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Notch receptors regulate many aspects of metazoan development and tissue renewal, such as binary cell-fate decisions, survival, proliferation and differentiation, in different cell types and in a context dependentmanner.
In hematopoiesis, Notch signalling actively contributes to Tcell development by driving hematopoietic stem cell- HSC- derived progenitors seeding the thymus into the T-cell lineage, while simultaneously avoiding alternative cell fates. According to this critical role, deregulated Notch signalling has important consequences in T-cell generation, survival and proliferation during thymopoiesis, and significantly contributes to the generation of T-cell acute lymphoblastic leukemias T-ALL.
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Therefore, understanding Notch-dependent molecular pathways that control physiological and pathological development of T-cell progenitors within the thymus has become an intensive artjculos of research in recent years. In this review, we highlight recent studies on Notch that reveal new molecular details about how Notch signalling guides human thymic immigrants along the Hematopoyseis lineage and how deregulated activation of Notch can contribute to T cell leukemogenesis, in part by directly regulating expression of the IL-7R.
Hematopoietic stem cells HSCs give rise to all blood lineages, except T-cells, in a limited number of specialized niches within the fetal liver or the adult bone marrow. T lymphocytes are a unique exception, as their development takes place gematopoyesis a dedicated lymphoid organ, the thymus.
The generation of T lymphocytes from HSCs-derived precursors that seed the thymus is an orchestrated process specifically controlled by the thymic microenvironment Within hematpoyesis thymus, both interactions with surface molecules expressed by thymic epithelial cells TECs and response to soluble factors produced by TECs are mandatory events, which enable the delivery of signals that are essential for directing early thymic progenitors ETPs along the T-cell linage.
Specifically, interactions of Notch receptors with their gematopoyesis expressed on TECs 6, 7 and signalling mediated through the interleukin 7 receptor IL-7R in response to IL-7 produced by TECs 8, 9 are crucial events that regulate thymopoiesis in both mouse and man. Notch signalling is required both to promote T-cell specification and commitment adticulos multipotent progenitors MPPs that seed the thymus and to block intrathymic development of alternative cell fates, including myeloid, B or natural killer NK lineages 1, srticulos, Figure 1.
Once Tcell specification is achieved, survival and proliferation of T-cell precursors is induced at two successive checkpoints. Interestingly, several studies have pointed toward a prominent role of Notch signalling in the regulation of the latter proliferation events 21, 22while others have suggested the implication of Notch in the former Therefore, understanding the molecular basis that control Notch-dependent function in T-cell precursors and hematopooyesis malignant counterparts is an important issue that offers the opportunity of developing novel targeted therapies against this type of cancer.
Aimed at improving our knowledge of Notch l function on normal and leukemogenic human Tcell development, we have recently approached gain- and loss-of-function studies that have provided evidence of a crucial interplay between Notch l and IL-7R pathways 24which underscores the molecular bases of Notch1-IL-7R functional interactions in physiology and pathology and represents the focus of this review.
Proposed model of lymphoid and myeloid differentiation pathways in the human thymus. Early thymic progenitors ETPs seeding the thymus from bone marrow are multipotent, as they can differentiate into both myeloid- dendritic cells, macrophages and natural killer NK cells or lymphoidlineage cells T cells and NK cellsthrough intermediate myeloid- or lymphoid-primed progenitors, respectively.
Notch1 signaling promotes T-cell differentiation from ETPs by blocking the generation of intermediate myeloid progenitors thus favoring the lymphoid cell fate. Schematic representation of human intrathymic T-cell developmental stages. Two major waves of proliferation regulated by Notch1 signalling guarantee the generation of the T-cell pool.
The hematopoietic system of mammals produces billions of mature blood cells every day in response to physiological demand. HSCs resident in the bone marrow are ultimately responsible for maintaining the lifelong output of new blood cells owing to their pluripotency and extensive self-renewal capability.
All blood lineages but T cells derive in situ within the bone marrow from HSCs through a process characterized by the progressive loss of developmental potentials and the activation of lineage-specific transcriptional programs, which ultimately define gematopoyesis specialized function of the mature cell. T lymphocytes, however, develop within the thymic microenvironment from HSCs-derived progenitors that have lost self-renewing capacity.
Notch 1 signalling in human T-cell development and leukemia | Inmunología
hematopoyesiz Therefore, the thymus requires periodic or continuous input of hematopoietic progenitors to maintain T cell development. These hematopoietic progenitors must traffic through the circulation from the bone marrow to enter the adult thymus at the corticomedullary junction, and progeny of these entering cells occupy the perimedullary cortical zone, before migrating outward toward the subcapsular zone where substantial proliferation occurs.
Thymic progenitors develop through successive developmental stages that are generated in different stromal niches in the thymus owing to cellular interactions with stromal cells, mainly TECs that deliver Notch and other signals hematopoyesls are essential for intrathymic T cell differentiation 1, The particular identity of the thymus immigrant population has been a matter of debate during the last years, principally because only a few cells are required for efficient thymopoiesis Such ETPs, which represent 0.
A great advance towards understanding how Hematopoyeesis undergo T-cell development within the thymus was obtained from initial studies in humans, and later confirmed in mice. These studies showed that such ETPs are multipotent lympho-myeloid progenitors LMPs that retain the capability of developing into NK cells, myeloid cells such as macrophages and dendritic cells DCsand even give rise to granulocyte-macrophage GM colonies, in addition to T-ceUs 14′ Figure 1.
ETPs can also generate B cells 28, 37although at low frequencies, suggesting that the B-cell potential of thymus immigrants is lost immediately after thymus entry T-cell aarticulos has been proposed to occur sequentially in the mouse In humans, however, progression towards the T- lineage fate involves an early split of ETPs into two alternative developmental pathways that proceed through independent myeloid- or lymphoid-primed intermediate progenitors Figure 1characterized by downregulation of CD34 and the simultaneous up or downregulation of CD44, associated with exclusive expression of receptors for either GM-colony-stimulating factor GM-CSF or IL-7, respectively As the numbers of progenitors that enter the thymus are limited, an enormous expansion takes place during the DN1 and DN2 stages 8.
Downregulation of CD1 at the SP stage marks acquisition of functional maturation of human thymocytes 49 followed by migration to the periphery as MHC-restricted selftolerant T-cells Figure 2.
Although there is now ample evidence that intrathymic T-cell development is a stepwise Notch-dependent process, the particular role that Notch signalling plays at successive stages of early thymopoiesis is still not fully understood and current knowledge on this issue is described below. Notch receptors represent a highly conserved family of transmembrane proteins 50 comprising four members Notch in mammals. Notch receptors are synthesized as a kDa precursor that is fucosylated in the endoplasmic reticulum and is cleaved at hematopoywsis S1 site in the trans-Golgi network by a furine-like convertase.
The resulting fragments are non-covalently associated into a mature heterodimer receptor that is exported to the cell surface The extracellular EC domain of Notch contains tandem epidermal growth factor EGF -like repeats, some of which mediate interactions with the Notch ligand Figure 3a.
The EC domain is followed by a unique negative regulatory region NRR composed of three Lin Notch repeats LNR and a heterodimerization domain HDresponsible for stable subunit association, which maintains the receptor in an inactive conformation in the absence of ligand ANK repeats associate with coactivators of the Mastermind-like family MAMLwhich are obligatory for Notch signalling 53, 54while the PEST domain regulates protein stability through targeting by ubiquitin ligases required for proteosome-dependent Notch degradation and thereby for termination of signalling 55 Figure 3a.
Structure and function of Notch receptors. Ligand affinity can be modulated by glycosylation of O-linked fucose residues attached to EGF-repeats by the Fringe family of glycosyltransferases, specifically Lunatic Fringe in T-cell development Notch l-deficient mice showed a smaller thymus with a 5-fold reduction in total thymocyte numbers and an abnormal architecture of both cortical and medullar thymic regions.
Complementary to these findings, gain-of-function approaches showed that Notch1 was sufficient to promote extrathymic T-cell development 7.
When hejatopoyesis marrow HSCs cells genetically modified to express constitutively active ICN1 were transferred into irradiated hosts, a thymus-independent DP T-cell population appeared hematoooyesis the bone marrow and B cell differentiation was completely inhibited.
However, the CLP concept 64 has recently been challenged by the emergence of revisited models of hematopoiesis 65, 66 supporting a closer relationship between lymphoid and myeloid lineages than “conventional” models 67 Figure 4 and, articlos, by the finding that lymphoid-primed multipotent lympho-myeloid progenitors, rather than CLPs, include the canonical T-cell precursors in the postnatal hemato;oyesis 13, Accordingly, the initial proposal on the role that Notch signalling hemaropoyesis in early thymopoiesis was re-examined.
Classical and alternative models for adult hematopoietic stem cell lineage commitment. Classical model for hematopoietic development postulates that lineage commitment of long-term hematopoietic stem cells LT-HSCs underlies an strict separation of myelopoiesis and lymphopoiesis that involve independent CMP and CLP progenitors, respectively.
The alternative model suggests that HSCs give rise to a lymphoid-primed intermediate progenitors that retain myeloid potential upon loss of Mk and E potential. Generation of T cells from these progenitors occurs upon loss of B cell potential and independent generation of CLPs. Both strategies provided evidence that the most prominent role of Notch1 signalling in early human T-cell development is to block non-T cell differentiation Figure 1.
Inhibition of non T cell fates by active Notch1 promotes the exclusive development of T-lineage cells and results in the transcriptional induction of specific T-lineage genes63a finding that supports an instructive role of Notch1 in T-cell specification. However, while Notch activation itself is sufficient to block non-T cell development, additional stromal-derived inductive signals are concurrently required to promote full differentiation along the T-cell lineage.
Hematopoyesis extramedular renal: Caso clínico
Thus, Notch signalling was proposed to play a key role in the maintenance and expansion of HSCs and thymic progenitors. Importantly, Notch-induced cell proliferation of both HSCs and ETPs was found dependent on unique signals provided by cytokines see below. Experimental strategies used to analyse the impact of Notch1 signalling in hematopoyesjs T-cell differentiation.
Different studies have focussed on the impact of either ligand-dependent or ligand-independent Notch signalling on the developmental potential of human ETPs. Ligandindependent Notch signalling articulks induced by retroviral transduction with a bicistronic vector encoding active ICN1 and green-fluorescent protein GFP as cell tracer.
Complementary loss-of-function approaches have been also designed in an effort to address the consequences of Notch signalling inhibition and to better understand the role of this pathway in early T-cell development. Gammasecretase inhibitors GSIsmall pharmacological molecules that block Notch cleavage 75have been particularly useful as inhibitors of Notch signalling in vitro.
Artkculos strategies supported the proposed regulatory function of Notch1 in the amplification of the intrathymic pool of T-cell progenitors 14, However, recent in vivo studies on Notch inhibition in mouse ruled out an essential physiological hematopoeysis for canonical Notch signals in maintenance and expansion of more immature HSCs 77despite pioneering gain-of-function studies by Irvin Bernstein and coworkers supported the involvement of Notch signalling in self-renewal of HSCs Whether these discrepancies rely on the experimental strategy used, or reflect a differential contribution of Notch to hematopoiesis under steady state or stress conditions remains to be clarified.
Loss-of-function studies also confirmed that Notch signalling is essential to impair intrathymic differentiation of non-T lineage cells. How thus is Notch signalling regulated in quantitative terms?. Particularly, Jagged ligands seem to induce lower Notch activation in comparison with DL ligands 57suggesting that expression of distinct Notch ligands at particular intrathymic locations could be responsible for the existence of different Notch activation thresholds along thymopoiesis.
However, formal proof was recently provided that DL4 is the essential, nonredundant ligand for Notch1 during thymic T-cell lineage commitment 81 and, therefore, alternative mechanisms such as differential regulation of DL4 expression levels may underlie the quantitative control of Notch signalling within the thymus.
However, it is becoming increasingly clear that, once in the periphery, cell-fate and functional differentiation of T cells might critically depend on Notch signals 9l. However, the field remains controversial and more studies, including genetic approaches in mice made deficient for the different Notch ligands, as well as identification of critical effectors of the Notch pathway, are needed hfmatopoyesis reach a general conclusion about the role of Notch signalling in those processes.
As described above, two main phases of cellular proliferation occur after thymus settling to generate the abundant population of DP thymocytes, one before and the other after induction of TCR gene rearrangements Figure 2. IL-7 is a 25 kDa cytokine produced by stromal cells within the bone marrow and the thymus that transmits signals for survival and proliferation to T and B cells. Interleukin 7 receptor signaling pathway.
Raticulos cycle induction is mediated by degradation of the cell cycle inhibitor p27Kip1, in a PKC-dependent fashion. The stage-specific function of IL-7 during intrathymic development is accomplished by a dynamic regulation of IL-7R expression and function To further guarantee IL-7R-unresponsiveness, obligatory for development of DP thymocytes 98IL-7R signalling is actively suppressed in pre-selection DP thymocytes by suppressor of cytokine signalling SOCS -1, but it is restored by positive selection Moreover, down-regulation of IL-7R expression during thymopoiesis zrticulos required to avoid a direct competition between DN progenitors and DP thymocytes for the limiting amounts of endogenous IL-7 within the thymus Hematopoyesie results point toward the pro-survival function as the most important function of IL-7 during T-cell development.
The stage- and lineage-specific functions reported for IL-7 indicate that strict mechanisms may control the dynamic regulation of IL-7R expression in the thymus and its differential expression in T- and B-lineage cells during lymphopoiesis. Formal proof that Notch1 directly controls IL7R gene expression in developing T cells was provided by luciferasereporter and chromatine immunoprecipitation assays showing that IL7R is indeed a downstream target of Notch1 in human thymocytes PEST mutations are short insertions or deletions that result in partial or complete absence of PEST domain, thus increasing Notch1 stability and half-life T-ALLs, initially linked to a very poor prognosis, have shown an improved outcome in recent years due to intense chemotherapy treatments.
Investigators have therefore focused on understanding the molecular mechanisms downstream of Notch1 responsible for disease induction and maintenance, with the final aim of identifying new therapeutic targets for T-ALL based on Notch1 inhibition.
Several Notch-related molecular pathways involved in normal T-cell development have been implicated in Tcell transformation. Initial studies showed that mice transplanted with bone marrow progenitors expressing active Notch1 alleles rapidly develop aggressive T cell leukemias 7,but only when signalling mediated by the pre-TCR hematoopyesis was intact These results supported a synergistic role between Notch1 and pre-TCR signalling in leukemogenesis, as also shown for the Notch3 receptor Whether the two pathways act in a linear or in a parallel way remains an open question.
It is therefore possible that the Notch pathway could be upstream of pre-TCR expression. An alternative possibility is that Notch1 and pre-TCR pathways act in parallel but converge at signalling intermediates in T-ALLs, as both pathways can activate the transcription factors cmyc, NF-?? According to this second view, c-myc, which is a crucial regulator of cellular metabolism and cell cycle progression, has been identified as a key target in Notch1-dependent leukemogenesis 59, In fact, conditional ablation of c-myc in ICN1-expressing DP cells prevents tumour formation, indicating that both ICN1 and c-myc are required for tumour maintenance Similarly, Notch1 signalling leads to activation hematkpoyesis the NF-??
Therefore, although therapeutic strategies directed to Notch1 inhibition, particularly treatment with GSI, initially emerged as a promising therapy owing to its ability to decrease Notch1 expression and leukemic cell viability 23our more recent knowledge of the molecular pathology of the disease demands the design of novel targeted therapies. The study of the molecular mechanisms regulated by Notch1 activation in human T-cell development and T-cell leukemias higomplex in response to Notch1.
Therefore, understanding Notch1 signalling effectors involved in physiologic and oncogenic proliferation is crucial for designing new therapeutic strategies that target relevant oncogenic pathways in T-ALLs. Indeed, the most prevalent artiuclos of Notch1 in T-cell development is the induction of cellular expansion: