scholarly journals Extra Copies of der(21)t(12;21) plus Deletion ofETV6Gene due to dic(12;18) in B-Cell Precursor ALL with Poor Outcome

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Marina Araújo Fonzar Hernandes ◽  
Terezinha de Jesus Marques-Salles ◽  
Hasmik Mkrtchyan ◽  
Eliane Maria Soares-Ventura ◽  
Edinalva Pereira Leite ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Good Prognosis ◽  
Chromosome 21 ◽  
Cell Precursor ◽  
Childhood All ◽  
Molecular Cytogenetic ◽  
Cytogenetic Studies ◽  
Chromosome 12P

Acute lymphoblastic leukemia (ALL), CD10+ B-cell precursor, represents the most frequent type of childhood ALL from 3 to 6 years of age. The t(12;21)(p13;q22) occurs in 25% of cases of B-cell precursor ALL, it is rare in children less than 24 months and have been related to good prognosis. Some relapse cases and unfavorable prognosis in ALL CD10+ are associated with t(12;21) bearing additional aberrations as extra copies of chromosome 21 andETV6gene loss. This report describes the case of a 15 month-year old girl, who displayed a karyotype with addition on chromosome 12p plus trisomy 10 and tetrasomy of chromosome 21. Molecular cytogenetic studies revealed two extra copies of the der(21) t(12;21), trisomy 10 and deletion of the secondETV6gene due to the dic(12;18). These findings show the great importance of molecular cytogenetic studies to clarify complex karyotypes, to define prognostic, to carry out risk group stratification and to support correctly disease treatment in childhood acute lymphoblastic leukemia.

Amplification of RUNX1 gene in two new cases of childhood B-cell precursor acute lymphoblastic leukemia: A case report

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e21000-e21000
Author(s):  
A. Fauzdar ◽  
A. Mahajan ◽  
D. Jain ◽  
M. Mishra ◽  
V. Raina
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Fish Analysis ◽  
Cell Precursor ◽  
Childhood All ◽  
Mll Gene ◽  
Runx1 Gene

e21000 Background: Chromosome abnormalities of leukemia cells have important prognostic significance in childhood acute lymphoblastic leukemia (ALL). B-cell precursor acute lymphoblastic leukemia (BCP-ALL) ETV6/RUNX1 (alias TEL/AML1) is most frequent i.e. 15 - 35% in the children with 2 - 18 age group. We report two new cases with Pre B- cell ALL without ETV6/RUNX1 rearrangement, showing amplification of AML1 gene detected by FISH analysis. Methods: Bone marrow samples were analyzed for chromosomal abnormalities with conventional G-banding techniques and interphase fluorescence in situ hybridization (FISH) using probes to detect BCR/ABL t(9;22)(q34-q11) fusion, cryptic TEL/AML1 t(12:21)(p13-q22) and MLL rearrangement for del 11q23. Results: In first case a 3-year girl with four copies of AML (RUNX1) gene were observed in 95% of the cell with normal two copies of TEL (ETV6) gene in both interphase and metaphase FISH. We observed BCR-ABL negative translocation and no MLL gene rearrangement in all the interphase cells after doing FISH. We got a normal 46XX karyotype from bone marrow with conventional cytogenetics (CC) in the same patient. In second case, a 4-year male we observed four copies of AML and two copies of TEL gene in more than 80% of cells. In this patient, we got BCR-ABL negative translocation and three copies of MLL gene without any rearrangement through FISH. We got normal 46XY karyotype in the same patient through CC. Conclusions: In both the patients, we observed hyperdiploidy detected with four copies of RUNX1 gene showing tetrasomy of chromosome 21 detected with metaphase FISH analysis whereas G-banding shows normal diploidy. Bone marrow karyotype in combination with molecular cytogenetic techniques like FISH should be done for improvement in sensitivity and accurate cytogenetic analysis in childhood ALL patients for proper identification of prognostic group for optimum treatment. This is one of the few reported studies worldwide for amplification of RUNX1 gene from Indian subcontinent in childhood BCP-ALL. No significant financial relationships to disclose.

scholarly journals Intrachromosomal Amplification of Chromosome 21 in Childhood Acute Lymphoblastic Leukemia: Study of 3 Cases

2021 ◽  
pp. 592-598
Author(s):  
Aleksandra Mroczkowska ◽  
Monika Lejman
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Single Nucleotide Polymorphism Array ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Genetic Diagnostics ◽  
Cell Precursor ◽  
Childhood All ◽  
Fish Method

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The presence or absence of a characteristic genetic abnormality usually observed in childhood ALL plays a very important role in determining the prognosis and stratification for treatment. Intrachromosomal amplification of chromosome 21 (iAMP21) is an uncommon high-risk chromosomal abnormality than can occur only in 2% of childhood B-cell precursor lymphoblastic leukemia. Molecular genetic analysis and the fluorescence in situ hybridization (FISH) technique are the basic methods used to detect the presence of the most common genetic abnormalities, the presence or absence of which has an impact on the patient’s classification into the appropriate risk group. This work presents 3 BCP-ALL iAMP21-positive patients who were detected during routine genetic diagnostics using the FISH method and microarray test. iAMP21 is associated with a poor prognosis and high risk for relapse. Children with B-cell precursor lymphoblastic leukemia with this genetic entity are associated with a delayed treatment response. The FISH method and single-nucleotide polymorphism array provides a useful method to detect characteristic genetic changes.

Clinical Significance of NT5C2 Mutations in Children with First Relapse of B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3789-3789 ◽  
Author(s):  
Jana Hof ◽  
Annabell Szymansky ◽  
Arend von Stackelberg ◽  
Cornelia Eckert ◽  
Renate Kirschner-Schwabe
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Clinical Significance ◽  
Lymphoblastic Leukemia ◽  
Similar Proportion ◽  
Cell Precursor ◽  
Childhood All ◽  
Relapse Treatment ◽  
First Relapse

Abstract The ubiquitous cytosolic 5´nucleotidase II (NT5C2) dephosphorylates purine nucleotide monophosphates and has an important role in cellular purine metabolism. Increased levels of nucleotidase activity have been correlated with resistance to nucleoside analog drugs that are commonly used in the treatment of children with acute lymphoblastic leukemia (ALL). Recently, activating mutations of NT5C2 have been identified in relapsed childhood ALL. NT5C2 mutations were present in 20% and 10% of children with relapsed T-cell ALL and with relapsed B-cell precursor ALL, respectively. In vitro studies showed that NT5C2 mutations conferred an increased resistance to purine analog drugs to ALL cell lines. However, the predictive and prognostic value of NT5C2 mutations for response and outcome of patients has remained elusive and systematic studies are warranted. Therefore, we studied the presence of NT5C2 mutations in 259 children with first relapse of B-cell precursor ALL. The patient cohort was a representative subset the German relapse trial ALL-REZ BFM 2002. NT5C2 exons 9, 13, 15 and 16 were sequenced according to Sanger in leukemic samples taken at diagnosis of first relapse. The clinical significance of NT5C2 mutations was assessed by comparing clinical parameters and survival differences between patients with and without NT5C2 mutation, and by multivariate Cox regression modelling. We identified NT5C2 mutations in 5.8% (15/259) of patients with first relapse of B-cell precursor ALL. This confirms the overall lower NT5C2 mutation rate in children with relapsed B-cell precursor ALL compared to those with relapsed T-cell ALL. Sixty percent (9/15) of the patients with NT5C2 mutation showed a G to A transition in codon 367 in exon 13. This mutation substitutes arginine with glutamine (p.R367Q) and represents a mutation hot spot in relapsed T-cell ALL. Our study reveals that p.R367Q is the predominant site of mutation also in relapsed ALL of B-cell precursor lineage. Patients with NT5C2 mutation significantly more often presented with a very early relapse within 18 months after initial diagnosis (P<0.001) compared to patients with wildtype NT5C2. Likewise, the median time of first remission was significantly shorter in patients with NT5C2 mutation (1.5 years versus 2.83 years, P<0.001). Regarding outcome after relapse treatment, patients with NT5C2 mutation showed a significantly reduced event-free (0.143±0.094 vs. 0.483±0.032; P=0.003) and overall survival rate (0.284±0.121 vs. 0.569±0.033; P=0.007) compared to patients with wildtype NT5C2. The predominant second event in relapse patients with NT5C2 mutation was the occurrence of a second relapse. Accordingly, the cumulative incidence of second relapse was significantly increased in patients with NT5C2 mutations compared to patients with wildtype NT5C2 (0.643±0.140 vs. 0.302±0.030; P=0.001). Multivariate analysis including time of relapse and site of relapse as established risk stratification factors in relapsed ALL revealed that NT5C2 mutation is an independent predictor for the occurrence of a second relapse (P=0.002). Surprisingly, mutation of NT5C2 was not associated with response to relapse treatment. Response was assessed by histological examination and by PCR-based sensitive detection of minimal residual disease at different time points during treatment. However, patients with NT5C2 mutation showed a similar proportion of responding and non-responding patients than relapsed children with wildtype NT5C2. We conclude that mutation of NT5C2 can serve as predictor for the occurrence of a second relapse independent of response to relapse treatment in children with relapsed B-cell precursor ALL. Disclosures No relevant conflicts of interest to declare.

Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2519-2526 ◽  
Author(s):  
Petra S. Bachmann ◽  
Rosemary Gorman ◽  
Karen L. MacKenzie ◽  
Louise Lutze-Mann ◽  
Richard B. Lock
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor ◽  
B Cell ◽  
Nuclear Translocation ◽  
Lymphoblastic Leukemia ◽  
Glucocorticoid Resistance ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Childhood All ◽  
Dexamethasone Resistance

AbstractGlucocorticoids are among the most effective agents used in the treatment of childhood acute lymphoblastic leukemia (ALL), and patient response to treatment is an important determinant of long-term outcome. Despite its clinical significance, the molecular basis of glucocorticoid resistance in lymphoid malignancies is still poorly understood. We have recently developed a highly clinically relevant experimental model of childhood ALL, in which primary childhood ALL biopsies were established as xenografts in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The in vivo and in vitro responses of a panel of these xenografts to the glucocorticoid, dexamethasone, reflected the outcome of the patients from whom they were derived. In this report we show that glucocorticoid resistance in B-cell precursor (BCP) ALL xenografts was not due to down-regulation of the glucocorticoid receptor (GR) nor to defective ligand binding of the GR. Moreover, dexamethasone-induced GR translocation from the cytoplasm to the nucleus was comparable in all xenografts. However, glucocorticoid resistance was associated with profoundly attenuated induction of the BH3-only proapoptotic protein, Bim, when xenograft cells were exposed to dexamethasone. These results show that dexamethasone resistance in BCP ALL xenografts occurs downstream of ligand-induced nuclear translocation of the GR, but upstream of Bim induction.

Minimal Residual Disease Values Discriminate Between Low and High Relapse Risk in Children With B-Cell Precursor Acute Lymphoblastic Leukemia and an Intrachromosomal Amplification of Chromosome 21: The Austrian and German Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster (ALL-BFM) Trials

2008 ◽  
Vol 26 (18) ◽  
pp. 3046-3050 ◽  
Author(s):  
Andishe Attarbaschi ◽  
Georg Mann ◽  
Renate Panzer-Grümayer ◽  
Silja Röttgers ◽  
Manuel Steiner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Intermediate Risk ◽  
Cell Precursor ◽  
Minimal Residual

Purpose We aimed to identify relapse predictors in children with a B-cell precursor acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21), a novel genetic entity associated with poor outcome. Patients and Methods We screened 1,625 patients who were enrolled onto the Austrian and German ALL–Berlin-Frankfurt-Münster (ALL-BFM) trials 86, 90, 95, and 2000 with ETV6/RUNX1-specific fluorescent in situ hybridization probes, and we identified 29 patient cases (2%) who had an iAMP21. Minimal residual disease (MRD) was quantified with clone-specific immunoglobulin and T-cell receptor gene rearrangements. Results Twenty-five patients were good responders to prednisone, and all achieved remission after induction therapy. Eleven patients experienced relapse, which included eight who experienced relapse after cessation of front-line therapy. Six-year event-free and overall survival rates were 37% ± 14% and 66% ± 11%, respectively. Results of MRD analysis were available in 24 (83%) of 29 patients: nine (37.5%) belonged to the low-risk, 14 (58.5%) to the intermediate-risk, and one (4%) to the high-risk group. MRD results were available in 8 of 11 patients who experienced a relapse. Seven occurred among the 14 intermediate-risk patients, and one occurred in the high-risk patient. Conclusion The overall and early relapse rates in the BFM study were lower than that in a previous United Kingdom Medical Research Council/Childhood Leukemia Working Party study (38% v 61% and 27% v 47%, respectively), which might result from more intensive induction and early reintensification therapy in the ALL-BFM protocols. MRD values were the only reliable parameter to discriminate between a low and high risk of relapse (P = .02).

Molecular cytogenetic characterization ofTCF3 (E2A)/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia

2007 ◽  
Vol 46 (5) ◽  
pp. 478-486 ◽  
Author(s):  
Kerry E. Barber ◽  
Christine J. Harrison ◽  
Zoe J. Broadfield ◽  
Adam R. M. Stewart ◽  
Sarah L. Wright ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Molecular Cytogenetic ◽  
Cytogenetic Characterization

Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 117 (25) ◽  
pp. 6848-6855 ◽  
Author(s):  
Vikki Rand ◽  
Helen Parker ◽  
Lisa J. Russell ◽  
Claire Schwab ◽  
Hannah Ensor ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Standard Therapy ◽  
Lymphoblastic Leukemia ◽  
Chromosome 21 ◽  
Cell Precursor ◽  
Genetic Event ◽  
Distinct Subgroup ◽  
Genomic Characterization ◽  
Complex Structural

Abstract Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome.

Mutations and Deletions of the TP53 Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia

2011 ◽  
Vol 29 (23) ◽  
pp. 3185-3193 ◽  
Author(s):  
Jana Hof ◽  
Stefanie Krentz ◽  
Claudia van Schewick ◽  
Gabriele Körner ◽  
Shabnam Shalapour ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Tp53 Gene ◽  
Cell Precursor ◽  
Childhood All ◽  
Number Of Patients ◽  
First Relapse

Purpose In the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies. Patients and Methods Therefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Mü nster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification. Results We observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G2-M phase of the cell cycle at relapse diagnosis. Conclusion Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.

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