Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia.
BACKGROUND
Survivors of childhood acute lymphoblastic leukemia (ALL) are at an increased risk of developing secondary malignant neoplasms. Radiation and chemotherapy can cause mutations and cytogenetic abnormalities and induce genomic instability. Host immunity and appropriate DNA damage responses are critical inhibitors of carcinogenesis. Therefore, we sought to determine the long-term effects of ALL treatment on immune function and response to DNA damage.


METHODS
Comparative studies on 14 survivors in first complete remission and 16 siblings were conducted.


RESULTS
In comparison to siblings on the cells that were involved in adaptive immunity, the patients had either higher numbers (CD19+ B cells and CD4+CD25+ T regulatory cells) or similar numbers (alphabetaT cells and CD45RO+/RA- memory T cells) in the blood. In contrast, patients had lower numbers of all lymphocyte subsets involved in innate immunity (gammadeltaT cells and all NK subsets, including KIR2DL1+ cells, KIR2DL2/L3+ cells, and CD16+ cells), and lower natural cytotoxicity against K562 leukemia cells. Thymopoiesis was lower in patients, as demonstrated by less CD45RO-/RA+ naïve T cell and less SjTREC levels in the blood, whereas the Vbeta spectratype complexity score was similar. Array of gene expression response to low-dose radiation showed that about 70% of the probesets had a reduced response in patients. One of these genes, SCHIP-1, was also among the top-ranked single nucleotide polymorphisms (SNPs) during the whole-genome scanning by SNP microarray analysis.


CONCLUSIONS
ALL survivors were deficient in innate immunity, thymopoiesis, and DNA damage responses to radiation. These defects may contribute to their increased likelihood of second malignancy.
Leung
Wing
W
Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-2794, USA. wing.leung@stjude.org
Neale
Geoffrey
G
Behm
Fred
F
Iyengar
Rekha
R
Finkelstein
David
D
Kastan
Michael B
MB
Pui
Ching-Hon
CH
D000293:Adolescent; D000328:Adult; D002648:Child; D004249:DNA Damage; D015870:Gene Expression / Q000528:radiation effects*; D006801:Humans; D007113:Immunity, Innate; D008231:Lymphopenia / Q000150:complications; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D017741:Survivors; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D013995:Time; D055815:Young Adult