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Keywords:

  • MLL;
  • AF10;
  • MPD;
  • cytokine

Abstract

Several mouse models studying the MLL fusion-induced leukemic transformation showed that a myeloproliferation stage precedes leukemia or occurred as the only phenotype of hematological disorder in mice. We established 6 MLL/AF10(OM-LZ)-immortalized cell lines by retrovirally transducing the fusion gene into bone marrow cells from B6 or congenic GFP-B6 mice. Immunophenotypic and cytological analyses revealed that the immortalized cell lines could be divided into 2 types. Type I had a high percentage of cells expressing monocytic lineage marker CD115 in the medium containing IL3 and could terminally differentiate into granulocytes and monocytes in response to granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) treatments, respectively. On the other hand, type II had a low percentage of cells expressing CD115. The type II cell lines could not differentiate into granulocytes by G-CSF treatment and died rapidly in response to M-CSF treatment. Transplantation of both types I and II cells induced lethal myeloproliferative disease (MPD)-like myeloid leukemia in most of the sublethally irradiated B6 mice. Flow cytometric analysis of GFP and lineage markers of the peripheral blood cells from MPD mice revealed that the monocytes and granulocytes were generated not only from the donor cells but also from the host cells. RT-PCR analysis revealed that the MLL/AF10(OM-LZ)-immortalized cells expressed mRNAs encoding colony-stimulating factors (CSFs) of M-CSF and GM-CSF and inflammatory cytokines of IL-1α, IL-1β and TNF-α. Our results showed that the MLL/AF10(OM-LZ)-immortalized cells could induce host cell proliferation in the transplanted mice, probably through stimulation by CSFs or cytokines produced by the donor cells.