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Try out PMC Labs and tell us what you think. Learn More. T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium aling and ion channels.
We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility. T cell acute lymphoblastic leukemias T-ALL are aggressive neoplastic disorders of the lymphoblasts committed to the T lineage. It is widely accepted that the T cell leukemogenesis is tightly related to the normal T cell development. Various genetic errors during T cell maturation may cause the healthy progenitor to convert into a leukemic precursor cell that lost its ability to differentiate but possesses high potential for proliferation and self-renewal.
Accordingly, leukemogenesis is a multistep process, where the genes encoding proteins implicated in the normal T cell development are deregulated.
Among them there are transcriptional factors and tumor suppressors, receptors and al transduction molecules, secreted molecules and growth factors, ion channels, and transporters. Specific genetic alterations define distinct groups of T-ALL with different profiles and levels of gene expression denominated as a gene expression ature.
Moreover, gene expression atures may vary in every special clinical case. Although numerous experimental and clinical reports and detailed reviews dealing with T-ALL are available, the relationships between various components of transcriptional and aling regulatory networks are very complex and many issues are still to be addressed. In the present review we are going to reveal a relationship Local adult chat Talmay different abnormalities that drive the T cell neoplasias, with special accent on those occurring in the expression of ion channels in this type of lymphoproliferative disorders.
We suggest that changes in regulation of various ion channels in different types of the T-ALL may provide an Local adult chat Talmay ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation in T cell precursors, and enhance their motility.
We first review normal T cell maturation and recurrent cytogenetic abnormalities reported in the T-ALL, with their relation to main aling pathways that contributed to leukemogenesis. And finally, we will discuss the possibility of targeting ion channels to improve the existing protocols of the T-ALL treatment. It is widely accepted that T leukemogenesis is a multistep process where several genetic lesions drastically mislead the normal thymocyte maturation [ 2 ].
A short overview of key events in early thymocyte development and their links to the leukemogenesis is presented at Figure 1. Hierarchical mutagenesis during T cell maturation causes different types of T-ALL see text for details. T cells can be distinguished from other lymphoid lineages by the presence of the unique antigen-specific T cell receptor TCR on the cell surface. Each of the several millions of T cells circulating in the organism possesses a unique TCR capable of recognizing its own MHC molecules, which present specific antigenic structure, distinct for every T cell clone and without cross-reactivity to self-antigens.
Maturation of self-tolerant T cells, which differ in specificity of their TCR receptors and which are restricted to self-MHC, takes place in the thymus. The genomic locus coding every TCR chain contains gene clusters corresponding to the variable Vthe diversity Dthe Jand the constant C regions. Functional TCR genes are produced by the recombination process that assembles V, D, J, and C segments dispersed along a large genetic locus into a single transcriptable gene.
At this phase, only those thymocytes survive, in which genetic rearrangements were productive and resulted in the appearance of a final unique lineal coding sequence of TCR chains. The apoptotic program is triggered in the rest of cells, which managed the rearrangement task poorly [ 56 ]. At the late DN2 stage, T cell precursors are fully committed to the T cell lineage and reduce expression of both c-kit and CD Cellular differentiation involves epigenetic changes that regulate the transcription of genes encoding lineage-specific proteins and pluripotency factors.
Developmental stage-specific regulation of transcriptional accessibility helps control V D J or VJ recombination. T cells that recognize self-MHC molecules and peptides with high affinity are deleted from the repertoire of cells during negative selection, providing self-tolerance [ 7 ]. Key steps in T cell maturation are controlled by several transcriptional regulators.
Notch aling pathway is evolutionarily conserved and operates in many cell types of different tissues at various developmental stages [ 11 ]. It is an important coordinator of different stages of the T cell maturation prior to the DP stage, including self-renewal of common lymphoid progenitor CLPcommitment decision of the CLP toward T cell versus B-cell fate choice, and assembly of pre-TCR in immature thymocytes [ 21213 ].
Mammals possess four Notch receptors Notch 1—4 and five corresponding ligands Delta-like 1, 3, 4, and Jagged 1 and 2. Subsequently ICN translocates to the nucleus, to form a part of the large transcription activator complex. Notch aling is regulated at multiple levels. Primarily, expression of Notch receptors and their ligands is restricted to a certain cell population within certain context.
Another level of regulation is to insure that ICN is a short-lived protein, due to ubiquitylation within its degradation Local adult chat Talmay domain rich in proline Pglutamic acid Eserine Sand threonine T [ 11 ]. Notch1 activation in maturing thymocytes occurs upon engagement with its ligand, expressed on the thymic stromal cells [ 1415 ]. Myc exhibits a steady expression at early stages and an abrupt drop in DP thymocytes [ 16 ]. The preTCR expression shuts down Notch aling and therefore negatively regulates these mitogenic pathways [ 10 ].
Other important regulators of T cell maturation are numerous cytokines, produced by thymocytes themselves or by thymus stromal cells [ 22 ]. Among them, IL-2 and IL-7 are of special importance. IL-2 is an autocrine factor coming into the play as early as at DN2 see above and regulating the TCR-dependent clone expansion from this moment over the entire life of a T cell.
In contrast, IL-7 is paracrine thymic cytokine produced by stromal cells in subcapsular zone, where DN cells are located. IL-7 participates in a coordination of the basic processes of early thymocyte development, namely, survival through Bcl-2 upregulationproliferation, and TCR rearrangement.
As far as neoplastic transformation may occur at different stages of T cell differentiation Figure 1T-ALLs represent a very heterogeneous group of tumors with regard to their immunophenotype, cytogenetic, and clinical features and response to treatment. Arrest of differentiation program at specific stage of normal thymocyte development is a priming event in the T leukemogenesis.
Simultaneously, uncontrolled cell growth and clonal expansion occur as a result of several mutations in Local adult chat Talmay genes, involved in regulation of cellular metabolism, cell cycle control, and self-renewal of stem cells. The most of T-ALL oncogenes are downregulated at early stages of the thymocyte development or are not at all expressed in the normal thymus. Different mechanisms of genetic structural rearrangements are implicated in the T-ALL leukemogenesis: 1 translocations involving TCR loci, 2 gene fusion encoding chimeric proteins, and 3 deletions of tumor suppressive genes.
As a result, corresponding gene is upregulated activating mutation or downregulated suppressing mutation for detailed review, see [ 2 ]. A hierarchical model of mutations, which contributed to the T leukemogenesis, was recently proposed [ 23 ]. In accordance with this model, the leukemogenesis occurs in several consequent steps Figure 1. At the first stage, genetic alterations of transcription factors, leading to the activation of self-renewal program, occur in the immature T cell progenitors and generate the preleukemic stem cells pre-LSCs.
Self-renewal phenotype is essential for acquisition and accumulation of subsequent mutations. Activating mutations of aling pathways important for T cell maturation allow expansion of pre-LSC, independent of the thymic microenvironment niche. Partner oncogenes, involved in the TCR gene translocation, encode developmentally regulated transcription factors and aling molecules. They are transcribed simultaneously at early stages of the thymocytes maturation and possess open chromatin configuration, which is vulnerable to the action of recombinase enzymes RAG1 and RAG2.
As a result, target genes are put adjacent to strong promoter or enhancer elements of the TCR genes. The data about frequency of cytogenetic and molecular changes in T-ALL clinical cases are reviewed in detail elsewhere [ 226 ]. Here we present summarizing remarks of the most frequent genetic lesions. TLX1 and TLX3 are normally involved in the early embryogenesis being implicated in the organogenesis and differentiation of specific cell types. They are not expressed in developing T cells but seem to be involved in spleen development.
In leukemogenesis, they are the most frequent aberrantly expressed genes becoming active due to the translocation involving the TCR loci [ 128 ]. The LYL1 gene is not normally expressed in T lineage. LYL1 reflects an early arrest in the T cell differentiation. LYL was shown to be also important for the angiogenesis [ 27 ].
It is involved in the embryonic and adult hematopoiesis and in the angiogenesis but is not normally expressed in maturating T cells. Genetic evidences that the TAL-1 aberrant overexpression may involve t 1;14 pq11 translocation or submicroscopic interstitial 1p32 deletion with resulting fusion of TAL1 with SIL promoter were provided.
Since Notch coordinates self-renewal program of early lymphoid progenitors, activating Notch1 mutations increase the self-renewal capacity of the LSC, resulting in their susceptibility to acquire and accumulate additional genetic abnormalities. Thus, Notch1 aling deregulation is considered to be crucial for the T cell leukemogenesis.
Most common causes in Notch1 aling deregulation are activating mutations clustered in regions coding HD and PEST domains [ 38 ], whereas HD mutations seem to enable the ligand-independent Notch cleavage resulting in the constitutive activation of the Notch Local adult chat Talmay [ 39 ], PEST domain mutations are thought to stabilize the structure and prolong the half-life of the active Notch 1 [ 40 ]. Additionally, the half-life of Notch protein may be also increased due to loss-of-function mutations in the FBXW7 gene, coding for a component of ubiquitin ligase complex.
The FBXW7 mutations result in inability to bind to its target proteins Notch1 or bind its targets but fail to tag them for degradation Mycin both cases prolonging their half-life. Aberrant Notch1 activation in T-ALL is suggested to promote deregulated proliferation and prevent apoptosis. Most important genetic lesions and aling pathways are indicated, together with percentages for each type of lesion recognized in clinical cases. For more details, see the text. The question whether Notch aberrant expression is sufficient to induce T-ALL on its own was addressed.
For this, different human gain-of-function Notch1 alleles were tested for their ability to drive an ectopic T cell development and to induce leukemia, when expressed in murine bone marrow progenitors [ 4050 ]. It was shown that the induction of the T cell leukemia is dependent on the Notch1 al strength. Only rare Notch1 mutations with strong downstream aling were able to drive the T cell leukemia per sewhereas common weak gain-of-function alleles were effective only in combination with a constitutively active Ras oncogene; nonetheless they gave rise to tumors sensible to inhibition of Notch1 aling.online adult chat
Thus, Notch1 mutations, being indispensable for the majority of clinical T-ALL, require additional mutations in order to drive the leukemogenic process. Ras proteins play a critical role in the transmission of survival als from the cell membrane receptors to the intracellular transduction pathways. Mutations of RAS genes are common and have been described in various malignancies including acute leukemias [ 2 ]. The interest to identify these aberrations resides in the fact that they involve tyrosine kinases, for which specific inhibitors are known. These pathways are attractive candidates for a targeted therapy [ 51 ].
The AKT pathway plays a key role in the cell cycle progression and differentiation. Genetic abnormalities that cause leukemia should meet a special favorable microenvironment to be realized. Antigen recognition through TCR receptor is a key event in the T lymphocyte physiology, leading to cell activation, clone expansion, and differentiation to effector cells reviewed in [ 57 ].
CD45 dephosphorylates inhibitory tyrosine of membrane-localized Src family kinases Fyn and Lck, ly recruited and activated by CD4 or CD8 co-receptors. NFAT activity is regulated by its phosphorylation status. Under resting conditions, NFAT is highly phosphorylated. During activating events, dephosphorylation of multiple sites by Cn causes a conformational switch of NFAT protein that allows its translocation to the nucleus. Once inside the nucleolus, NFAT cooperates with multiple transcriptional partners and binds to specific DNA response elements to regulate the transcriptional program, which is specific for every cell type and for the stimulation pattern [ 6465 ].
Later it was shown that this pathway regulates the expression of numerous genes, including cytokines, as well as genes, encoding proteins involved in the regulation of survival and proliferation, apoptosis, and cell cycle [ 6465 ]. TCR aling coordinates thymocytes maturation as well [ 6 ]. The ligand-independent nature of pre-TCR aling has been attributed to its localization closely to other aling molecules in lipid rafts and to the relatively low aling threshold of pre-T cells [ 7172 ]. Notch1 is considered as a probable candidate for this aling molecule, because the interaction between Notch and its Delta-like ligand expressed at stromal cells indeed plays an essential Local adult chat Talmay in enabling the autonomous aling capacity of the pre-TCR complex [ 1773 ].
These findings provided a functional basis for the observed pattern of the Notch receptor expression and activation in developing thymocytes, since several reports have showed that levels of Notch1 and Notch3 expression and activity are ificantly higher in the DN than in the DP thymocytes [ 1074 — 76 ]. The current working model suggests that the interaction strength between the TCR and the self-MHC complex determinates the destiny of maturated thymocyte. Little-or-none al means that this thymocyte is unable to recognize self-MHC and will undergo death by neglect.
A too strong al will lead to a negative selection to avoid a generalized T cell aggression toward self-tissues. Only als of intermediate range will culminate in survival positive selection [ 6 ]. By Cn inactivating during haematopoietic development, it was demonstrated that this aling pathway plays an important, nonredundant role in the regulation of lymphocyte developmental checkpoints, in contrast to development of myeloid lineages [ 78 ].
More specifically, absolute requirement for Cn in positive but not in negative selection was demonstrated [ Local adult chat Talmay ]. NFAT is upregulated during the T cells maturation [ 1819 ]. Nevertheless, there are still few studies on this subject.
It was suggested that it may activate the Cn- and Erk-dependent pathways, leading to the survival and maturation. Loss-of-function STIM1 mutations were also reported in human patients [ 87 ]. Clinically, they demonstrated severe immunodeficiency with susceptibility to viral and bacterial infections, but practically normal T cell repertoire.
The latter clearly indicates that the T cell maturation was not greatly affected. There are some evidences in favor of this hypothesis. They did not reveal any uniform profile characteristic for cancerous cells [ 90 ]. Rather, they point out to some potentially predictable consequences of the trends.
Therefore it looks that question about these kinds of alterations should be addressed specifically for every type of tumors. Proliferation of leukemic cells is obviously antigen-independent. The cytoplasmic and then membrane expression of CD3 is an early event in the T cell ontogeny [ 94 ]. Then the presence of CD3, either at the surface sCD3 or in the cytoplasm cCD3is a determinative feature of these malignances [ 94 ].
TCR genes rearrangements are found in a majority of the T-ALL; the presence of TCR chains at the surface or in cytoplasm is mostly characteristic for mature stages [ 95 ]. TI leukemias do not possess the TCR chains [ 2 ].
In some animal models like E2A-deficient mice, defects that prevent the pre-T cell antigen receptor expression even tend to accelerate the Notch-dependent lymphomagenesis [ 96 ]. It has been observed that the pre-TCR assists leukemogenesis, driven by the Notch activation [ 97 — 99 ], c-Myc overexpression [ ], or Ikaros deficiency [ ].
Some of these studies are described in more detail below.Local adult chat Talmay
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