Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al.. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6: 587-596

Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cancer Cell (Impact Factor: 23.52). 01/2005; 6(6):587-96. DOI: 10.1016/j.ccr.2004.10.015
Source: PubMed


To better understand the origin of leukemic stem cells, we tested the hypothesis that all leukemia oncogenes could transform committed myeloid progenitor cells lacking the capacity for self-renewal, as has recently been reported for MLL-ENL. Flow-sorted populations of common myeloid progenitors and granulocyte-monocyte progenitors were transduced with the oncogenes MOZ-TIF2 and BCR-ABL, respectively. MOZ-TIF2-transduced progenitors could be serially replated in methylcellulose cultures and continuously propagated in liquid culture, and resulted in an acute myeloid leukemia in vivo that could be serially transplanted. In contrast, BCR-ABL transduction conferred none of these properties to hematopoietic progenitors. These data demonstrate that some, but not all, leukemia oncogenes can confer properties of leukemic stem cells to hematopoietic progenitors destined to undergo apoptotic cell death.

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    • "These properties make HSCs, like other tissue stem cells, prime targets for malignant transformation. Nevertheless, the fact that some mutations can transform differentiating cells suggests that HSCs might not be the only source of LSCs (Cozzio et al., 2003; Huntly et al., 2004). "
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    • "These fusion genes produce the same disease pattern with blast cells of a monocytoid phenotype. Previous studies have revealed that KAT6A is essential for the self-renewal of hematopoietic stem cells (Katsumoto et al., 2006; Thomas et al., 2006), and KAT6A fusion proteins enable the transformation of non-self-renewing myeloid progenitors into leukemia stem cells (Huntly et al., 2004). Other data have shown that KAT6A cooperates with MLL to regulate HOX gene expression in human cord blood CD341 cells (Paggetti et al., 2010). "
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    • "; Table S1 available online). We then functionally evaluated the effect of knocking down these genes on Cebpa KO cells (Mx1-Cre + Cebpa loxP/loxP ; from here on referred to as Cebpa KO following Cre-mediated deletion) after serially replating in methylcellulose cultures, a cell culture assay that has been correlated with the ability to induce leukemia in mice (Huntly et al., 2004; Lavau et al., 1997; Moran-Crusio et al., 2011). We transduced Cebpa KO LSK cells with lentiviruses carrying either a mix of scrambled small hairpin RNA (shRNA) (control) or a pool of five shRNAs all targeting one specific candidate and assessed their capability to undergo serial replating (Figure S1A). "
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