scholarly journals V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites⋆

2002 ◽  
Vol 195 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Rodrig Marculescu ◽  
Trang Le ◽  
Paul Simon ◽  
Ulrich Jaeger ◽  
Bertrand Nadel
Keyword(s):  
T Cell ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Lymphoid Malignancies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human ◽  
Hodgkin's Lymphomas ◽  
The Impact

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.

Deletion of Atm in the Hematopoetic Stem Cell As a Mouse Model for Human T Cell Acute Lymphoblastic Leukemia/Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2418-2418
Author(s):  
Lori A. Ehrlich ◽  
Katherine S. Yang-Iott ◽  
Amy DeMicco ◽  
Craig H. Bassing
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Drug Combinations ◽  
Thymic Epithelial Cells ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 2418 Acute lymphoblastic leukemia (ALL) is diagnosed in approximately 2500 children per year. Although high cure rates have been achieved for ALL, these cancers account for the highest number of non-brain tumor cancer-related deaths in children. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature TCRβ−CD4+/CD8+ T-cells that represents ∼15% of pediatric ALL diagnoses, comprises most of the therapy-resistant ALL tumors, and exhibits a high frequency of relapse. The Ataxia Telangiectasia mutated (ATM) protein kinase activates the cellular response to DNA double strand breaks (DSBs) to coordinate DNA repair with cell survival, proliferation, and differentiation. Somatic inactivating ATM mutations occur in 10–20% of T-ALL and T cell lymphoblastic lymphoma (T-LL) tumors and are associated with resistance to genotoxic chemotherapy drugs and therapy relapse, likely driven by increased genomic instability in cells lacking functional ATM. The impaired DSB response of ATM-deficient cells can be exploited to design combinations of genotoxic drugs that specifically kill these cells in vitro. However, the in vivo potential of such drug combinations to treat T-ALL have not been reported. We sought to develop a pre-clinical mouse model that could be used to test effectiveness of such drug combinations to treat T-ALLs and T-LLs with somatic ATM inactivation. Although germline ATM-deficient (Atm−/−) mice succumb by six months of age to immature CD4+/CD8+ T-cell lymphomas containing genomic instability analogous to human T-ALL tumors, we sought a more physiologic model that would avoid potential complications due to ATM-deficiency in thymic epithelial cells. Thus, we generated and characterized VavCre:Atmflox/flox mice with conditional Atm inactivation restricted to hematopoietic cell lineages. These mice contain reduced numbers of TCRβ−CD4+/CD8+, TCRβ+CD4+/CD8−, and TCRβ+CD4−/CD8+ thymocytes and of TCRβ+CD4+ and TCRb+CD8+ splenic T-cells, mirroring the phenotype of Atm−/− mice. We have found that VavCre:Atmflox/flox mice succumb at an average of 95 days (range 53–183 days) to clonal TCRβ−CD4+/CD8+ or TCRβ+CD4−/CD8+ thymic lymphomas. Evaluation of the bone marrow in a subset of these mice indicates that the lymphoma has disseminated and are classified as leukemia. Our initial cytogenetic analyses of these tumors indicate that they contain both clonal translocations involving chromosome 12 and/or chromosome 14 and deletion of one allelic copy of the haploinsufficient Bcl11b tumor suppressor gene. Hemizygous BCL11B inactivation occurs in ∼20% of human T-ALL tumors, indicating the clinical relevance of VavCre:Atmflox/flox mice as a model for human T-ALL. Our ongoing studies include complete cytogenetic and molecular characterization of VavCre:Atmflox/flox tumors and in vivo testing of chemotherapeutics targeting the Atm pathway in this mouse model of T-ALL/T-LL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cellular context-dependent effects of H2ax and p53 deletion on the development of thymic lymphoma

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 175-185 ◽  
Author(s):  
Bu Yin ◽  
Katherine S. Yang-Iott ◽  
Linda H. Chao ◽  
Craig H. Bassing
Keyword(s):  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Cellular Origin ◽  
Lymphoid Malignancies ◽  
Conditional Deletion ◽  
Human T Cell ◽  
Receptor Locus ◽  
Cellular Context ◽  
Cell Acute Lymphoblastic Leukemia

Abstract H2AX and Artemis each cooperate with p53 to suppress lymphoma. Germline H2ax−/−p53−/− mice die of T-cell receptor-β− (TCR-β−) thymic lymphomas with translocations and other lesions characteristic of human T-cell acute lymphoblastic leukemia. Here, we demonstrate that mice with inactivation of H2ax and p53 in thymocytes die at later ages to TCR-β− or TCR-β+ thymic lymphomas containing a similar pattern of translocations as H2ax−/−p53−/− tumors. Germline Artemis−/−p53−/− mice die of lymphomas with antigen receptor locus translocations, whereas Artemis−/−H2ax−/−p53−/− mice die at earlier ages from multiple malignancies. We show here that Artemis−/− mice with p53 deletion in thymocytes die of TCR-β− tumors containing Tcrα/δ translocations, other clonal translocations, or aneuploidy, as well as Notch1 mutations. Strikingly, Artemis−/− mice with H2ax and p53 deletion in thymocytes exhibited a lower rate of mortality from TCR-β− tumors, which harbored significantly elevated levels of genomic instability. Our data reveal that the cellular origin of H2ax and p53 loss impacts the rate of mortality from and developmental stage of thymic lymphomas, and suggest that conditional deletion of tumor suppressor genes may provide more physiologic models for human lymphoid malignancies than germline inactivation.

Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 388-392 ◽  
Author(s):  
Willem A. Dik ◽  
Bertrand Nadel ◽  
Grzegorz K. Przybylski ◽  
Vahid Asnafi ◽  
Piotr Grabarczyk ◽  
...  
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Regulatory Element ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Cell Receptor ◽  
Main Determinant ◽  
Chromosomal Breakpoints ◽  
Cell Acute Lymphoblastic Leukemia

The t(11;14)(p13;q11) is presumed to arise from an erroneous T-cell receptor delta TCRD V(D)J recombination and to result in LMO2 activation. However, the mechanisms underlying this translocation and the resulting LMO2 activation are poorly defined. We performed combined in vivo, ex vivo, and in silico analyses on 9 new t(11;14)(p13;q11)-positive T-cell acute lymphoblastic leukemia (T-ALL) as well as normal thymocytes. Our data support the involvement of 2 distinct t(11;14)(p13;q11) V(D)J-related translocation mechanisms. We provide compelling evidence that removal of a negative regulatory element from the LMO2 locus, rather than juxtaposition to the TCRD enhancer, is the main determinant for LMO2 activation in the majority of t(11;14)(p13;q11) translocations. Furthermore, the position of the LMO2 breakpoints in T-ALL in the light of the occurrence of TCRD-LMO2 translocations in normal thymocytes points to a critical role for the exact breakpoint location in determining LMO2 activation levels and the consequent pressure for T-ALL development.

scholarly journals RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia

Blood ◽  
2017 ◽  
Vol 130 (15) ◽  
pp. 1722-1733 ◽  
Author(s):  
AHyun Choi ◽  
Anuradha Illendula ◽  
John A. Pulikkan ◽  
Justine E. Roderick ◽  
Jessica Tesell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cells ◽  
Enhancer Activity ◽  
Key Points ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human

Key Points RUNX1 maintains Myb and Myc enhancer activity and is required for leukemogenesis in vivo. RUNX1 inhibition impairs the growth of primary T-ALL patient cells without an effect on normal human hematopoietic cells.

Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3072-3078 ◽  
Author(s):  
Vahid Asnafi ◽  
Agnes Buzyn ◽  
Xavier Thomas ◽  
Francoise Huguet ◽  
Norbert Vey ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Prospective Trial ◽  
Cell Receptor ◽  
Early Response ◽  
Salvage Treatment ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Relapse Rates ◽  
Intermediate Dose

AbstractPatients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucémies Aiguës Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)–expressing T-ALL patients (TCRαβ+ or TCRγδ+), pre-αβ T-ALL patients (cTCRβ+, TCR–), and immature (IM) cTCRβ–, TCR– T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-αβ, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.

Immunoglobulin/T-cell receptor gene rearrangements in the diagnostic paradigm of pediatric patients with T-cell acute lymphoblastic leukemia

2012 ◽  
Vol 53 (7) ◽  
pp. 1425-1428 ◽  
Author(s):  
Monika D. Kraszewska ◽  
Małgorzata Dawidowska ◽  
Maria Kosmalska ◽  
Łukasz Sędek ◽  
Władysław Grzeszczak ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Gene Rearrangements ◽  
Cell Acute Lymphoblastic Leukemia ◽  
T Cell Receptor Gene ◽  
Cell Receptor Gene

scholarly journals Lactate dehydrogenase isoenzymes in normal and malignant human lymphoid cells

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 491-494 ◽  
Author(s):  
J Blatt ◽  
RJ Spiegel ◽  
NM Papadopoulos ◽  
SA Lazarou ◽  
IT Magrath ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lactate Dehydrogenase ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Diagnostic Category ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Lymphoid Malignancies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Isoenzyme Patterns

Abstract Intracellular lactate dehydrogenase (LD) isoenzyme patterns were studied in the malignant cells of patients with a variety of lymphoid malignancies. These were compared with intracellular LD isoenzyme patterns of normal lymphoid cells and were also correlated with immunologic cell surface marker characteristics. Results showed that, in general, the malignant B cells of Burkitt's lymphoma and the lymphoblasts of T-cell acute lymphoblastic leukemia had isoenzyme patterns similar to those of normal B and T cells, respectively. The isoenzyme patterns of malignant lymphoid cells from patients with non- T, and non-B acute lymphoblastic leukemia, cutaneous T-cell lymphoma, and chronic lymphocytic leukemia were more heterogeneous. These data, although based on small numbers of patients, are consistent with the hypothesis that LD isoenzymes may reflect differences in the maturational status of cells within a single diagnostic category.

scholarly journals High prevalence of T-cell receptor V delta 2-(D)-D delta 3 or D delta 1/2-D delta 3 rearrangements in B-precursor acute lymphoblastic leukemias

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1834-1840 ◽  
Author(s):  
A Biondi ◽  
P Francia di Celle ◽  
V Rossi ◽  
G Casorati ◽  
G Matullo ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Lymphoproliferative Disorders ◽  
Cell Precursor ◽  
Gene Assembly ◽  
Lymphoid Malignancies ◽  
High Prevalence

Abstract Rearrangement of the immunoglobulin (Ig) and T-cell receptor (TcR) genes generally has been considered a useful marker of B- and T-cell lineage in lymphoproliferative disorders. However, concomitant rearrangements of Ig and TcR genes have been commonly reported in the most immature lymphoid malignancies, mainly in B-cell precursor acute lymphoblastic leukemia (ALL). To better characterize the nature of this lineage promiscuity, we have analyzed the configuration of the TcR delta locus in 75 B-precursor ALL. The large majority of cases (87%) displayed a rearrangement or deletion at the delta locus. Among the 57 nondeletional rearrangements, two patterns were predominant and both appeared to derive from partial joining: a V delta-(D)-D delta 3 (32/57) and a D delta 1/2-D delta 3 (11/57) type. A single V delta gene (V delta 2) appeared to be involved in the first type of rearrangement. These findings are at variance with T-ALL, where rearrangements 5′ to V delta 2 are usually found. It remains to be elucidated whether this incomplete attempt of V delta 2 gene assembly is related to the neoplastic event or represents a physiologic predisposition occurring during early stages of the normal lymphocyte differentiation.

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