Article

Somervaille, T. C. P. & Cleary, M. L. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257-268

Stanford University, Stanford, California, United States
Cancer Cell (Impact Factor: 23.52). 11/2006; 10(4):257-68. DOI: 10.1016/j.ccr.2006.08.020
Source: PubMed

ABSTRACT

Using a mouse model of human acute myeloid leukemia (AML) induced by the MLL-AF9 oncogene, we demonstrate that colony-forming cells (CFCs) in the bone marrow and spleen of leukemic mice are also leukemia stem cells (LSCs). These self-renewing cells (1) are frequent, accounting for 25%-30% of myeloid lineage cells at late-stage disease; (2) generate a phenotypic, morphologic, and functional leukemia cell hierarchy; (3) express mature myeloid lineage-specific antigens; and (4) exhibit altered microenvironmental interactions by comparison with the oncogene-immortalized CFCs that initiated the disease. Therefore, the LSCs responsible for sustaining, expanding, and regenerating MLL-AF9 AML are downstream myeloid lineage cells, which have acquired an aberrant Hox-associated self-renewal program as well as other biologic features of hematopoietic stem cells.

Full-text preview

Available from: univ-mrs.fr
  • Source
    • "The observation that PAR1 expression differed significantly in human acute myeloid leukemia and especially in AML M4 and M5 (Fig. 4C) led us to analyze Par1 functions in murine leukemogenesis. To model AML in vivo, wild type or Par1-knockout (−/−) bone marrow cells were retrovirally transduced with the leukemogenic MLL-AF9, which occurs in human AML M5 [32] and reliably induces an AML in mice [33], [34], [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: External signals that are mediated by specific receptors determine stem cell fate. The thrombin receptor PAR1 plays an important role in haemostasis, thrombosis and vascular biology, but also in tumor biology and angiogenesis. Its expression and function in hematopoietic stem cells is largely unknown. Here, we analyzed expression and function of PAR1 in primary hematopoietic cells and their leukemic counterparts. AML patients' blast cells expressed much lower levels of PAR1 mRNA and protein than CD34+ progenitor cells. Constitutive Par1-deficiency in adult mice did not affect engraftment or stem cell potential of hematopoietic cells. To model an AML with Par1-deficiency, we retrovirally introduced the oncogene MLL-AF9 in wild type and Par1-/- hematopoietic progenitor cells. Par1-deficiency did not alter initial leukemia development. However, the loss of Par1 enhanced leukemic stem cell function in vitro and in vivo. Re-expression of PAR1 in Par1-/- leukemic stem cells delayed leukemogenesis in vivo. These data indicate that Par1 contributes to leukemic stem cell maintenance.
    Full-text · Article · Apr 2014 · PLoS ONE
  • Source
    • "Chromosomal translocations involving the mixed lineage leukemia gene (MLL) with multiple fusion partners are common in human AML (Liedtke and Cleary, 2009). Experimental overexpression of MLL fusion proteins such as MLL-AF9 (MA9) causes transformation of murine myeloid progenitors (Krivtsov et al., 2006; Somervaille and Cleary, 2006). The resulting AML cells can be propagated in cytokine-supplemented cultures and cause serially transplantable AML in recipient mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
    Full-text · Article · Jan 2014 · Cell Reports
  • Source
    • "Chromosomal translocations involving the mixed lineage leukemia gene (MLL) with multiple fusion partners are common in human AML (Liedtke and Cleary, 2009). Experimental overexpression of MLL fusion proteins such as MLL-AF9 (MA9) causes transformation of murine myeloid progenitors (Krivtsov et al., 2006; Somervaille and Cleary, 2006). The resulting AML cells can be propagated in cytokine-supplemented cultures and cause serially transplantable AML in recipient mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slide
    Full-text · Article · Jan 2014
Show more