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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Available from: Ifor R Williams, Oct 10, 2015
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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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    ABSTRACT: Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers.
    Disease Models and Mechanisms 08/2014; 7(8):941-951. DOI:10.1242/dmm.015974 · 4.97 Impact Factor
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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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    ABSTRACT: The monocytic leukemia zinc finger protein KAT6A (formerly MOZ) gene is recurrently rearranged by chromosomal translocations in acute myeloid leukemia (AML). KAT6A is known to be fused to several genes, all of which have histone acetyltransferase (HAT) activity and interact with a number of transcription factors as a transcriptional coactivator. The present study shows that the leucine twenty homeobox (LEUTX) gene on 19q13 is fused to the KAT6A gene on 8p11 in a therapy-related AML with t(8;19)(p11;q13) using the cDNA bubble PCR method. The fusion transcripts contained 83 nucleotides upstream of the first ATG of LEUTX and are presumed to create in-frame fusion proteins. LEUTX is known to have a homeobox domain. Expression of the LEUTX gene was only detected in placenta RNA by RT-PCR, but not in any tissues by Northern blot analysis. The putative LEUTX protein does not contain any HAT domain, and this is the first study to report that KAT6A can fuse to the homeobox gene. The current study, with identification of a new partner gene to KAT6A in a therapy-related AML, does not elucidate the mechanisms of leukemogenesis in KAT6A-related AML but describes a new gene with a different putative function. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 04/2014; 53(4). DOI:10.1002/gcc.22140 · 4.04 Impact Factor
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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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    ABSTRACT: Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ∼10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.
    Cancer cell 10/2013; 25(2). DOI:10.1016/j.ccr.2013.09.018 · 23.52 Impact Factor
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