Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors.

By A. Cozzio, E. Passegué, P. Ayton, H. Karsunky, M. Cleary, Irving L. Weissman. Genes & Development, 2003

746 citations recorded by the source corpus.

We have used the hematopoietic system as a model to investigate whether acute myeloid leukemia arises exclusively from self-renewing stem cells or also from short-lived myeloid progenitors. When transduced with a leukemogenic MLL fusion gene, prospectively isolated stem cells and myeloid progenitor populations with granulocyte/macrophage differentiation potential are efficiently immortalized in vitro and result in the rapid onset of acute myeloid leukemia with similar latencies following transplantation in vivo. Regardless of initiating cell, leukemias displayed immunophenotypes and gene expression profiles characteristic of maturation arrest at an identical late stage of myelomonocytic differentiation, putatively a monopotent monocytic progenitor stage. Our findings unequivocally establish the ability of transient repopulating progenitors to initiate myeloid leukemias in response to an MLL oncogene, and support the existence of cancer stem cells that do not necessarily overlap with multipotent stem cells of the tissue of origin.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/91327d323395a6571d172c5115d1d87dfed9863b

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Citations in the corpus

TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. (2011, neutral): “In human acute leukemia, this crucial property can be acquired by committed progenitors with limited self-renewal capacities through a genetic event or maintained through the targeting of hematopoietic stem cells (HSCs) (Cozzio et al., 2003; Goardon et al., 2011; Huntly et al., 2004).”
Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “…can arise from restricted progenitors or differentiated cells as a result of mutations that ectopically activate selfrenewal mechanisms in these cells (Figure 2A) (Cozzio et al., 2003; Huntly et al., 2004; Krivtsov et al., 2006; Schüller et al., 2008; Yang et al., 2008; Zhao et al., 2010).”
MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. (2004, background): “For example, there is evidence for increased in committed myeloid progenitors (Cozzio et al., 2003).”
Tumour stem cells and drug resistance (2005, background): “Alternatively, the original tumour cell could be a more differentiated cell that develops the capacity for continual self-renewal, thus acquiring the properties of a stem cel”
Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition (2008, background): “Congruent with previously reported experiments using models of hematopoietic malignancies [7–10], transformed breast cancer cells were obtained in vitro by introducing a series of oncogenes and cancer-associated genes into normal primary human mammary epithelial cells.”
Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. (2007, background): “The critical requirement of appropriate control of such factors in oligopotent—but normally not self-renewing—progenitors has been highlighted by the development of leukemias arising as a consequence of the misappropriate expression of such transcriptional regulators (Cozzio et al., 2003; Krivtsov e”
Tumour-initiating cells: challenges and opportunities for anticancer drug discovery (2009, background): “It has been shown that mixed-lineage leukaemia (MLL) fusion proteins, which modulate chromatin structure through histone modification, can reprogramme differentiated myeloid cells and activate self-renewal in cells with no inherent self-renewal propertie”
Stems cells and the pathways to aging and cancer. (2008, background): “After the transition to blast crisis, GMPs were found to have gained the capacity to self-renew and to transfer blast crisis leukemia to immunodeficient mice, in part, as a consequence of self-renewal driven by aberrant Wnt/b-catenin signaling (Jamieson et al., 2004).”