Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362-367

Nature (Impact Factor: 41.46). 01/2011; 469(7330). DOI: 10.1038/nature09733
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Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.

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    • "For example, increased tumor cell heterogeneity was recently correlated with chemotherapy resistance in renal cell carcinoma (Gerlinger et al., 2012) and metastasis in pancreatic adenocarcinoma (Yachida et al., 2010). Similar associations have been reported in acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic lymphocytic leukemia (CLL), where genetic diversity within the primary leukemia was correlated with an increased likelihood of drug resistance, disease progression, and relapse (Anderson et al., 2011; Ding et al., 2012; Landau et al., 2013; Mullighan et al., 2008; Notta et al., 2011). While these studies have provided valuable insight into intratumoral heterogeneity and patient outcome, analyses of bulk patient samples often identifies large numbers of mutations within a single tumor, making it difficult to determine how genetic diversity and acquired mutations promote cancer progression. "
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    ABSTRACT: Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia-propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia-propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection.
    Cancer cell 03/2014; 25(3). DOI:10.1016/j.ccr.2014.01.032 · 23.52 Impact Factor
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    • "An elegant study by the Jacobsen's group (Castor et al., 2005) demonstrated that different subtypes of ALL exhibit heterogeneity regarding the cell of origin for transformation based on analysis of fusion genes (e.g., the TEL-AML1 translocation is detected in B-cell progenitor subsets while the BCR-ABL translocation that generates the breakpoint cluster region (BCR)/Abelson murine leukemia viral oncogene homolog 1 (ABL1) p210BCR/ABL protein is detected in the stem cell compartment); however , the ability to reconstitute a leukemic process in NOD/SCID mice resided in the committed B-progenitor subset in both cases (Castor et al., 2005). A recent study (Notta et al., 2011) has demonstrated that Philadelphia chromosome (Ph1) ALL samples are heterogeneous in the ability to reconstitute a leukemic process in immunodeficient mice and that this behavior correlates with the presence of specific genetic aberrations (e.g., samples with deletion of the CDKN2A/B locus induce a more aggressive disease) and the frequency of LICs; however, multiple, genetically-distinct subclones were identified in the leukemia that developed in xenotransplanted mice, indicating that Ph1 ALL is composed of varying numbers of genetically distinct subclones with different capacity to reconstitute a leukemic process in immunodeficient mice. However, the study did not address the issue of whether different LICs reside in immunophenotypically distinct stem-and/or progenitor subsets and the role of these subsets in leukemia maintenance. "
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    ABSTRACT: Myeloid leukemias are heterogeneous malignancies in morphology, immunophenotype, genetic and epigenetic alterations, and response to therapy. This heterogeneity is thought to depend on the accumulation of secondary mutations enhancing proliferation/survival and/or blocking differentiation in a small subset of leukemia-initiating cells capable of self-renewal. This model of clonal evolution is based on xenotransplantation studies demonstrating that leukemia can be initiated and maintained in immunodeficient mice by a small subset of purified leukemic cells immunophenotypically similar to normal hematopoietic stem cells and is known as the leukemia stem cell model. Since its original formulation, many studies have validated the main conclusion of this model. However, recent data from xenotransplantation studies in more severely immunodeficient mice suggest that imunophenotype and behaviour of leukemic stem cells is more heterogeneous and "plastic" than originally thought. We will discuss here the evolution of the leukemia stem cell model and its impact for the therapy of patients with myeloid malignancies.
    Molecular Aspects of Medicine 06/2013; 39. DOI:10.1016/j.mam.2013.06.003 · 10.24 Impact Factor
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    • "Therefore, individual clones of leukemic cells can be identified using methods, such as multiplexed fluorescence in situ hybridization, to detect the combination of genetic lesions they contain. These studies have revealed that leukemic cells have a dynamic clonal architecture, with clones and subclones exhibiting competitive regenerative capacity (Anderson et al., 2011; Notta et al., 2011b). Predictions regarding lineage relationships between clones of leukemic cells with different mutations can then be tested experimentally by transplantation in immunocompromised mice (Notta et al., 2011a, 2011b). "
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    ABSTRACT: Lineage tracing is the identification of all progeny of a single cell. Although its origins date back to developmental biology of invertebrates in the 19(th) century, lineage tracing is now an essential tool for studying stem cell properties in adult mammalian tissues. Lineage tracing provides a powerful means of understanding tissue development, homeostasis, and disease, especially when it is combined with experimental manipulation of signals regulating cell-fate decisions. Recently, the combination of inducible recombinases, multicolor reporter constructs, and live-cell imaging has provided unprecedented insights into stem cell biology. Here we discuss the different experimental strategies currently available for lineage tracing, their associated caveats, and new opportunities to integrate lineage tracing with the monitoring of intracellular signaling pathways.
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