NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3753-3762 ◽  
Author(s):  
Joachim R. Göthert ◽  
Rachael L. Brake ◽  
Monique Smeets ◽  
Ulrich Dührsen ◽  
C. Glenn Begley ◽  
...  
Keyword(s):  
T Cell ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Surface Expression ◽  
Normal Surface ◽  
Double Positive ◽  
Functional Link ◽  
Pathway Activation ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)–inducible transgenic mice (lck-ERT2-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4+CD8+ (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor αβ (TCRαβ) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8+TCRβlow cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process.

A Novel Cellular Pathway of SCL T-Leukemogenesis Revealed by a Conditional Transgenic Mouse Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1835-1835
Author(s):  
Joachim R. Gothert ◽  
Rachael Brake ◽  
C. Glenn Begley ◽  
David J. Izon
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Trichostatin A ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Surface Expression ◽  
Transgenic Mouse Model ◽  
Tamoxifen Treatment ◽  
Double Positive

Abstract The acquired activation of stem cell leukemia (SCL) during T-lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia. Here, we generated a novel tamoxifen-inducible transgenic mouse model (lck-ERT2-SCL) to study the cellular targets of acquired SCL activation during T-cell development. Upon tamoxifen treatment we observed the thymic emergence of abnormal, non-cycling CD8+TCRβlow and immature CD4+CD8+ (double-positive, DP) cells displaying increased viability. Unexpectedly, fetal thymic organ culture analysis of lck-ERT2-SCL thymi revealed the development of DP cells before the emergence of CD8+TCRβlow cells, which implied the derivation of CD8+TCRβlow cells from DPs rather than immature CD8 single-positive (SP) thymocytes. Interestingly, histone deacetylase (HDAC) inhibition with trichostatin A (TSA) had a divergent effect on SCL perturbed thymopoiesis: TSA increased T-cell receptor surface expression within DP and CD8 SP cells however did not alter the CD8 shifted CD4/CD8-ratio. Furthermore, we studied the expression of NOTCH1 in SCL induced TCRβlow thymocytes. Strikingly, we found that SCL induced NOTCH1-upregulation in DP TCRβlow cells. We therefore conclude that SCL promotes the emergence of abnormal CD8+TCRβlow cells by an only partially HDAC dependent mechanism from DP TCRβlow cells. Moreover, SCL induced DP TCRβlow cells are characterized by upregulated NOTCH1, which in turn might promote the effect of acquired NOTCH1 mutations during T-leukemogenesis.

scholarly journals Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2878-2886 ◽  
Author(s):  
Shu-Fang Wang ◽  
Misayo Aoki ◽  
Yasuhiro Nakashima ◽  
Yoriko Shinozuka ◽  
Hiroki Tanaka ◽  
...  
Keyword(s):  
T Cell ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Nucleotide Exchange ◽  
Double Positive ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Enhanced Expression ◽  
Rap1 Activation

SPA-1 (signal-induced proliferation associated gene-1) functions as a suppressor of myeloid leukemia by negatively regulating Rap1 signaling in hematopoietic progenitor cells (HPCs). Herein, we showed that transplantation of HPCs expressing farnesylated C3G (C3G-F), a Rap1 guanine nucleotide exchange factor, resulted in a marked expansion of thymocytes bearing unique phenotypes (CD4/CD8 double positive [DP] CD3− TCRβ−) in irradiated recipients. SPA-1−/− HPCs expressing C3G-F caused a more extensive expansion of DP thymocytes, resulting in lethal T-cell acute lymphoblastic leukemia (T-ALL) with massive invasion of clonal T-cell blasts into vital organs. The C3G-F+ blastic thymocytes exhibited constitutive Rap1 activation and markedly enhanced expression of Notch1, 3 as well as the target genes, Hes1, pTα, and c-Myc. All the T-ALL cell lines from C3G-F+ SPA-1−/− HPC recipients expressed high levels of Notch1 with characteristic mutations resulting in the C-terminal truncation. This proliferation was inhibited completely in the presence of a γ-secretase inhibitor. Transplantation of Rag2−/− SPA-1−/− HPCs expressing C3G-F also resulted in a marked expansion and transformation of DP thymocytes. The results suggested that deregulated constitutive Rap1 activation caused abnormal expansion of DP thymocytes, bypassing the pre-T-cell receptor and eventually leading to Notch1 mutations and Notch-dependent T-ALL.

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 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.

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

CD7/CD19 Double-Positive T-Cell Acute Lymphoblastic Leukemia

2006 ◽  
Vol 83 (4) ◽  
pp. 324-327
Author(s):  
Shinya Fujisawa ◽  
Fumihiko Tanioka ◽  
Toshihiko Matsuoka ◽  
Takachika Ozawa ◽  
Kensuke Naito ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Double Positive ◽  
Cell Acute Lymphoblastic Leukemia
Sign in / Sign up

Export Citation Format

Share Document