A New Recurrent 9q34 Duplication in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 89-89
Author(s):  
Pieter Van Vlierberghe ◽  
Jules P.P. Meijerink ◽  
Charles Lee ◽  
Adolfo A. Ferrando ◽  
A. Thomas Look ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Fish Analysis ◽  
Comparative Genome Hybridization ◽  
Patient Cohort ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Chemotherapeutic Treatment

Abstract Over the last decade, genetic characterization of pediatric T cell acute lymphoblastic leukemia (T-ALL) has led to the identification of a variety of chromosomal abnormalities, including translocations, deletions and amplifications. In this study, we used array-comparative genome hybridization (array-CGH) to identify a novel recurrent 9q34 amplification in 33 percent (12/36) of pediatric T-ALL samples, which is therefore one of the most frequent cytogenetic abnormalities observed in T-ALL thus far. The exact size of the amplified region differed slightly among patients, but the critical region involved VAV2, TRAF2 and NOTCH1. FISH analysis revealed that this 9q34 amplification was the result of a 9q34 duplication on one chromosome and could be identified in 17 to 39 percent of the leukemic cells at diagnosis. Although the presence of this leukemic subclone did not predict for poor clinical outcome in our small patient cohort, leukemic cells carrying this duplication were still present at times of relapse, indicating that these cells effectively survived intensive chemotherapeutic treatment. Episomal NUP214-ABL1 amplification and activating mutations in NOTCH1, two other recently identified 9q34 abnormalities in T-ALL, were also detected in our pediatric patient cohort. We showed that both genetic abnormalities are independent from this newly identified 9q34 duplication.

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).

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.

The Recurrent SET-NUP214 Fusion as a New HOXA Activation Mechanism in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 233-233 ◽  
Author(s):  
Pieter Van Vlierberghe ◽  
Joelle Tchinda ◽  
Martine van Grotel ◽  
Charles Lee ◽  
H. Berna Beverloo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Transcriptional Activation ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Molecular Genetic ◽  
Activation Mechanism ◽  
Fusion Product ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Hoxa Genes

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner possibly delineating specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv(7)(p15q34) cases, is characterized by elevated expression of HOXA genes. Using a gene expression based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new cases with elevated HOXA levels. Using array-CGH, a cryptic and recurrent deletion, del(9)(q34.11q34.13), was exclusively identified in 3 of these 5 cases. This deletion results in a conserved SET-NUP214 fusion product, that was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CMR1 and DOT1L leading to the transcriptional activation of HOXA genes. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 contributes to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.

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.

Efficacy of Imatinib-Based Therapy in a Patient with Resistant NUP214-ABL1 T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4329-4329
Author(s):  
Jacques Delaunay ◽  
Raouf Ben Abdelali ◽  
Cyrille Touzeau ◽  
Patrice Chevallier ◽  
Guillaume Thierry ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Pcr Analysis ◽  
Fish Analysis ◽  
Molecular Response ◽  
Rt Pcr ◽  
First Case ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease which represents 25% of adult ALL. In T-ALL, many cryptic abnormalities can only be detected by FISH or RQ-PCR. Herein, we describe the case of a 25 year-old man presenting with a NUP214-ABL1 T-ALL. This rearrangement is observed in about 5% of adult T-ALL, results in ABL1 amplification and has been associated with sensitivity to imatinib in vitro At diagnosis, the patient presented with multiple lymphadenopathies and a high WBC (120 G/L). Blast cells expressed T (CD3, CD5, CD7, and CD8) and myeloid (CD13 and CD33) markers. Karyotype was normal, while FISH analysis revealed HOX11L2 rearrangement and extrachromosomal ABL amplification. Presence of NUP214 exon32-ABL1 exon2 transcript and overexpression of HOX11L2 were both confirmed by RT-PCR. Treatment induction according to the GRAALL-2003 protocol, consisted of a corticosteroïd prephase (d1–7) followed by 5-drug induction (doxorubicin, cyclophosphamide, vincristine, corticosteroid and asparaginase) (d8–21). Because of ALL resistance and presence of severe infection, treatment was stopped at d21 and salvage therapy associating imatinib (400 mg, bid), vincristine (2 mg d1,d8,d15,d21) and dexamethasone (30 mg/m2 d1–2,d8–9,d15–16,d21–22) was initiated at d25. At d50, the patient had reached complete hematological response. He then received monthly consolidation courses combining imatinib (400 mg bid d1–28), vincristine (2 mg d1) and prednisolone (40mg/m2 d1–7). After the second course, he reached major molecular response at d120 (NUP214/ABL1 = 1x10-3 by RQ-PCR) but relapsed at d150. Karyotype was still normal and FISH analysis showed persistance of HOX11L2 rearrangement but loss of extrachromosomal ABL amplification and presence of a third ABL signal (cryptic rearrangement) in the majority of metaphases. Quantitative RT-PCR analysis detected a low level of NUP214/ABL1. We initiated a second salvage combining dasatinib (70 mg bid) and Hyper-CVAD, with achievement of a second hematological CR. After two consolidation courses, the patient is still in hematological CR (8 months) and complete molecular response. He will receive a double cord blood transplant In conclusion, we report here the first case of transitory imatinib efficacy in a patient with NUP214/ABL1 T-ALL, followed by achievement of a secondary remission with dasatinib, despite the partial loss of NUP214-ABL1, in favor of the use of ABL inhibitors in this specific T-ALL subset. We also raise the hypothesis that NUP214/ABL1 may be a secondary oncogenic event.

scholarly journals The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4668-4680 ◽  
Author(s):  
Pieter Van Vlierberghe ◽  
Martine van Grotel ◽  
Joëlle Tchinda ◽  
Charles Lee ◽  
H. Berna Beverloo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Activation Mechanism ◽  
Fusion Product ◽  
Comparative Genomic ◽  
Hoxa Cluster ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Hoxa Genes

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression–based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.

scholarly journals B cell acute lymphoblastic leukemia (ALL) with a 14q+ chromosome abnormality

Blood ◽  
1979 ◽  
Vol 53 (2) ◽  
pp. 235-243
Author(s):  
DG Roth ◽  
MC Cimino ◽  
D Variakojis ◽  
HM Golomb ◽  
JD Rowley
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Chromosome Banding ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Marker Chromosome ◽  
Leukemic Cells ◽  
Chromosome 11 ◽  
Adenosine Deaminase Activity ◽  
Cell Acute Lymphoblastic Leukemia

An adult patient with acute lymphoblastic leukemia associated with a 14q+ marker chromosome is presented. The abnormality resulted from a translocation of material from the long arm of chromosome 11. The leukemic cells were found to be B cells on the basis of surface immunoglobulins, lack of receptors for sheep erythrocytes, and a characteristically low level of adenosine deaminase activity. In other patients with ALL studied by us or reported by others in whom chromosome banding was done, a 14q+ chromosome was present in only one instance, also a case of B cell ALL. These two cases are the only examples of B cell ALL studied with chromosome banding reported to date. The frequent occurrence of a 14q+ chromosome in other malignant lymphoproliferative diseases of B cell origin suggests that a general association may exist between the 14q+ abnormality and B cell neoplasms. Cytogenetic analysis may therefore be useful in defining subtypes of ALL and in relating specific chromosomal abnormalities to lymphoproliferative disorders.

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