Establishment of a Normal Hematopoietic and Leukemia Stem Cell Hierarchy

Chao, Mark; Seita, Jun; Weissman, Irving L.

doi:10.1101/sqb.2008.73.031

Cited by 116 publications

(113 citation statements)

References 99 publications

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“…There are many precedents for progenitor cell populations in other organisms that contain numerous cell types with different properties or lineage potential (Spangrude et al, 1988;Chao et al, 2008;Biressi and Rando, 2010). Furthermore, blastema cells in amphibians were long considered to be a multipotent progenitor type, but it is now known that there is lineage restriction in the cells of the blastema in Xenopus and axolotl, as well as in zebrafish (Gargioli and Slack, 2004;Kragl et al, 2009;Knopf et al, 2011;Tanaka and Reddien, 2011;Tu and Johnson, 2011).…”

Section: The Specialized Neoblast Modelmentioning

confidence: 99%

Specialized progenitors and regeneration

Reddien

2013

Development

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SummaryPlanarians are flatworms capable of regenerating all body parts. Planarian regeneration requires neoblasts, a population of dividing cells that has been studied for over a century. Neoblast progeny generate new cells of blastemas, which are the regenerative outgrowths at wounds. If the neoblasts comprise a uniform population of cells during regeneration (e.g. they are all uncommitted and pluripotent), then specialization of new cell types should occur in multipotent, non-dividing neoblast progeny cells. By contrast, recent data indicate that some neoblasts express lineage-specific transcription factors during regeneration and in uninjured animals. These observations raise the possibility that an important early step in planarian regeneration is the specialization of neoblasts to produce specified rather than naïve blastema cells.

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Section: The Specialized Neoblast Modelmentioning

confidence: 99%

Specialized progenitors and regeneration

Reddien

2013

Development

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“…These cells eventually differentiate into lineagerestricted common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs), which are committed to terminal differentiation and unable to selfrenew (Chao et al 2008). Previous studies have demonstrated that oncogenic Kras drives proliferation and differentiation of HSCs and myeloid progenitors, but does not promote-and, in fact, depends on-self-renewal capabilities to initiate disease (Sabnis et al 2009;Zhang et al 2009).…”

Section: Krasmentioning

confidence: 99%

p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal

Zuber²,

et al. 2010

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The p53 tumor suppressor limits proliferation in response to cellular stress through several mechanisms. Here, we test whether the recently described ability of p53 to limit stem cell self-renewal suppresses tumorigenesis in acute myeloid leukemia (AML), an aggressive cancer in which p53 mutations are associated with drug resistance and adverse outcome. Our approach combined mosaic mouse models, Cre-lox technology, and in vivo RNAi to disable p53 and simultaneously activate endogenous Kras G12D -a common AML lesion that promotes proliferation but not self-renewal. We show that p53 inactivation strongly cooperates with oncogenic Kras G12D to induce aggressive AML, while both lesions on their own induce T-cell malignancies with long latency. This synergy is based on a pivotal role of p53 in limiting aberrant self-renewal of myeloid progenitor cells, such that loss of p53 counters the deleterious effects of oncogenic Kras on these cells and enables them to self-renew indefinitely. Consequently, myeloid progenitor cells expressing oncogenic Kras and lacking p53 become leukemia-initiating cells, resembling cancer stem cells capable of maintaining AML in vivo. Our results establish an efficient new strategy for interrogating oncogene cooperation, and provide strong evidence that the ability of p53 to limit aberrant selfrenewal contributes to its tumor suppressor activity.[Keywords: AML; Ras; cancer stem cells; leukemia; p53; self-renewal; tumor suppressor] Supplemental material is available at http://www.genesdev.org.

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“…Similar to hematopoietic stem cells (HSCs) in normal blood development, LSCs can give rise to the entire cellular hierarchy and sustain leukemia expansion through an unlimited self-renewal capability. 1 This model is supported by studies in which LSC-enriched cell populations, such as the CD34 ϩ CD38 Ϫ leukemic cells in human acute myeloid leukemia (AML), transplanted into SCID mice are able to fully recapitulate the process of leukemia development. 2,3 LSCs can be derived from different cellular compartments according to the leukemia type and disease stage.…”

Section: Introductionmentioning

confidence: 99%

KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia

Nguyen

Zhang

2011

Blood

187

144

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The histone H3 lysine 36 dimethylspecific demethylase KDM2b/JHDM1b, which is highly expressed in various human leukemias, was previously found to be important in regulating cell proliferation and cellular senescence. However, its functions in leukemia development and maintenance are unclear. Here, we demonstrate that ectopic expression of IntroductionPrevious studies have shown that human leukemic cells from the same patient are composed of heterogeneous cell populations with various proliferation capacities and differentiation status. In the proposed leukemia stem cell (LSC) model, a fraction of LSCs resides at the apex of leukemia cellular hierarchy. Similar to hematopoietic stem cells (HSCs) in normal blood development, LSCs can give rise to the entire cellular hierarchy and sustain leukemia expansion through an unlimited self-renewal capability. 1 This model is supported by studies in which LSC-enriched cell populations, such as the CD34 ϩ CD38 Ϫ leukemic cells in human acute myeloid leukemia (AML), transplanted into SCID mice are able to fully recapitulate the process of leukemia development. 2,3 LSCs can be derived from different cellular compartments according to the leukemia type and disease stage. In a Junb inactivation-induced chronic myeloid leukemia (CML) murine model, the CML-like disease can only develop from Junbinactivated HSCs but not progenitor cells, indicating that LSCs may derive from HSCs. 4 However, in the accelerated and myeloid blast crisis phases of human CML, only leukemic granulocytemacrophage progenitors can be expanded and display an aberrant self-renewing capacity in vitro in the methylcellulose replating assay. 5 In addition, the fact that certain murine AMLs can be induced by retroviral transduction of oncogenes, such as Mll fusion genes, into the granulocyte-macrophage progenitor population indicates that LSCs can originate from committed progenitor cells directly. 6,7 These studies suggest that the "stemness" program of LSCs could be activated by various oncogenic stimuli in different cellular contexts. However, the molecular mechanisms underlying LSC self-renewal is not well understood. 8 The leukemic stem cell model implies that epigenetic regulation at certain critical gene loci might be important in determining the phenotypic difference between self-renewing LSCs and their non-self-renewing progeny. 8 One example that supports this notion comes from the demonstration that the Ink4a-Arf-Ink4b locus, which encodes 3 tumor suppressors, including p16 Ink4a , p15 Ink4b , and p19 Arf is controlled by the Polycomb repressive complex 1 (PRC1) in both normal HSCs and LSCs. 9,10 Biochemical analysis has shown that the PRC1 complex contains an ubiquitin E3 ligase activity and catalyzes the monoubiquitylation of histone H2A at lysine 119, which may serve as an epigenetic mark for the recruitment of other transcriptional repressors to the Ink4a-ArfInk4b locus. 11,12 Consistently, deletion of BMI-1, a component of the PRC1 complex, in LSCs leads to de-repression of Ink4a-Arf expression...

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Establishment of a Normal Hematopoietic and Leukemia Stem Cell Hierarchy

Cited by 116 publications

References 99 publications

Specialized progenitors and regeneration

Specialized progenitors and regeneration

p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal

KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia

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