- Paracrine regulation of normal and malignant hematopoiesis.
- Normal and malignant hematopoiesis | Oncogene
- Hematopoiesis (D3)
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Paracrine regulation of normal and malignant hematopoiesis.
Old Password. New Password. Password Changed Successfully Your password has been changed. Create a new account Email. Returning user. Can't sign in? Forgot your password? Enter your email address below and we will send you the reset instructions. The zebrafish has proven to be a powerful organism for studies in this area owing to its amenability to large-scale genetic and chemical screening.
In addition, the externally fertilized and transparent embryos allow convenient genetic manipulation and in vivo imaging of normal and aberrant hematopoiesis. This review discusses available methods for studying hematopoiesis in zebrafish, summarizes key recent advances in this area, and highlights the current and potential contributions of zebrafish to the discovery and development of drugs to treat human blood disorders.
Abstract Zebrafish studies in the past two decades have made major contributions to our understanding of hematopoiesis and its associated disorders. Therefore, conceptually, the elimination of CSC is not only necessary, but also potentially sufficient to result in the complete eradication of a tumor and subsequent cure.
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As a consequence, the identification and characterization of CSC has obvious implications for the development of efficient and durable treatments [ ]. Myeloid neoplasms are an excellent model of CSC as candidate LSC have been identified in the majority of myeloid tumors [ — ].
In chronic myeloid malignancies, such as CML, Myelodysplastic Syndromes or Myeloproliferative Neoplasms, the mutation of the founding clone can be traced to the phenotypic HSC compartment [ , ]. Single-cell technologies offer an unprecedented opportunity to resolve such heterogeneity of cancer propagating populations as well as to characterize their transcriptional program, which may correlate with clinical outcome, as demonstrated at the bulk level [ ]. Indeed, the principle of identifying LSCs using single cell gene expression analysis has already been shown in model systems [ ].
Single cell analysis could not only identify LSCs but also provide functional insights, including proteomic characteristics [ ], which in turn will help to guide new therapeutic strategies towards their elimination. Intratumoral heterogeneity is closely linked to therapy resistance [ 81 , ], raising the possibility that single cell analysis could be applied to identify and characterize subpopulations of cells that are selectively resistant to the treatment Figure 4C.
This approach has been applied in AML by carrying out single cell targeted mutation analysis following treatment with the FLT3 inhibitor quizartinib [ ], demonstrating marked clonal complexity associated with therapy resistance that was mediated by multiple subclones carrying both on- and off-target mutations. Single cell gene expression analysis has recently been applied to identify therapy resistant LSCs in CML patients receiving tyrosine kinase inhibitor TKI therapy, either using a targeted gene expression analysis [ ], or by scRNA-seq [ ].
This study serves as a proof of concept for the application of scRNA-seq to uncover cellular and molecular mechanisms of therapy resistance in LSCs, an approach that could be more broadly applied to analyze any cancer. As scRNA-seq and similar single cell technologies become more routinely available, cost-effective and high-throughput, such analysis could be integrated into diagnostic pathways to definitively establish the cellular composition of the blood or bone marrow and aid disease classification, including analysis of tissue sections by in situ sequencing [ ].
The more obvious and immediate clinical application of single cell analysis techniques, however, is in cancer diagnostics, for example, to identify new biomarkers for prediction of prognosis or response to candidate therapies in order to help refine personalized medicine.
Normal and malignant hematopoiesis | Oncogene
Using single cell approaches to analyse non-clonally involved cells can also be informative for prognosis; we recently demonstrated the potential prognostic utility of scRNA-seq in patients with CML through analysis of inflammatory signatures in the non-leukemic HSC compartment [ ]. Single cell gene expression analysis has also been shown to predict response to certain therapies in multiple myeloma [ ].
Another possible application of single cell techniques includes use of single cell approaches for minimal residual disease MRD detection. Indeed, flow-cytometry based MRD analysis a single cell method is already in clinical use for leukemia monitoring [ ]. In a recent proof of concept study, massively-parallel RNA-sequencing has also been used to establish the percentage of host versus donor chimerism in bone marrow mononuclear cells of two patients who underwent hematopoietic stem cell transplantation [ ].
This study illustrates how single-cell technologies can aid treatment monitoring and at the same time provide biological insights into the characteristics of these residual cells. This principle could also be applied to cancer patients receiving therapy, with single-cell analysis applied to monitor for the presence of therapy-resistant cells at earlier stages allowing early clinical intervention. Whilst considerable hurdles remain before new single cell genomics techniques can be applied directly in the clinic for patient benefit, the next few years are likely to see extensive efforts towards translation of this new technology towards personalized medicine, including biomarker identification to predict response to specific therapies, prognostic risk stratification, MRD detection and therapeutic target discovery.
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Keywords: Hematopoietic stem cell, single cell RNA-seq, hematopoiesis, leukemia, genomics, heterogeneity. Introduction The hematopoietic system is perhaps the best-defined model of cellular differentiation due to ease of access, readily identifiable mature blood lineages and plethora of in vitro and in vivo assays. Open in a separate window. Figure 1. Timeline illustrating key developments in the application of single-cell assays in hematopoiesis.
Single cell analysis and normal hematopoiesis 2. Limitations of phenotypically defined cell populations in hematopoiesis The ability to prospectively isolate immunophenotypic subsets of bone marrow was established through the use of monoclonal fluorescent antibodies and fluorescence-activated cell sorting FACS, Figure 2A , pioneered by the Weissman laboratory. Figure 2.
Unique insights gained through single cell techniques in hematopoiesis. Single-cell functional assays in hematopoiesis Hematopoiesis has the considerable advantage of an array of in vitro and in vivo single-cell assays [ 9 , 11 ]. Figure 3. Single cell analysis applied to understand the hematopoietic roadmap.jira.uptrail.com/4853-cell-phone-skype.php
Single cell gene expression analysis applied to hematopoiesis In parallel with single cell functional assays, early single cell gene expression analysis of HSPC provided evidence of transcriptional lineage-priming, preceding lineage specification [ 25 ]. Other single cell analysis approaches applied to hematopoiesis Another exciting technical development in single cell analysis is the ability to measure multiple proteins expressed by single cells through mass cytometry. Integrating multiple single cell approaches in hematopoiesis Linking together analysis of gene expression and cellular function at the single cell level is a potentially very powerful approach.
Analysis of intratumoral heterogeneity with single cell analysis Solid tumors are characterized by the serial acquisition of consecutive genetic lesions, sometimes in a linear fashion, but more often leading to a complex subclonal structure which is generated through branched and convergent patterns of evolution Figure 4A [ 81 ]. Figure 4. Concepts and applications of single cell genomics in resolving heterogeneity during malignant hematopoiesis. Resolving transcriptional and epigenetic heterogeneity Tumor heterogeneity is not restricted to different genetic subclones, as molecular heterogeneity in cancer also reflects different transcriptional and epigenomic states [ ].
Hierarchical organization of hematopoietic tumors There is a growing body of evidence suggesting that some tumors are organized in a cellular hierarchy, with cancer stem cells CSC , which are the cells responsible for initiating and propagating the disease, residing at the apex of that hierarchy [ 82 , ] Figure 4B. Single cell analysis of therapy resistant mechanisms in malignant hematopoiesis Intratumoral heterogeneity is closely linked to therapy resistance [ 81 , ], raising the possibility that single cell analysis could be applied to identify and characterize subpopulations of cells that are selectively resistant to the treatment Figure 4C.
Bibliography 1. Hematopoiesis: an evolving paradigm for stem cell biology. Heterogeneity and hierarchy of hematopoietic stem cells. Exp Hematol. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells.
Brenner S. Life sentences: Hunters and gatherers. Genome Biology. Purification and characterization of mouse hematopoietic stem cells. Uchida N, Weissman IL. Searching for hematopoietic stem cells: evidence that Thy J Exp Med. Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell. Doulatov S, et al. Hematopoiesis: a human perspective. Ema H, et al.
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