Gene rearrangements of MLL and RUNX1 sporadically occur in normal CD34+ cells under cytokine stimulation.

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.

• Authors: Yuka Harada, Naoki Shingai, Ye Ding, Daichi Sadato, Yoshihiro Hayashi, Masaki Yamaguchi, Yoshiki Okuyama, Tatsu Shimoyama, Kazuteru Ohashi, Hironori Harada
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 5 Pg. 1851-1855 (May 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32216001 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Cytokines
• KMT2A protein, human
• RUNX1 protein, human
• Topoisomerase II Inhibitors
• Myeloid-Lymphoid Leukemia Protein
• Etoposide
• Histone-Lysine N-Methyltransferase

Topics

• 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, 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, metabolism)
• Topoisomerase II Inhibitors (pharmacology)