation exposure.
In radiation-induced acute myeloid leukemia (rAML), clonal chromosomal abnormalities are often observed in bone marrow cells of patients, suggesting that their formation is crucial in the development of the disease. Since rAML is considered to originate from hematopoietic stem and progenitor cells (HSPC), we investigated the frequency and spectrum of radiation-induced chromosomal abnormalities in human CD34(+) cells. We then measured stable chromosomal abnormalities, a possible biomarker of leukemia risk, in clonally expanded cell populations which were grown for 14 days in a 3D-matrix (CFU-assay). We compared two radiation qualities used in radiotherapy, sparsely ionizing X-rays and densely ionizing carbon ions (29 and 60-85 keV/μm, doses between 0.5 and 4 Gy). Only a negligible number of de novo arising, unstable aberrations (≤ 0.05 aberrations/cell, 97% breaks) were measured in the descendants of irradiated HSPC. However, stable aberrations were detected in colonies formed by irradiated HSPC. All cells of the affected colonies exhibited one or more identical aberrations, indicating their clonal origin. The majority of the clonal rearrangements (92%) were simple exchanges such as translocations (77%) and pericentric inversions (15%), which are known to contribute to the development of rAML. Carbon ions were more efficient in inducing cell killing (maximum of ∼ 30-35% apoptotic cells for 2 Gy carbon ions compared to ∼ 25% for X-rays) and chromosomal aberrations in the first cell-cycle after exposure (∼ 70% and ∼ 40% for 1 Gy of carbon ions and X-rays, respectively), with a higher fraction of non-transmissible aberrations. In contrast, for both radiation qualities the percentage of clones with chromosomal abnormalities was similar (40%). Using the frequency of colonies with clonal aberrations as a surrogate marker for the leukemia risk following radiotherapy of solid tumors, charged particle therapy is not expected to lead to an increased risk of leukemia in patients.
GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt, Germany; Institute for Transfusion Medicine und Immunohematology, DRK-Blutspendedienst Baden-Wuerttemberg-Hessen, Johann Wolfgang Goethe-University Hospital, Sandhofstrasse 1, 60528 Frankfurt, Germany. Electronic address: d.kraft@gsi.de.
Daniela
D
Kraft
GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt, Germany. Electronic address: s.ritter@gsi.de.
Sylvia
S
Ritter
GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt, Germany; Institute for Condensed Matter Physics, Physics Department, Technical University Darmstadt, Hochschulstraße 6-8, 64289 Darmstadt, Germany. Electronic address: m.durante@gsi.de.
Marco
M
Durante
Institute for Transfusion Medicine und Immunohematology, DRK-Blutspendedienst Baden-Wuerttemberg-Hessen, Johann Wolfgang Goethe-University Hospital, Sandhofstrasse 1, 60528 Frankfurt, Germany. Electronic address: e.seifried@blutspende.de.
Erhard
E
Seifried
GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt, Germany. Electronic address: c.fournier@gsi.de.
Claudia
C
Fournier
Institute for Transfusion Medicine und Immunohematology, DRK-Blutspendedienst Baden-Wuerttemberg-Hessen, Johann Wolfgang Goethe-University Hospital, Sandhofstrasse 1, 60528 Frankfurt, Germany; Technische Universität Dresden, Med. Fakultät Carl Gustav Carus; Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Blasewitzer Straße 68/70, 01307 Dresden, Germany. Electronic address: t.tonn@blutspende.de.
Torsten
T
Tonn
D000328:Adult; D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000528:radiation effects*; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000528:radiation effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014965:X-Rays / Q000009:adverse effects
Carbon ions; Cell death; Clonal chromosomal abnormalities; Genomic instability; Hematopoietic stem and progenitor cells; Ionizing radiation