Gene Summary

Gene:MTCP1; mature T cell proliferation 1
Aliases: p8MTCP1, P13MTCP1
Summary:This gene was identified by involvement in some t(X;14) translocations associated with mature T-cell proliferations. This region has a complex gene structure, with a common promoter and 5' exon spliced to two different sets of 3' exons that encode two different proteins. This gene represents the upstream 13 kDa protein that is a member of the TCL1 family. This protein may be involved in leukemogenesis. [provided by RefSeq, Mar 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein p13 MTCP-1
Source:NCBIAccessed: 29 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Proto-Oncogene Proteins
  • Gene Deletion
  • Cytoplasm
  • Ataxia-telangiectasia
  • T-Lymphocytes
  • Amino Acid Sequence
  • Oncogenes
  • X Chromosome
  • Oncogene Proteins
  • Leukemic Gene Expression Regulation
  • Leukaemia
  • Mutation
  • Tumor Suppressor Proteins
  • Mice, Transgenic
  • Messenger RNA
  • Sequence Alignment
  • Leukemia, Prolymphocytic, T-Cell
  • Transcription Factors
  • Gene Expression
  • Cancer Gene Expression Regulation
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Chromosome 14
  • Disease Models, Animal
  • T-Cell Leukemia
  • Base Sequence
  • Polymerase Chain Reaction
  • Translocation
  • Janus Kinase 3
  • Cohort Studies
  • Xenograft Models
  • DNA Sequence Analysis
  • DNA Primers
  • Leukemia, Prolymphocytic
  • Immunophenotyping
  • DNA, Complementary
  • Sequence Homology
  • RHOA
  • Molecular Sequence Data
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MTCP1 (cancer-related)

López C, Bergmann AK, Paul U, et al.
Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia.
Br J Haematol. 2016; 173(2):265-73 [PubMed] Related Publications
T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.

Stengel A, Kern W, Zenger M, et al.
Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker.
Genes Chromosomes Cancer. 2016; 55(1):82-94 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell neoplasm with aggressive clinical course and short overall survival. So far, due to the rareness of this disease, genetic data are available only from individual cases or small cohorts. In our study, we aimed at performing a comprehensive cytogenetic and molecular genetic characterization of T-PLL comprising the largest cohort of patients with T-PLL analyzed so far, including correlations between the respective markers and their impact on prognosis. Genetic abnormalities were found in all 51 cases with T-PLL, most frequently involving the TCRA/D locus (86%). Deletions were detected for ATM (69%) and TP53 (31%), whereas i(8)(q10) was observed in 61% of cases. Mutations in ATM, TP53, JAK1, and JAK3 were detected in 73, 14, 6, and 21% of patients, respectively. Additionally, BCOR mutations were observed for the first time in a lymphoid malignancy (8%). Two distinct genetic subgroups of T-PLL were identified: A large subset (86% of patients) showed abnormalities involving the TCRA/D locus activating the proto-oncogenes TCL1 or MTCP1, while the second group was characterized by a high frequency of TP53 mutations (4/7 cases). Further, analyses of overall survival identified JAK3 mutations as important prognostic marker, showing a significant negative impact.

Bergmann AK, Schneppenheim S, Seifert M, et al.
Recurrent mutation of JAK3 in T-cell prolymphocytic leukemia.
Genes Chromosomes Cancer. 2014; 53(4):309-16 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either the TCL1 or MTCP1 gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations in JAK3 have been identified in other T-cell malignancies. Since JAK3 is essential for T-cell maturation, we analyzed a cohort of 32 T-PLL patients for mutational hot spots in the JAK3 gene using a step-wise screening approach. We identified 14 mutations in 11 of 32 patients (34%). The most frequently detected mutation in our cohort was M511I (seen in 57% of cases) previously described as an activating change in other T-cell malignancies. Three patients carried two mutations in JAK3. In two patients M511I and R657Q were simultaneously detected and in another patient V674F and V678L. In the latter case we could demonstrate that the mutations were on the same allele in cis. Protein modeling and homology analyses of mutations present in other members of the JAK family suggested that these mutations likely activate JAK3, possibly by disrupting the activation loop and the interface between N and C lobes, increasing the accessibility of the catalytic loop. In addition, four of the 21 patients lacking a JAK3 point mutation presented an aberrant karyotype involving the chromosomal band 19p13 harboring the JAK3 locus. The finding of recurrent activating JAK3 mutations in patients with T-PLL could enable the use of JAK3 inhibitors to treat patients with this unfavorable malignancy who otherwise have a very poor prognosis.

Le Toriellec E, Despouy G, Pierron G, et al.
Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia.
Blood. 2008; 111(4):2321-8 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is consistently associated with inactivation of the ATM gene and chromosomal re-arrangements leading to an overexpression of MTCP1/TCL1 oncoproteins. These alterations are present at the earliest stage of malignant transformation, suggesting that additional events are required for overt malignancy. In this study, we pursued the investigation of the 12p13 deletion, previously shown to occur in approximately half of T-PLLs. We refined the minimal region of deletion by single nucleotide and microsatellite polymorphism allelotyping. We defined a 216-kb region containing the CDKN1B gene that encodes the cyclin-dependent kinase inhibitory protein p27(KIP1). Sequencing this gene in 47 T-PLL patient samples revealed a nonsense mutation in one case without 12p13 deletion. The absence of biallelic inactivation of CDKN1B for most patients suggested a haploinsufficiency mechanism for tumor suppression, which was investigated in an animal model of the disease. In a Cdkn1b(+/-) background, MTCP1 transgenics had consistent and multiple emergences of preleukemic clones not observed in control cohorts. The second Cdkn1b allele was maintained and expressed in these preleukemic clones. Altogether, these data strongly implicate CDKN1B haploinsufficiency in the pathogenesis of T-PLL.

Chun HH, Castellví-Bel S, Wang Z, et al.
TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal proliferations associated with ataxia-telangiectasia.
Int J Cancer. 2002; 97(6):726-31 [PubMed] Related Publications
We analyzed the role of 4 genes, TCL-1, MTCP-1, TML-1 and ATM, in the early pathogenesis of T cell leukemia, with particular interest in the characteristics of long-standing non-leukemic clonal proliferations in ataxia-telangiectasia (A-T) patients. Five patients were studied: 4 patients had A-T (2 of whom had non-leukemic clonal proliferations [ATCP]), 1 had B cell lymphoma and 1 had T-ALL; a fifth patient with T-PLL did not have A-T. We measured the levels of expression for TCL-1, MTCP-1 and TML-1. TCL-1, not expressed in unstimulated mature T cells, was upregulated in the peripheral blood leukocytes (PBL) of the 2 A-T patients with ATCP. It was also expressed in the malignant cells of the A-T patient with B cell lymphoma and the T-PLL cells of the patient without A-T. In the same cells, MTCP-1 type A was expressed equally in all 5 patients, as well as in the controls; MTCP-1 type B transcripts were not observed. TML-1, also not expressed in unstimulated T cells, was expressed in the PBL of one A-T patient with ATCP and in the leukemic cells of the non-A-T T-PLL patient. These expression patterns were compared to cellular immunophenotypes. The non-leukemic clonal T cell populations had the characteristics of immature T cells. We conclude that TCL-1 and TML-1 play a role in cell proliferation and survival but are not pivotal genes in the progression to malignancy, even when the ATM gene is mutated. Additional genetic alterations must occur to initiate tumorigenesis.

Herbert GB, Shi B, Gartenhaus RB
Expression and stabilization of the MCT-1 protein by DNA damaging agents.
Oncogene. 2001; 20(46):6777-83 [PubMed] Related Publications
The contribution of oncogene amplification and/or overexpression to T-cell lymphoid neoplasms has only of late been established with the implication of the TCL1 and MTCP1 genes in T-cell malignancies. Our laboratory has recently discovered a novel oncogene, MCT-1, amplified in a T-cell lymphoma and mapped to chromosome Xq22-24. MCT-1 has been shown to decrease cell-doubling time, dramatically shortening the duration of G(1) transit time and/or G1-S transition, and transforms NIH3T3 fibroblasts. Constitutive expression of MCT-1 results in a strong proliferative signal and is associated with deregulation of protein kinase-mediated G1/S phase checkpoints. In this study we analysed the level and subcellular localization of this novel cell cycle regulatory molecule as a function of cell cycle phase. In human lymphoid tumors expression of MCT-1 is constant throughout the cell cycle and remains cytoplasmic. Cells overexpressing MCT-1 have increased expression of cyclin D1 with dysregulation of the G(1)-S checkpoint. Both cyclin D1 and MCT-1 are involved in regulating passage of cells through the G1 phase of the cell cycle. Since prior work has shown that gamma irradiation induces cyclin D1 expression we investigated the induction of MCT-1 to DNA damaging agents. We demonstrate that increases in MCT-1 protein in irradiated human lymphoid cells do not occur at the mRNA level and do not require new protein synthesis.

Soulier J, Pierron G, Vecchione D, et al.
A complex pattern of recurrent chromosomal losses and gains in T-cell prolymphocytic leukemia.
Genes Chromosomes Cancer. 2001; 31(3):248-54 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare malignant proliferation of lymphoid cells with a postthymic phenotype. Previous cytogenetic and molecular studies reported complex karyotypes with recurrent chromosomal abnormalities, including translocations involving either TCL1 at 14q32.1 or MTCP1 at Xq28, inactivation of the ATM gene by deletion and/or mutation, and isochromosomes 8. For extensive study of chromosomal imbalances in T-PLL, we analyzed 22 tumoral DNAs using comparative genomic hybridization (CGH). Abnormal CGH profiles were detected in all cases, demonstrating highly recurrent gains and losses and largely extending the abnormalities previously established. Only a few nonrecurrent abnormalities were observed, in contrast to the genetic instability anticipated from ATM inactivation. Nine recurrent regions of loss were identified at 8p (frequency 86%), 11q (68%), 22q11 (45%), 13q (41%), 6q (36%), 9p (27%), 12p (23%), 11p11-p14 (23%), and 17p (23%), as well as four regions of gain at 8q (82%), 14q32 (50%), 22q21-qter (41%), and 6p (23%). Several recurrent chromosomal abnormalities were simultaneously present in each case (mean, 5.7; up to 10), none being mutually exclusive of another. Fluorescence in situ hybridization analysis confirmed and extended 22q11 and 13q losses, giving final frequencies of 55% and 45%, respectively. Analysis of one case over a 7-year period confirmed the overall genetic stability of T-PLL and showed that tumor progression was associated with the onset of a few chromosomal abnormalities. This study establishes a complex pattern of highly recurrent chromosomal abnormalities in T-PLL, including some, such as chromosome 13 deletion, commonly found in other lymphoid malignancies.

De Schouwer PJ, Dyer MJ, Brito-Babapulle VB, et al.
T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation.
Br J Haematol. 2000; 110(4):831-8 [PubMed] Related Publications
T-cell prolymphocytic leukaemia (T-PLL) is a sporadic, mature T-cell disorder in which there is usually an aberrant T-cell receptor alpha (TCRA) rearrangement that activates the TCL1 or MTCP1-B1 oncogenes. As mutations of the Ataxia Telangiectasia (A-T) gene, ATM, are frequent in T-PLL and as ATM seems to act as a tumour suppressor through a mechanism involving V(D)J recombination, we examined V(D)J recombination in T-PLL. Using Southern blotting and the polymerase chain reaction, two of 60 TCRG coding joints were abnormal. In all cases, both TCRD alleles were deleted, IGH was germline, and patterns of TCRB and TCRA rearrangement were normal. However, in a case harbouring t(X;7)(q28;q35), we identified TCRB segment J beta 2.7 juxtaposed to MTCP1 exon 1. This is the first time that TCRB has been implicated in MTCP1 B1 activation. The structure of the breakpoint supports a model in which translocation activates a cryptic MTCP1 promoter. This analysis of V(D)J recombination is consistent with it being a variable that is independent of ATM in T-PLL.

Narducci MG, Pescarmona E, Lazzeri C, et al.
Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid tissues.
Cancer Res. 2000; 60(8):2095-100 [PubMed] Related Publications
Chromosomal rearrangements observed in T-cell prolymphocytic leukemia involve the translocation of one T-cell receptor gene to either chromosome 14q32 or Xq28, deregulating the expression of cellular protooncogenes of unknown function, such as TCL1 or its homologue, MTCP1. In the human hematopoietic system, TCL1 expression is predominantly observed in developing B lymphocytes, whereas its overexpression in T cells causes mature T-cell proliferation in transgenic mice. In this study, using a newly generated monoclonal antibody against recombinant TCL1 protein, we extended our analysis mainly by immunohistochemistry and also by fluorescence-activated cell sorting and Western blot to a large tumor lymphoma data bank including 194 cases of lymphoproliferative disorders of B- and T-cell origin as well as reactive lymphoid tissues. The results obtained show that in reactive lymphoid tissues, TCL1 is strongly expressed by a subset of mantle zone B lymphocytes and is expressed to a lesser extent by follicle center cells and by scattered interfollicular small lymphocytes. In B-cell neoplasia, TCL1 was expressed in the majority of the cases, including lymphoblastic lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (60%), and primary cutaneous B cell lymphoma (55%). TCL1 expression was observed in both the cytoplasmic and nuclear compartments, as confirmed by Western blot analysis. Conversely, TCL1 was not expressed in Hodgkin/Reed-Sternberg cells, multiple myelomas, marginal zone B-cell lymphomas, CD30+ anaplastic large cell lymphoma, lymphoblastic T-cell lymphoma, peripheral T-cell lymphoma, and mycosis fungoides. These data indicate that TCL1 is expressed in more differentiated B cells, under both reactive and neoplastic conditions, from antigen committed B cells and in germinal center B cells and is down-regulated in the latest stage of B-cell differentiation.

Barthe P, Chiche L, Declerck N, et al.
Refined solution structure and backbone dynamics of 15N-labeled C12A-p8MTCP1 studied by NMR relaxation.
J Biomol NMR. 1999; 15(4):271-88 [PubMed] Related Publications
MTCP1 (for Mature-T-Cell Proliferation) was the first gene unequivocally identified in the group of uncommon leukemias with a mature phenotype. The three-dimensional solution structure of the human p8MTCP1 protein encoded by the MTCP1 oncogene has been previously determined by homonuclear proton two-dimensional NMR methods at 600 MHz: it consists of an original scaffold comprising three alpha-helices, associated with a new cysteine motif. Two of the helices are covalently paired by two disulfide bridges, forming an alpha-hairpin which resembles an antiparallel coiled-coil. The third helix is orientated roughly parallel to the plane defined by the alpha-antiparallel motif and appears less well defined. In order to gain more insight into the details of this new scaffold, we uniformly labeled with nitrogen-15 a mutant of this protein (C12A-p8MTCP1) in which the unbound cysteine at position 12 has been replaced by an alanine residue, thus allowing reproducibly high yields of recombinant protein. The refined structure benefits from 211 additional NOEs, extracted from 15N-edited 3D experiments, and from a nearly complete set of phi angular restraints allowing the estimation of the helical content of the structured part of the protein. Moreover, measurements of 15N spin relaxation times and heteronuclear 15N¿1H¿NOEs provided additional insights into the dynamics of the protein backbone. The analysis of the linear correlation between J(0) and J(omega) was used to interpret relaxation parameters. It appears that the apparent relative disorder seen in helix III is not simply due to a lack of experimental constraints, but associated with substantial contributions of sub-nanosecond motions in this segment.

Sugimoto J, Hatakeyama T, Narducci MG, et al.
Identification of the TCL1/MTCP1-like 1 (TML1) gene from the region next to the TCL1 locus.
Cancer Res. 1999; 59(10):2313-7 [PubMed] Related Publications
The region on chromosome 14q32.1 is frequently involved in chromosomal translocations and inversions with one of the T-cell receptor loci in human T-cell leukemias and lymphomas. The breakpoints of the different rearrangements segregate into two clusters: inversion on the centromeric side and simple balanced translocations on the telomeric side. If the target gene activated by these different types of chromosomal rearrangements is the same, the gene must reside between the two clusters of breakpoints in a region of approximately 160 kb. By screening of a placenta cDNA library using genomic probes derived from the vicinity of TCL1 locus, we have identified a gene coding for a 1.7-kb transcript that is expressed in leukemic cells carrying a t(14;14)(q11;q32) chromosome translocation. The cognate cDNA sequence reveals an open reading frame of 384 nucleotides encoding a Mr 15,000 protein with approximately 30% of homology with both p14TCL1 and p13MTCP1 oncoproteins. The genomic organization of the TML1 locus was characterized, with three exons located 15 kb from and tail-to-tail in relation to TCL1 locus. Because of its location and sequence similarity with TCL1 and MTCP1 oncoproteins, this gene, named TML1 (TCL1/MTCP1-like 1) is a candidate gene that is potentially involved in leukemogenesis.

Gritti C, Dastot H, Soulier J, et al.
Transgenic mice for MTCP1 develop T-cell prolymphocytic leukemia.
Blood. 1998; 92(2):368-73 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature T-cell leukemia associated with chromosomal rearrangements implicating MTCP1 or TCL1 genes. These genes encode two homologous proteins, p13(MTCP1) and p14(TCL1), which share no similarity with other known protein. To determine the oncogenic role of MTCP1, mice transgenic for MTCP1 under the control of CD2 regulatory regions (CD2-p13 mice) were generated. No abnormality was detected during the first year after birth. A late effect of the transgene was searched for in a cohort of 48 CD2-p13 mice aged 15 to 20 months, issued from 3 independent founders. Lymphoid hemopathies, occurring in the three transgenic lines, were characterized by lymphoid cells with an irregular nucleus, a unique and prominent nucleolus, condensed chromatin, a basophilic cytoplasm devoid of granules, and an immunophenotype of mature T cells. The molecular characterization of Tcrb rearrangements demonstrated the monoclonal origin of these populations. Histopathological analysis of the cohort demonstrated early splenic and hepatic infiltrations, whereas lymphocytosis and medullar infiltrations were found infrequently. The engraftment of these proliferations in H2-matched animals demonstrated their malignant nature. Cumulative incidence of the disease at 20 months was 100%, 50%, and 21% in F3, F4, and F7 lines, respectively, and null in the control group. The level of expression of the transgene, as estimated by Western blotting in the transgenic lines correlated with the tumoral incidence, with the highest expression of p13(MTCP1) being found in F3 mice. CD2-p13 transgenic mice developed an hemopathy similar to human T-PLL. These data demonstrate that p13(MTCP1) is an oncoprotein and that CD2-p13 transgenic mice represent the first animal model for mature T-PLL.

Fu ZQ, Du Bois GC, Song SP, et al.
Crystal structure of MTCP-1: implications for role of TCL-1 and MTCP-1 in T cell malignancies.
Proc Natl Acad Sci U S A. 1998; 95(7):3413-8 [PubMed] Free Access to Full Article Related Publications
Two related oncogenes, TCL-1 and MTCP-1, are overexpressed in T cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T cell receptor gene to either chromosome 14q32 or Xq28. The crystal structure of human recombinant MTCP-1 protein has been determined at 2.0 A resolution by using multiwavelength anomalous dispersion data from selenomethionine-enriched protein and refined to an R factor of 0.21. MTCP-1 folds into a compact eight-stranded beta barrel structure with a short helix between the fourth and fifth strands. The topology is unique. The structure of TCL-1 has been predicted by molecular modeling based on 40% amino acid sequence identity with MTCP-1. The identical residues are clustered inside the barrel and on the surface at one side of the barrel. The overall structure of MTCP-1 superficially resembles the structures of proteins in the lipocalin family and calycin superfamily. These proteins have diverse functions, including transport of retinol, fatty acids, chromophores, pheromones, synthesis of prostaglandin, immune modulation, and cell regulation. However, MTCP-1 differs in the topology of the beta strands. The structural similarity suggests that MTCP-1 and TCL-1 form a unique family of beta barrel proteins that is predicted to bind small hydrophobic ligands and function in cell regulation.

Hoh F, Yang YS, Guignard L, et al.
Crystal structure of p14TCL1, an oncogene product involved in T-cell prolymphocytic leukemia, reveals a novel beta-barrel topology.
Structure. 1998; 6(2):147-55 [PubMed] Related Publications
BACKGROUND: Chromosome rearrangements are frequently involved in the generation of hematopoietic tumors. One type of T-cell leukemia, T-cell prolymphocytic leukemia, is consistently associated with chromosome rearrangements characterized by the juxtaposition of the TCRA locus on chromosome 14q11 and either the TCL1 gene on 14q32.1 or the MTCP1 gene on Xq28. The TCL1 gene is preferentially expressed in cells of early lymphoid lineage; its product is a 14 kDa protein (p14TCL1), expressed in the cytoplasm. p14TCL1 has strong sequence similarity with one product of the MTCP1 gene, p13MTCP1 (41% identical and 61% similar). The functions of the TCL1 and MTCP1 genes are not known yet. They have no sequence similarity to any other published sequence, including those of well-documented oncogene families responsible for leukemia. In order to gain a more fundamental insight into the role of this particular class of oncogenes, we have determined the three-dimensional structure of p14TCL1.
RESULTS: The crystal structure of p14TCL1 has been determined at 2.5 A resolution. The structure was solved by molecular replacement using the solution structure of p13MTCP1, revealing p14TCL1 to be an all-beta protein consisting of an eight-stranded antiparallel beta barrel with a novel topology. The barrel consists of two four-stranded beta-meander motifs, related by a twofold axis and connected by a long loop. This internal pseudo-twofold symmetry was not expected on basis of the sequence alone, but structure-based sequence analysis of the two motifs shows that they are related. The structures of p13MTCP1 and p14TCL1 are very similar, diverging only in regions that are either flexible and/or involved in crystal packing. p14TCL1 forms a tight crystallographic dimer, probably corresponding to the 28 kDa species identified in solution by gel filtration experiments.
CONCLUSIONS: Structural similarities between p14TCL1 and p13MTCP1 suggest that their (unknown) function may be analogous. This is confirmed by the fact that these proteins are implicated in analogous diseases. Their structure does not show similarity to other oncoproteins of known structure, confirming their classification as a novel class of oncoproteins.

Gritti C, Choukroun V, Soulier J, et al.
Alternative origin of p13MTCP1-encoding transcripts in mature T-cell proliferations with t(X;14) translocations.
Oncogene. 1997; 15(11):1329-35 [PubMed] Related Publications
The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with T-cell prolymphocytic leukemia and related conditions. This gene is unusual in that it codes for two distinct proteins: a small mitochondrial protein, p8MTCP1, and a putative oncogenic protein, p13MTCP1. Scarcity of material from t(X;14)-associated proliferations and very low levels of mRNA expression have so far prevented a thorough description of p13MTCP1-encoding transcripts. Here, we characterize two additional t(X;14) bearing leukemias allowing this analysis. In one case, with a breakpoint located 5' to the MTCP1 gene, the level of transcription of previously described p13MTCP1-encoding transcripts is enhanced. In the second case, with a breakpoint within the MTCP1 intron I, an alternative transcription initiation site is demonstrated in the tumor cells at 229 bp upstream to exon II. The identification of this internal promoter, together with the similarity between TCL1 and MTCP1 genomic structures, allow us to propose a model in which the duplication of an ancestral gene was followed by the insertion of one copy within the intron of a p8-encoding gene, accounting for the unusual feature of the MTCP1 gene.

Madani A, Choukroun V, Soulier J, et al.
Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations.
Blood. 1996; 87(5):1923-7 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL), a rare form of mature T-cell leukemias, and ataxia telangiectasia clonal proliferation, a related condition occurring in patients suffering from ataxia telangiectasia, have been associated to translocations involving the 14q32.1 or Xq28 regions, where are located the TCL1 and MTCP1 putative oncogenes, respectively. The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with these T-cell proliferations. Alternative splicing generates type A and B transcripts that potentially encode two entirely distinct proteins; type A transcripts code for a small mitochondrial protein, p8MTCP1, and type B transcripts, containing an additional open reading frame, may code for 107 amino-acid protein, p13MTCP1. The recently cloned TCL1 gene, also involved in translocations and inversions associated with T-cell proliferations, codes for a 14-kD protein that displays significant homology with p13MTCP1. We have generated rabbit antisera against this putative p13MTCP1 protein and screened for expression of p13MTCP1 normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations using a sensitive Western blot assay. We also investigated the MTCP1 locus configuration by Southern blot analysis. The p13MTCP1 protein was detected in the three T-cell proliferations with MTCP1 rearrangements because of t(X;14) translocations, but neither in normal resting and activated lymphocytes nor in the other T-cell leukemias. Our data support the hypothesis that p13MTCP1 and p14TCL1 form a new protein family that plays a key role in the pathogenesis of T-PLL and related conditions.

Thick J, Metcalfe JA, Mak YF, et al.
Expression of either the TCL1 oncogene, or transcripts from its homologue MTCP1/c6.1B, in leukaemic and non-leukaemic T cells from ataxia telangiectasia patients.
Oncogene. 1996; 12(2):379-86 [PubMed] Related Publications
Patients with the recessively inherited disorder ataxia telangiectasia (A-T) have a high level of specific chromosome translocations which can be easily observed in peripheral T cells and show a greatly increased predisposition to leukaemia/lymphoma, mainly of T cell origin. Some translocation cells proliferate into a large clone and may develop into T cell prolymphocytic leukaemia (T-PLL). By the time of diagnosis of T-PLL, the clone contains many more genetic changes in the form of additional translocations. T-PLL is also seen in non-A-T individuals where expression of either TCL1 (at 14q32) or the c6.1B/MTCP1 A1 transcript (at-Xq28) has been demonstrated in just a few instances. We show here, that expression of TCL1 occurs in leukaemic T cells from A-T patients with chromosome 14 rearrangements. Expression of TCL1 also occurs in the preleukaemic clone cells of A-T patients containing the primary translocation alone. Some expression of TCL1 could also be detected in randomly selected A-T patients without large cytogenetic clones and without any evidence of leukaemic change. We also show that expression of the B1 transcript from a second gene, MTCP1, occurred at a relatively high level only in two T-PLL tumours from A-T patients with t(X;14) translocations whereas the MTCP1/A1 transcript is much more widely expressed in both tumour and non tumour cells of A-T and non-A-T individuals.

Soulier J, Madani A, Cacheux V, et al.
The MTCP-1/c6.1B gene encodes for a cytoplasmic 8 kD protein overexpressed in T cell leukemia bearing a t(X;14) translocation.
Oncogene. 1994; 9(12):3565-70 [PubMed] Related Publications
The t(X;14)(q28;q11.2) translocation is associated with mature T-cell proliferations. Recently this translocation has been shown to implicate the MTCP-1/c6.1B gene on chromosome Xq28, leading to aberrant or overexpressed MTCP-1 transcripts. The potential coding role of this gene was made uncertain by the lack of a long open reading frame in its major transcripts. However, a short 204 bases open reading frame is potentially coding for a 68 amino-acid protein. Here, we show that this open reading frame sequence and the deduced product are well conserved in mouse. A 8 kD protein (p8), which corresponds to the predicted molecular weight was revealed in transient transfectants and in cell lines by Western blotting, using a rabbit antiserum. This product was absent in lymphoblastoid cell lines with deletions of the MTCP-1/c6.1B locus. A dramatic overexpression of p8 was found in leukemic cells from a patient with a t(X;14). This small protein was localized in the cytoplasm by immunofluorescence. In conclusion, MTCP-1 encodes for a cytoplasmic 8 kD product. Its potential role in leukemogenesis is supported by its overexpression in leukemia with t(X;14), but its function remains unknown.

Stern MH, Soulier J, Rosenzwajg M, et al.
MTCP-1: a novel gene on the human chromosome Xq28 translocated to the T cell receptor alpha/delta locus in mature T cell proliferations.
Oncogene. 1993; 8(9):2475-83 [PubMed] Related Publications
T-cell lymphoproliferative diseases are often associated with recurrent chromosomal translocations involving T cell receptor genes (TCR) and genes that are thought to play a role in the pathogenesis of these diseases. Whereas numerous such genes have already been identified in acute T cell leukemias, no candidate gene has yet been identified to play a role in the heterogeneous group of T cell proliferations with a mature phenotype. We here report the molecular cloning of two examples of the rare but recurrent t(X;14) translocation. The first translocation was associated with a benign clonal proliferation in an ataxia telangiectasia patient and the second with a T cell prolymphocytic leukemia. Both translocations implicated the TCR alpha/delta locus and a common breakpoint region on chromosome Xq28. A previously unidentified gene, abnormally transcribed in both T cell proliferations, was characterized in the immediate proximity of the breakpoints. This Xq28 gene has no homology with known sequences, uses a complex alternative splicing pattern and demonstrates two short open reading frames. This gene, named MTCP-1 (Mature T Cell Proliferation-1) is the first candidate gene potentially involved in the leukemogenic process of mature T cell proliferations.

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