scholarly journals Alteration in Expression of miR-32 and FBXW7 Tumor Suppressor in Plasma Samples of Patients with T-cell Acute Lymphoblastic Leukemia

2020 ◽  
Vol Volume 12 ◽  
pp. 1253-1259
Author(s):  
Sanaz Mansouri ◽  
Behzad Khansarinejad ◽  
Ghasem Mosayebi ◽  
Aziz Eghbali ◽  
Mahdieh Mondanizadeh
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Plasma Samples ◽  
Cell Acute Lymphoblastic Leukemia

Analysis of Clonal T-Cell Receptor Gamma Gene Rearrangements, NOTCH1, FBW7 and PTEN Mutations in Paired Pediatric T-Cell Acute Lymphoblastic Leukemia Samples at Diagnosis and Relapse Reveals Evidence of Relapse in New Leukemic Clones.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1488-1488
Author(s):  
Qing Chen ◽  
Amanda Larson Gedman ◽  
Larry H. Matherly ◽  
Jeffrey W. Taub
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Gene Rearrangements ◽  
Pten Mutation ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Mutations

Abstract Relapse following remission induction chemotherapy remains the major challenge in the successful treatment of childhood T cell acute lymphoblastic leukemia (T-ALL). Relapse often results from the outgrowth of residual leukemia cells that are present below the limit of detection or involves a new therapy-related secondary leukemia. Individualization of treatment might improve the outcome and long-term quality of life for T-ALL patients. Molecular genetic markers represent clinically useful factors which predict responses to therapy. T-cell receptor gamma (TCRG) gene rearrangements occur in more than 90% of T-ALL and provide markers of lymphoblast clonality. Determining rearrangements in the TCRG could be critical to the diagnosis and treatment of T-ALL in children and adults. Mutations in the NOTCH1, FBW7, and PTEN genes have been identified at high frequencies in pediatric T-ALL cases. Activating NOTCH1 mutations have been found in more than 50% of ALL patients, resulting in constitutive NOTCH1 signalling, whereas PTEN mutations are inactivating, resulting in increased PI3K/AKT signalling. FBW7 has been identified as an important tumor suppressor. Several studies reported that frequent mutations in the substrate binding domain (e.g. Arg465, Arg479, Arg505) for FBW7 in T-ALL cell lines and primary T-ALL specimens result in sustained NOTCH1 levels and downstream signalling and gamma secretase inhibitor resistance, suggesting an alternate mechanism for NOTCH1 deregulation. To investigate the mechanism of T-ALL relapse, we analyzed the TCRG gene rearrangements and mutational status of the NOTCH1, FBW7, and PTEN genes by comparing sequences in paired diagnostic and relapsed T-ALL samples from 11 children to evaluate their stabilities throughout disease progression and association with treatment failure. The age distribution of 11 patients ranged from four years to fifteen years. Original TCRG sequence (a measure of leukemia clonality) was fully preserved at relapse in 3 (27.3%) patients. Clonal evolution was identified in 8 (72.7%) patients, reflected in changes in TCRG sequence. In 3 patients at diagnosis, NOTCH1 mutations were detected. At relapse, the major leukemia clones exhibited different NOTCH1 mutations. For another patient, a NOTCH1 mutation was detected at relapse but not at diagnosis. No FBW7 mutations were detected either at diagnosis or relapse. In 5 patients at diagnosis, PTEN mutations were detected and at relapse, 2 preserved the same mutation and 2 lost their mutations, while the additional sample harbored a different PTEN mutation. Our comparative sequence analysis of pediatric T-ALL samples provided detailed insight in the stabilities and changes of TCRG rearrangements and NOTCH1, FBW7 and PTEN mutation status during disease development. Re-emergence of the initial ALL clone or the occurrence of a secondary ALL clone may be clinically important to guide subsequent therapy. Collectively, our results suggest that for the majority of cases, relapse is associated with appearance of a new leukemic clone. For a subset of these cases, this is accompanied by a distinct subset of NOTCH1 mutations and, to a lesser extent, PTEN mutations. FBW7 mutations are rare. Better understanding of the changes in oncogenes and tumor suppressor genes with progression of T-ALL may identify new targets for therapy and facilitate the design of individualized therapy for this disease. Further study is needed to determine whether the newly identified relapse ALL clones were present at diagnosis as minor subclinical populations.

scholarly journals A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Moneeb A. K. Othman ◽  
Martina Rincic ◽  
Joana B. Melo ◽  
Isabel M. Carreira ◽  
Eyad Alhourani ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Lymphoblastic Leukemia ◽  
Normal Karyotype ◽  
Comparative Genomic ◽  
Suppressor Genes ◽  
Molecular Approaches ◽  
Cell Acute Lymphoblastic Leukemia

Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95).

scholarly journals MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia

Leukemia ◽  
2014 ◽  
Vol 29 (4) ◽  
pp. 798-806 ◽  
Author(s):  
E Mets ◽  
J Van der Meulen ◽  
G Van Peer ◽  
M Boice ◽  
P Mestdagh ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2180-2186 ◽  
Author(s):  
JM Cayuela ◽  
A Madani ◽  
L Sanhes ◽  
MH Stern ◽  
F Sigaux
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Lymphoblastic Leukemia ◽  
Genetic Defect ◽  
Suppressor Gene ◽  
Genetic Alteration ◽  
Multiple Tumor ◽  
Cell Acute Lymphoblastic Leukemia

No constant genetic alteration has yet been unravelled in T-cell acute lymphoblastic leukemia (T-ALL), and, to date, the most frequent alteration, the SIL-TAL1 deletion, is found in approximately 20% of cases. Recently, two genes have been identified, the multiple tumor- suppressor gene 1 (MTS1) and multiple tumor-suppressor gene 2 (MTS2), whose products inhibit cell cycle progression. A characterization of the MTS locus organization allowed to determine the incidence of MTS1 and MTS2 inactivation in T-ALL. MTS1 and MTS2 configurations were determined by Southern blotting using 8 probes in 59 patients with T- ALL (40 children and 19 adults). Biallelic MTS1 inactivation by deletions and/or rearrangements was observed in 45 cases (76%). Monoallelic alterations were found in 6 cases (10%). The second MTS1 allele was studied in the 4 cases with available material. A point mutation was found in 2 cases. The lack of MTS1 mRNA expression was observed by Northern blot analysis in a third case. A normal single- strand conformation polymorphism pattern of MTS1 exons 1alpha and 2 was found and MTS1 RNA was detected in the fourth case, but a rearrangement occurring 5′ to MTS1 exon 1 alpha deleting MTS1 exon 1Beta was documented. One case presented a complex rearrangement. Germline configuration for MTS1 and MTS2 was found in only 7 cases. The localization of the 17 breakpoints occurring in the MTS locus were determined. Ten of them (59%) are clustered in a 6-kb region located 5 kb downstream to the newly identified MTS1 exon 1Beta. No rearrangement disrupting MTS2 was detected and more rearrangements spared MTS2 than MTS1 (P<.01). MTS1 but not MTS2 RNA was detected by Northern blotting in the human thymus. These data strongly suggest that MTS1 is the functional target of rearrangements in T-ALL. MTS1 inactivation, observed in at least 80% of T-ALL, is the most consistent genetic defect found in this disease to date.

scholarly journals Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia

2014 ◽  
Vol 7 (352) ◽  
pp. ra111-ra111 ◽  
Author(s):  
V. R. Sanghvi ◽  
K. J. Mavrakis ◽  
J. Van der Meulen ◽  
M. Boice ◽  
A. L. Wolfe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4169-4173 ◽  
Author(s):  
Alejandro Gutierrez ◽  
Alex Kentsis ◽  
Takaomi Sanda ◽  
Linda Holmfeldt ◽  
Shann-Ching Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Molecular Subtypes ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Missense Mutations ◽  
Thymocyte Development ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation.

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