Establishment of a Normal Hematopoietic and Leukemia Stem Cell Hierarchy

ArticleinCold Spring Harbor Symposia on Quantitative Biology 73:439-49 · December 2008with6 Reads
DOI: 10.1101/sqb.2008.73.031 · Source: PubMed
Many types of adult tissues, especially for high turnover tissues such as the blood and intestinal system, stand on a hierarchical tissue-specific stem cell system. Tissue-specific stem cells concurrently have self-renewal capacity and potential to give rise to all types of mature cells in their tissue. The differentiation process of the tissue-specific stem cell is successive restriction of these capacities. The first progeny of tissue-specific stem cells are multipotent progenitors (MPPs) that lose long-term self-renewal capacity yet have full lineage potential. MPPs in turn give rise to oligopotent progenitors, which then commit into lineage-restricted progenitors. This hierarchical system enables a lifelong supply of matured functional cells that generally have a short life span and a relatively high turnover rate. In this chapter, we review our findings and other key experiments that have led to the establishment of the current cellular stem and progenitor hierarchy in the blood-forming systems of mice and humans for both normal and leukemic hematopoiesis. We also review select signaling pathways intrinsic to normal hematopoietic and leukemic stem cell populations as well our recent findings elucidating the possible origin of the leukemia stem cell.
    • "A growing body of evidence indicates that de novo AML is composed of a cellular hierarchy initiated and maintained by self-renewing leukemia stem cells (LSC) that are functionally defined by their ability to reconstitute AML in xenograft models [11]. The cellular hierarchy in AML is analogous to normal hematopoiesis in which multipotent, self-renewing hematopoietic stem cells (HSC) give rise to downstream progenitor cells and ultimately all mature blood ele- ments [12]. Recent work has demonstrated that the disease stem cells in MDS are found in the HSC compartment [13][14][15][16][17]. Several lines of evidence argue that AML and MDS arise from the stepwise accumulation of multiple mutations in pre-leukemic HSC, eventually generating LSC capable of initiating disease [18][19][20] . "
    [Show abstract] [Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous group of aggressive bone marrow cancers arising from transformed hematopoietic stem and progenitor cells (HSPC). Therapy-related AML and MDS (t-AML/MDS) comprise a subset of AML cases occurring after exposure to alkylating chemotherapy and/or radiation and are associated with a very poor prognosis. Less is known about the pathogenesis and disease-initiating/leukemia stem cell (LSC) subpopulations of t-AML/MDS compared to their de novo counterparts. Here, we report the development of mouse models of t-AML/MDS. First, we modeled alkylator-induced t-AML/MDS by exposing wild type adult mice to N-ethyl-N-nitrosurea (ENU), resulting in several models of AML and MDS that have clinical and pathologic characteristics consistent with human t-AML/MDS including cytopenia, myelodysplasia, and shortened overall survival. These models were limited by their inability to transplant clinically aggressive disease. Second, we established three patient-derived xenograft models of human t-AML. These models led to rapidly fatal disease in recipient immunodeficient xenografted mice. LSC activity was identified in multiple HSPC subpopulations suggesting there is no canonical LSC immunophenotype in human t-AML. Overall, we report several new t-AML/MDS mouse models that could potentially be used to further define disease pathogenesis and test novel therapeutics.
    Full-text · Article · Jul 2016
    • "Recurrent mutations in transcription factors (TFs) and epigenetic regulators identified in AML (Dö hner et al., 2015; Cancer Genome Atlas Research Network, 2013) suggest that aberrant transcriptional circuits are a common feature of leukemogenesis. Collectively, these circuits drive oncogenic gene expression programs that inhibit differentiation and activate self-renewal, generating leukemia stem cells (LSCs) responsible for the initiation and propagation of disease (Chao et al., 2008; Reya et al., 2001; Somervaille and Cleary, 2006). In leukemias with rearrangements of the Mixed Lineage Leukemia (MLL) gene, activation of a self-renewal circuit involving the Hox gene cluster is a key aspect in the transformation of committed myeloid progenitor cells (Krivtsov et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.
    Article · Apr 2016
    • "The World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues is mainly based on the lineage and stage of differentiation of the tumour cells corresponding to that of normal haematolymphoid dif- ferentiation [1]. The pluripotent stem cell typically undergoes restriction of its developmental potential, thus transforming into multipotent progenitor cells, which, in turn, give rise to even more developmentally restricted progenitor cells or terminally differentiated functional cells [2] . Although the classical scheme of haematopoiesis envisages ordered unidirectional maturation of pluripotent stem cells into lineage-committed cells, with distinct morphologic, immunophenotypic and functional characteristics and a sealed and irreversible fate, the degree of commitment has come into question [3]. "
    [Show abstract] [Hide abstract] ABSTRACT: The concept of unidirectional differentiation of the haematopoietic stem cell has been challenged after recent findings that human B cell progenitors and even mature B cells can be reprogrammed into histiocytic/dendritic cells by altering expression of lineage-associated transcription factors. The conversion of mature B cell lymphomas to Langerhans cell neoplasms is not well documented. Three previous reports have described clonally related follicular lymphoma and Langerhans cell tumours, whereas no case has been published of clonally related marginal zone lymphoma and Langerhans cell sarcoma. We describe the case of a 77-year-old patient who developed a Langerhans cell sarcoma and 6 years later a nodal marginal zone lymphoma. Mutation status examination showed 100 % gene identity to the germline sequence, suggesting direct trans-differentiation or dedifferentiation of the nodal marginal zone lymphoma to the Langerhans cell sarcoma rather than a common progenitor. We found inactivation of paired box 5 (PAX-5) in the lymphoma cells by methylation, along with duplication of part of the long arm of chromosomes 16 and 17 in the sarcoma cells. The absence of PAX-5 could have triggered B cells to differentiate into macrophages and dendritic cells. On the other hand, chromosomal imbalances might have activated genes involved in myeloid lineage maturation, transcription activation and oncogenesis. We hypothesize that this occurred because of previous therapies for nodal marginal zone lymphoma. Better understanding of this phenomenon may help in unravelling the molecular interplay between transcription factors during haematopoietic lineage commitment and may expand the spectrum of clonally related mature B cell neoplasms and Langerhans cell tumours.
    Full-text · Article · Aug 2015
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