Telomeres and Telomerase in Pediatric Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4389-4389
Author(s):  
Johann Greil ◽  
Elke Kleideiter ◽  
Matthias Schwab ◽  
Petra Boukamp ◽  
Ewa Koscielniak ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Clinical Outcome ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Telomerase Activity ◽  
Leukemic Cells ◽  
Htert Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Shortened telomeres and elevated levels of telomerase activity are apparently characteristic features of hematologic neoplasias such as high-grade lymphomas and relapsing leukemia. Thus, their measurement might be useful for monitoring disease conditions or predicting clinical outcome. In order to investigate the potential of telomere length (TRF) and telomerase activity (TA) as prognostic indicator in pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) we analyzed TRF and TA in samples from 20 patients (age range 2–17.5 years). In addition, as TA is limited by the expression of the telomerase catalytic subunit (hTERT) we analyzed hTERT expression. We found that TRF varied widely (3.5 – 8.1 kb; mean ± SD: 6.4 +/− 1.3 kb) in leukemic cells and was significantly shorter (p<0.0001) than that of age-matched controls (8.3 ± 0.4 kb; n=19). Elevated levels of TA were present in 95% of the leukemic samples. Furthermore, expression of hTERT demonstrated a wide interindividual variability (range 141–424,000 normalized units). A statistically significant association between TA and hTERT expression was not found and TRF, TA and hTERT expression was not associated with the clinical outcome in pediatric T-ALL, thereby limiting their prognostic significance.

scholarly journals DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

2021 ◽  
Vol 22 (3) ◽  
pp. 1388
Author(s):  
Natalia Maćkowska ◽  
Monika Drobna-Śledzińska ◽  
Michał Witt ◽  
Małgorzata Dawidowska
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Epigenetic Modification ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Global Methylation ◽  
Current State ◽  
History Of ◽  
Cell Acute Lymphoblastic Leukemia

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

scholarly journals Does activation of the TAL1 gene occur in a majority of patients with T- cell acute lymphoblastic leukemia? A pediatric oncology group study

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 666-676 ◽  
Author(s):  
RO Bash ◽  
S Hall ◽  
CF Timmons ◽  
WM Crist ◽  
M Amylon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Leukemic Cells ◽  
Monoallelic Expression ◽  
Regulatory Sequences ◽  
Cis Acting ◽  
Polymorphic Dinucleotide ◽  
Cell Acute Lymphoblastic Leukemia

Almost 25% of patients with T-cell acute lymphoblastic leukemia (T-ALL) have tumor-specific rearrangements of the TAL1 gene. Although TAL1 expression has not been observed in normal lymphocytes, TAL1 gene products are readily detected in leukemic cells that harbor a rearranged TAL1 allele. Hence, it has been proposed that ectopic expression of TAL1 promotes the development of T-ALL. In this report, we show that TAL1 is expressed in the leukemic cells of most patients with T-ALL, including many that do not display an apparent TAL1 gene alteration. A polymorphic dinucleotide repeat in the transcribed sequences of TAL1 was used to determine the allele specificity of TAL1 transcription in primary T-ALL cells. Monoallelic expression of TAL1 was observed in the leukemic cells of all patients (8 of 8) bearing a TAL1 gene rearrangement. In the leukemic cells of patients without detectable TAL1 rearrangements, TAL1 transcription occurred in either a monoallelic (3 of 7 patients) or a biallelic (4 of 7 patients) fashion. Thus, TAL1 activation in these patients may result from subtle alterations in cis-acting regulatory sequences (affecting expression of a single TAL1 allele) or changes in trans-acting factors that control TAL1 transcription (affecting expression of both TAL1 alleles).

scholarly journals Toward a NOTCH1/FBXW7/RAS/PTEN–Based Oncogenetic Risk Classification of Adult T-Cell Acute Lymphoblastic Leukemia: A Group for Research in Adult Acute Lymphoblastic Leukemia Study

2013 ◽  
Vol 31 (34) ◽  
pp. 4333-4342 ◽  
Author(s):  
Amélie Trinquand ◽  
Aline Tanguy-Schmidt ◽  
Raouf Ben Abdelali ◽  
Jérôme Lambert ◽  
Kheira Beldjord ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Risk Patients ◽  
Cell Acute Lymphoblastic Leukemia

Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

Concurrent Subcutaneous Panniculitis-like T-Cell Lymphoma and B-Cell Acute Lymphoblastic Leukemia in 2 Pediatric Patients

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Geoffrey A. Smith ◽  
Anya L. Levinson ◽  
Robert T. Galvin ◽  
Leah E. Lalor ◽  
Timothy McCalmont ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Pediatric Patients ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
T Cell Lymphoma ◽  
Cell Acute Lymphoblastic Leukemia

Expanding The TLX1-Regulome In T Cell Acute Lymphoblastic Leukemia Towards Long Non-Coding RNAs

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 813-813
Author(s):  
Kaat Durinck ◽  
Joni Van der Meulen ◽  
Maté Ongenaert ◽  
Pieter-Jan Volders ◽  
Annelynn Wallaert ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Protein Coding ◽  
Chip Sequencing ◽  
Lncrna Expression ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Non Coding Rnas

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that results from the malignant transformation of T-cell precursors and affects children, adolescents and adults. In T-ALL, genetic lesions in several possible oncogenes and tumor suppressors have been shown to cooperatively contribute to leukemogenesis. The TLX1 (T-cell leukemia homeobox protein-1, HOX11) oncoprotein is aberrantly expressed in in 5-10% of pediatric patients and 30% of adult T-ALL patients due to chromosomal translocations. Although many downstream protein coding targets genes of TLX1 have been identified, the non-coding network downstream of TLX1 remains elusive. In this study we expand the TLX1 regulome towards long non-coding RNAs (lncRNAs). Hereto we measured the transcriptional response of all protein coding genes and 12,000 lncRNAs following TLX1 knock down in the ALL-SIL cell line using a custom designed mRNA/lncRNA expression platform (Agilent). In addition, similar mRNA-lncRNA expression profiles of 64 primary T-ALL patient samples were generated which included five TLX1+ cases. To establish the direct transcriptional TLX1 targets, we generated TLX1 ChIP-sequencing data from ALL-SIL leukemic cells. We confirm direct regulation of previously established protein coding gene targets and de novo TLX1 motif discovery also identified RUNX1 as an important mediator of the global TLX1 transcriptional network (Della Gatta et al., Nature Medicine, 2012). Complementary to these data, our analysis for the first time establishes the TLX1 driven lncRNAome in thymocyte derived leukemic cells. Remarkably, the majority of TLX1 controlled lncRNAs were upregulated suggesting that they may be implicated in the TLX1 driven repression of protein coding gene expression. Finally, pairwise mRNA-lncRNA correlation analysis allowed functional annotation of TLX1 targeted lncRNAs. In conclusion, we present the first landscaping of the genome-wide binding pattern of TLX1 and provide evidence for a previously unestablished role of lncRNAs in the TLX1 regulatory network. Disclosures: No relevant conflicts of interest to declare.

TGF-β induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6695-6698 ◽  
Author(s):  
Jean-Michel Terme ◽  
Ludovic Lhermitte ◽  
Vahid Asnafi ◽  
Pierre Jalinot
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Lymphoblastic Leukemia ◽  
Transforming Growth Factor Β ◽  
Leukemic Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Ubiquitin Proteasome ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Proteasome Pathway

Abstract T-cell acute lymphoblastic leukemia 1 (TAL1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelial cells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration of TAL1 is regulated by transforming growth factor β (TGF-β), which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1, which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF-β and phosphatidylinositol 3-kinase/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.

scholarly journals The evolution of relapse of adult T cell acute lymphoblastic leukemia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Inés Sentís ◽  
Santiago Gonzalez ◽  
Eulalia Genescà ◽  
Violeta García-Hernández ◽  
Ferran Muiños ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Leukemic Cells ◽  
Driver Mutations ◽  
Pediatric Malignancy ◽  
Genetic Mechanisms ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Moment

Abstract Background Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.

Dicentric Translocation (9;12) in Acute Lymphoblastic Leukemia: A Chromosomal Abnormality with an Excellent Prognosis?

2017 ◽  
Vol 103 (1_suppl) ◽  
pp. S44-S46
Author(s):  
Laura Illade ◽  
Victoria Fioravantti ◽  
Maitane Andion ◽  
Carmen Hernandez-Marques ◽  
Luis Madero ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Chromosomal Abnormality ◽  
Pediatric Patients ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
International Study ◽  
Leukemic Cells ◽  
Response To Treatment ◽  
Molecular Alteration

Purpose Recurrent chromosomal abnormalities present in the leukemic cells of pediatric patients with acute lymphoblastic leukemia (ALL) often allow us to classify patients according to their prognosis, in order to establish further treatment. The dicentric translocation (9;12) consists of the rearrangement of the short arms of chromosomes 9 and 12 generating a dicentric chromosome (9;12). Patients with this alteration present a very good response to treatment and an excellent prognosis. Methods We present the case of an adolescent with ALL in which the dicentric translocation (9;12) was observed in the karyotype of the blasts at diagnosis. Results and conclusion Given the excellent results of our patient and most of the series published to date, an international study is necessary to determine the true prognostic significance of this molecular alteration.

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