RRC ID 63826
Author Harada Y, Shingai N, Ding Y, Sadato D, Hayashi Y, Yamaguchi M, Okuyama Y, Shimoyama T, Ohashi K, Harada H.
Title Gene rearrangements of MLL and RUNX1 sporadically occur in normal CD34+ cells under cytokine stimulation.
Journal Cancer Sci
Abstract Gene rearrangements of MLL/KMT2A or RUNX1 are the major cause of therapy-related leukemia. Moreover, MLL rearrangements are the major cause of infant leukemia, and RUNX1 rearrangements are frequently detected in cord blood. These genes are sensitive to topoisomerase II inhibitors, and various genes have been identified as potential fusion partners. However, fetal exposure to these inhibitors is rare. Therefore, we postulated that even a proliferation signal itself might induce gene rearrangements in hematopoietic stem cells. To test this hypothesis, we detected gene rearrangements in etoposide-treated or non-treated CD34+ cells cultured with cytokines using inverse PCR. In the etoposide-treated cells, variable-sized rearrangement bands were detected in the RUNX1 and MLL genes at 3 hours of culture, which decreased after 7 days. However, more rearrangement bands were detected in the non-treated cells at 7 days of culture. Such gene rearrangements were also detected in peripheral blood stem cells mobilized by cytokines for transplantation. However, none of these rearranged genes encoded the leukemogenic oncogene, and the cells with rearrangements did not expand. These findings suggest that MLL and RUNX1 rearrangements, which occur with very low frequency in normal hematopoietic progenitor cells, may be induced under cytokine stimulation. Most of the cells with gene rearrangements are likely eliminated, except for leukemia-associated gene rearrangements, resulting in the low prevalence of leukemia development.
Volume 111(5)
Pages 1851-1855
Published 2020-5-1
DOI 10.1111/cas.14392
PMID 32216001
PMC PMC7226195
MeSH Aged Cell Survival / drug effects Cells, Cultured Core Binding Factor Alpha 2 Subunit / genetics* Cytokines / pharmacology* Etoposide / pharmacology Gene Rearrangement / drug effects* Hematopoietic Stem Cells / drug effects* Hematopoietic Stem Cells / metabolism Histone-Lysine N-Methyltransferase / genetics* Humans Lymphoma, Large B-Cell, Diffuse / pathology Middle Aged Myeloid-Lymphoid Leukemia Protein / genetics* Peripheral Blood Stem Cells / drug effects Peripheral Blood Stem Cells / metabolism Topoisomerase II Inhibitors / pharmacology
IF 4.966
Cord blood stem cells for research