期刊
EUROPEAN JOURNAL OF HAEMATOLOGY
卷 81, 期 3, 页码 185-195出版社
WILEY
DOI: 10.1111/j.1600-0609.2008.01103.x
关键词
etoposide; rearrangements; primitive hematopoietic stem cells; CD34+cells; Alu repetitive elements; genome instability; therapy-related leukemia; mixed lineage leukemia
类别
资金
- NCI NIH HHS [R01 CA100159, R56 CA100159, R01CA100159] Funding Source: Medline
Rearrangements initiating within the well-characterized break-point cluster region of the mixed lineage leukemia (MLL) gene on 11q23 are a hallmark of therapy-related leukemias following treatment with topoisomerase II poisons including etoposide. Hematopoietic stem cells (HSC) are believed to be the target cell for leukemia-initiating MLL rearrangement events. Although etoposide treatment is sufficient to induce readily detectable MLL rearrangements in primary human CD34+ cells, the majority of cells that gain translocations do not proliferate in culture possibly due to reduced proliferative capacity of most CD34+ cells during normal differentiation [Blood 2005;105:2124]. We characterized the impact of etoposide on primary human long-term repopulating HSC that represent only a minor portion of CD34+ cells. The proliferative capacity of HSC is dramatically increased following both a single and multiple exposures to etoposide as determined by their ability to engraft bone marrow of immune-deficient non-obese diabetic/severe combined immunodeficient mice and to initiate hematopoiesis in long-term initiating cultures. Similar to results in CD34+ cells, a significant proportion of etoposide-treated HSC-derived clones harbored stable MLL rearrangements, including duplications, inversions and translocations. These results indicate HSC are highly susceptible to etoposide-induced and potentially oncogenic rearrangements initiating within MLL, and these HSC are particularly proficient for continued long-term proliferation both in vivo and in vitro.
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