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Etoposide‐initiated MLL rearrangements detected at high frequency in human primitive hematopoietic stem cells with in vitro and in vivo long‐term repopulating potential
Author(s) -
Libura Jolanta,
Ward Maureen,
Solecka Joanna,
Richardson Christine
Publication year - 2008
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2008.01103.x
Subject(s) - haematopoiesis , etoposide , stem cell , in vitro , in vivo , biology , cancer research , immunology , microbiology and biotechnology , genetics , chemotherapy
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 .