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t(7;14)(q35;q32.1) TRB/TCL1A

inv(14)(q11q32.1) TRA-TRD/TCL1A

t(14;14)(q11;q32.1) TRA-TRD/TCL1A

Written2001-06Jacques Boyer
Laboratoire d' hématologie, CH du MANS, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 2049
 
  inv (14)(q11q32)and accompanying i(8q), G- banding - Courtesy Jean Luc Lai

Clinics and Pathology

Note these chromosome rearrangements can be found in:
  • prolymphocytic leukemia (T- PLL)
  • Ataxia Teliangectasia
  • Adult T-cell leukemia/lymphoma
  • Rarely : acute lymphoblastic leukemia of T-lineage or B-lineage, acute myeloid leukemia expressing lymphoid-associated antigens (see references)
    • Disease T Prolymphocytic leukemia (T-PLL)
    Phenotype / cell stem origin Mature post-thymic T-cell malignancy
  • CD4+CD8- (70%) CD4+CD8+ (25%) or CD4-CD8+ (<10%)
  • CD7+ bright and surface CD3 negative in 20% of cases.
    • Clinics T-PLL is rare and affects adults, occurs slightly more often in men at advanced age.
    T-PLL main disease features at presentation are splenomegaly (79%), lymphadenopathy (46%), hepatomegaly (39%), skin lesion (23%), pleural effusion (15%) and marked lymphocytosis (> 100 X 109/L) (72%)
    Cytology In 70% of cases proliferation of medium-sized lymphocytes with either a regular or a irregular nuclear outline and one single nucleolus (or absent). The cytoplasme is scanty, agranular, deeply basophilic and often with protrusions (blebs).
    In 20% of cases there are no obvious differencies between B and T prolymphocytes with proeminent nucleolus.
    In rare cases T prolymphocytes show a polylobated nucleus or a cerebriform configuration (as sezary cell)
    Cytogenetics Chromosomal abnormalities are detected in most T-PLL after culture with mitogens like PHA. Karyotype is often complex with high degree of instability.
    inv(14)(q11;q32) is the most frequent chromosomal abnormality and occurs in more than two thirds of cases. Few patients may have t(14;14)(q11;q32) the variant t(X;14)(q28;q11) may be found. ADDITIONAL ANOMALIES :
  • 55 to 80 % of cases have additional abnormality affecting the chromosome 8 : i(8)(q10) (43%) , t(8;8)(p12;q11) (14%), +8 (14%) and abnormality of the short arm of chromosome 8 (14%)
  • Anomalies of 11q23, where the ataxia teliangectasia mutated gene is located, have also been reported in T-PLL Anomalies of the short arm of chromosome 12 seem to be observed with a high frequency so as 13q14.3 deletions.
    • Prognosis T-PLL has an aggressive clinical course, although, in a small proportion on cases, disease evolves with a slowly progressive lymphocytosis (phenotype CD45RO-CD45RA-)

    Disease Ataxia telangiectasia (AT)
    Clinics AT is a chromosome instability syndrome with an increased risk of cancer : T-cell malignancies or carcinomas.
    Cytogenetics
  • Spontaneous chromatid/chromosome breaks are found in this disease with a high frequency.
  • The best diagnosis test is on the highly elevated level (10% of mitoses) of inv(7), t(14;14)
  • Clonal rearrangement further occurs in 10% of patients, but without manifestation of malignancy : t(14;14), inv(14) or t(X;14)
  • Clonal rearrangements in T-cell ALL and T-PLL in AT patients are complex with the frequent involvement of t(14:14) or t(X;14) as is found in T-PLL in non AT patients.

    • Disease Adult T-cell leukemia/lymphoma
    Cytogenetics
  • The karyotype is often complex
  • The translocation t(14;14)(q11;q32.1) and inv(14)(q11.q32.1) have been reported by a number of investigators.
  • Additional anomalies : trisomy 3, trisomy 7 or partial trisomy of the long arm of chromosome 7 are frequently found.

    • Disease Acute lymphoblastic leukemia (ALL) of T lineage
    Cytogenetics Inv(14) is exceedingly rare in T cell acute lymphoblastic leukemia. In two cases reported , inv(14) coexists with other cytogenetic aberrations well described in T-ALL, like t(11;14)(p13;q11) and rearrangement at chromosome 7q34.

    Disease Leukemias of B lineage
    Cytogenetics Inv(14) is a exceedingly rare phenomenon in lymphoid malignancy of B lineage. It has been reported in a patient with B-cell chronic lymphocytic leukemia but only in a PHA stimulated bone marrow. Only two cases of lymphoblastic leukemia of B-lineage with inv(14) have been reported. These two cases are pre-B2 ALL (CD10+ and cytoplamic μ chain negative).

    Disease Acute myeloid leukemia with lymphoid associated antigens

    Genes involved and Proteins

    Gene NameTCL1A (T-cell leukemia/lymphoma 1A)
    Location 14q32.13
    Note The TCL1 (or TCL1A) oncogene is located on chromosome 14q32.1. It belongs to the TCL1 family. TCL1A gene is 6.5 Kb in size and contains four exons
  • TCL1B is located on 14q32.1 16 Kb centromeric of TCL1A and shows 60% similarity to TCL1; TCL1A and TCL1B are located in the about 160 kb region of breakpoints observed in T cell leukemia cases with translocations at 14q32.1
  • Semi quantitative RT-PCR analysis revealed that both TCL1A and TCL1b genes are expressed in spleen, tonsil, fetal liver, fetal kidney and fetal thymus. However the TCL1B gene is expressed in a wide variety of tissues. Normally, TCL1A expression is observed in early T cell progenitors (CD4- CD8- CD3-) and lymphoid cell of the B lineage : pre B cells and immature IgM expressing B cells.
  • TCL1A, TCL1B encode for protein of about 14 kDa. TCL1A 14 kDa protein consists of an eight-stranded antiparallel beta barrel with a hydrophobic core and are predicted to bind small hydrophobic ligands such as retinoids, nucleosides or fatty acids.
  • NOTE : in addition to TCL1 and TCL1b the locus contains two additional genes TCL1- neighboring gene (TNG1 and TNG2) encoding proteins of 141 and 110 amino acids. Recently two novel genes have been identified in this region : TML1 and TCL6. Since the TCL1, TCL1b, TML1, TCL6 genes are expressed in T-cell leukemias carrying a t(14;14) translocation, they are four candidate genes potentially involved in leukemogenesis.
    • Gene NameMTCP1 (Mature T Cell Proliferation 1)
    Location Xq28
    Dna / Rna The MTCP1 is located at Xq28 and activated in rare cases of T-PLL with a t(X;14)(q28;q11) translocation.
    Protein MTCP1 encodes for two proteins p8MTCP1 and p13MTCP1
    Gene NameTRA (T cell Receptor Alpha)
    Location 14q11.2
    Dna / Rna
  • The size of TCR alpha/delta locus is about 1 Mb. The TCR delta variable (V) diversity (D) joining (J) and constant region genes are situated within the TCR alpha locus between the TCR alpha V and the TCR alpha J segments.
  • The TCR delta locus contains three D segments and four J segments, whereas the TCR alpha J regions spans approximately 80 Kb and contains at least 61 segments.
  • The TCR alpha/delta locus is transcribed in a centromer to telomer direction.
    • Protein T-cell receptor
    Gene NameTRD (T cell Receptor Delta)
    Location 14q11.2
    Dna / Rna
  • The size of TCR alpha/delta locus is about 1 Mb. The TCR delta variable (V) diversity (D) joining (J) and constant region genes are situated within the TCR alpha locus between the TCR alpha V and the TCR alpha J segments.
  • The TCR delta locus contains three D segments and four J segments, whereas the TCR alpha J regions spans approximately 80 Kb and contains at least 61 segments.
  • The TCR alpha/delta locus is transcribed in a centromer to telomer direction.
    • Protein T-cell receptor

    Result of the chromosomal anomaly

    Hybrid gene
    Description
  • TCL1A and TCL1B are expressed at very low level in normal bone marrow and peripheral lymphocytes but are activated in the T-PLL by juxtaposition to the T cell receptor alpha/delta locus at 14q11.
  • The another gene of TCL1 family, MTCP1 is activated in rare cases of T-PLL with a t(X;14) translocation and is also homologous to TCL1A gene.
  • Breakpoints at 14q32.1 involve a chromosomal segment of about 160 Kb and cluster in two regions. The centromeric region is mainly involved in inversions, whereas the telomeric region is involved in simple translocations.
    •   
    Fusion Protein
    Oncogenesis The protein kinase AKT , the homologue of v-akt isolated from the retrovirus AKT8, which causes T-cell lymphomas in mice, is a key player in transduction of antiapoptotic and proliferative signals in T-cell. The TCL1 protein, encoded by the TCL1A oncogene, interacts with the AKT, this interaction results in the enhancement of the AKT kinase activity and promotes its nuclear transport. In contrast, AKT kinase does not interact with the TCL1B protein. The biological outcome of the TCL1A-induced enhancement of AKT activity is expected to occur through the phosphorylation of AKT specific targets. Because the TCL1A activated AKT translocates into the nucleus, the most likely targets are nuclear.
      

    To be noted

  • A sporadic form of inv(14)(q11;q32) is found occasionally in cultured normal lymphocytes (at the level of about 1/500). It involves a site specific recombination between the immunoglobulin heavy chain (IgH) variable region on 14q32.3 with TCR J alpha on 14q11 and probably arises from illegitimate recombinase joining of the rearranged genes TCR J alpha and IgH in lymphoid progenitors.
  • The TCL1 is also activated in the majority of the cases of B cell lymphoma.
  • Although rearrangement of c-myc has not been demonstrated, cell from T-PLL with trisomy 8 or iso(8)(q10) overexpress the c-myc protein. It is then possible that a high expression of c-myc plays a role in disease progression as a secondary event.

    • Bibliography

    Cytogenetic studies on prolymphocytic leukemia. II. T cell prolymphocytic leukemia.
    Brito-Babapulle V, Pomfret M, Matutes E, Catovsky D
    Blood. 1987 ; 70 (4) : 926-931.
    PMID 3115337
     
    Concurrent presence of inv(14)(q11q32) and t(4;11)(q21;q23) in pre-B acute lymphoblastic leukemia.
    Chervinsky DS, Grossi M, Kakati S, Block AW, Aplan PD
    Genes, chromosomes & cancer. 1995 ; 12 (3) : 229-236.
    PMID 7536464
     
    Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes.
    Hallas C, Pekarsky Y, Itoyama T, Varnum J, Bichi R, Rothstein JL, Croce CM
    Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (25) : 14418-14423.
    PMID 10588720
     
    Rearrangements in the human T-cell-receptor alpha-chain locus in patients with adult T-cell leukemia carrying translocations involving chromosome 14q11.
    Isobe M, Sadamori N, Russo G, Shimizu S, Yamamori S, Itoyama T, Yamada Y, Ikeda S, Ichimaru M, Kagan J
    Cancer research. 1990 ; 50 (19) : 6171-6175.
    PMID 2169336
     
    Inversion (14)(q11q32) in childhood T-cell acute lymphoblastic leukemia.
    Kwong YL, Shing MK, Wan TM, Yuen PM, Chan AY, Wong KF, Chan LC
    Cancer genetics and cytogenetics. 1994 ; 72 (2) : 92-95.
    PMID 8143282
     
    The protooncogene TCL1 is an Akt kinase coactivator.
    Laine J, Künstle G, Obata T, Sha M, Noguchi M
    Molecular cell. 2000 ; 6 (2) : 395-407.
    PMID 10983986
     
    Molecular cloning of a DNA fragment from human chromosome 14(14q11) involved in T-cell malignancies.
    Mathieu-Mahul D, Caubet JF, Bernheim A, Mauchauffé M, Palmer E, Berger R, Larsen CJ
    The EMBO journal. 1985 ; 4 (13A) : 3427-3433.
    PMID 3912169
     
    Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia.
    Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, Sempere A, Catovsky D
    Blood. 1991 ; 78 (12) : 3269-3274.
    PMID 1742486
     
    Trisomy 8q due to i(8q) or der(8) t(8;8) is a frequent lesion in T-prolymphocytic leukaemia: four new cases and a review of the literature.
    Mossafa H, Brizard A, Huret JL, Brizard F, Lessard M, Guilhot F, Tanzer J
    British journal of haematology. 1994 ; 86 (4) : 780-785.
    PMID 7918072
     
    Inversion (14)(q11q32) in a case of acute myeloid leukemia expressing lymphoid-associated antigens.
    Raynaud SD, Brunet B, Ayraud N, Monpoux F, Philip P, Bayle J
    Cancer genetics and cytogenetics. 1993 ; 71 (1) : 100-101.
    PMID 8275446
     
    Significance of chromosome 14 anomaly at band 14q11 in Japanese patients with adult T-cell leukemia.
    Sadamori N, Nishino K, Kusano M, Tomonaga Y, Tagawa M, Yao E, Sasagawa I, Nakamura H, Ichimaru M
    Cancer. 1986 ; 58 (10) : 2244-2250.
    PMID 2875783
     
    Identification of the TCL6 genes within the breakpoint cluster region on chromosome 14q32 in T-cell leukemia.
    Saitou M, Sugimoto J, Hatakeyama T, Russo G, Isobe M
    Oncogene. 2000 ; 19 (23) : 2796-2802.
    PMID 10851082
     
    Abnormalities of the short arm of chromosome 12 in T cell prolymphocytic leukemia.
    Salomon-Nguyen F, Brizard F, Le Coniat M, Radford I, Berger R, Brizard A
    Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 ; 12 (6) : 972-975.
    PMID 9639428
     
    Karyotype and T-cell receptor expression in T-lineage acute lymphoblastic leukemia.
    Secker-Walker LM, Campana D, Hawkins JM, Sampson RE, Coustan-Smith E
    Genes, chromosomes & cancer. 1992 ; 4 (1) : 41-45.
    PMID 1377008
     
    A complex pattern of recurrent chromosomal losses and gains in T-cell prolymphocytic leukemia.
    Soulier J, Pierron G, Vecchione D, Garand R, Brizard F, Sigaux F, Stern MH, Aurias A
    Genes, chromosomes & cancer. 2001 ; 31 (3) : 248-254.
    PMID 11391795
     
    Identification of the TCL1/MTCP1-like 1 (TML1) gene from the region next to the TCL1 locus.
    Sugimoto J, Hatakeyama T, Narducci MG, Russo G, Isobe M
    Cancer research. 1999 ; 59 (10) : 2313-2317.
    PMID 10344735
     
    Identification of the TCL1 gene involved in T-cell malignancies.
    Virgilio L, Narducci MG, Isobe M, Billips LG, Cooper MD, Croce CM, Russo G
    Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (26) : 12530-12534.
    PMID 7809072
     
    Inversion 14q in acute lymphoblastic leukemia of B-lineage.
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    Citation

    This paper should be referenced as such :
    Boyer, J
    t(7;14)(q35;q32.1) - inv(14)(q11q32.1) - t(14;14)(q11;q32.1)
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(3):192-195.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Anomalies/inv14ID2049.html

    Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

    Genes TCL1A TRA TRD

    Translocations implicated (Data extracted from papers in the Atlas)

     inv(14)(q11q32.1) TRA-TRD/TCL1A
     t(14;14)(q11;q32.1) TRA-TRD/TCL1A
     t(7;14)(q35;q32.1) TRB/TCL1A

    External links

    Mitelman databaseinv(14)(q11q32.1) [Case List]    inv(14)(q11q32.1) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(14;14)(q11;q32.1) [Case List]    t(14;14)(q11;q32.1) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(7;14)(q35;q32.1) [Case List]    t(7;14)(q35;q32.1) [Association List] Mitelman database (CGAP - NCBI)
    arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMapTopo ( C42) Morph ( 9837/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
    Disease databaset(7;14)(q35;q32.1) TRB/TCL1A
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed
    All articlesautomatic search in PubMed


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