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 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.

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.

Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia.

1998 ◽  
Vol 16 (12) ◽  
pp. 3768-3773 ◽  
Author(s):  
C H Pui ◽  
J E Rubnitz ◽  
M L Hancock ◽  
J R Downing ◽  
S C Raimondi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Childhood All ◽  
Mll Gene ◽  
Blast Cells

PURPOSE To reassess the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We prospectively studied 334 newly diagnosed cases of this disease, using a comprehensive panel of antibodies that represented five myeloid cluster groups (CD13, CD14, CD15, CD33, and CD65). Blast cells were tested for ETV6 and MLL rearrangement using Southern blot analysis. RESULTS CD13 was expressed in 13.7% of cases, CD14 in 1%, CD15 in 6.6%, CD33 in 16%, and CD65 in 9.7%. Approximately one third of cases (31.4%) expressed one or more of these antigens (B-cell precursor, 31.9%; T-cell, 28.8%), while 10.5% expressed two or more (B-cell precursor, 11.3%; T-cell, 6.1%). Among the B-cell precursor leukemias, myeloid-associated antigen expression was significantly associated with a lack of hyperdiploidy and rearrangements of ETV6 or MLL gene. Most of the cases with MLL rearrangements (82%) expressed CD65, CD15, and CD33, either alone or in combination, whereas 48% of those with a rearranged ETV6 gene expressed CD13, CD33, or both. Myeloid-associated antigen expression did not correlate with event-free survival, whether the analysis was based on any of the five antigens in our panel or on the three more commonly tested antigens (CD13, CD33, and CD65). Importantly, this finding was not affected by exclusion of patients with ETV6 or MLL gene rearrangements. CONCLUSION Even though blast cell expression of myeloid-associated antigen expression shows significant associations with specific genetic abnormalities, it lacks prognostic value in childhood ALL.

ERG Intragenic Deletion Characterizes a Distinct Oncogenic Subtype of B-Cell Precursor Acute Lymphoblastic Leukemia with a Favourable Outcome Despite Frequent IKZF1 Deletions

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 121-121
Author(s):  
Emmanuelle Clappier ◽  
André Baruchel ◽  
Jérôme Rapion ◽  
Aurélie Caye ◽  
Ahlème Khemiri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Favourable Outcome ◽  
Fish Analysis ◽  
Cell Precursor ◽  
Pcr Assay ◽  
Genetic Lesion ◽  
Intragenic Deletion

Abstract Abstract 121 The genetic landscape of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in children above 10 years and adolescents remains poorly defined. Specifically, more than half of these patients have none of the cytogenetic abnormalities that define oncogenic subtypes and underlie risk stratification. To uncover new genetic abnormalities in these unassigned cases, we studied 85 BCP-ALL from patients aged 10 to 17 diagnosed at St-Louis hospital (Paris, France), for which the main classifying genetic lesions were assessed (i.e. high hyperdiploidy, t(12;21)/ETV6-RUNX1, t(1;19)/TCF3-PBX1, t(9;22)/BCR-ABL1, iAMP21, MLL translocations, low hypodiploidy, and near haploidy). Fifty of these BCP-ALL presented no classifying genetic lesions. Paired leukemic and remission samples could be analysed by high density array-CGH (Agilent 1M arrays) in 17 of these unassigned cases. We focused on acquired, focal, and recurrent copy-number abnormalities. A mono-allelic intragenic deletion of the ETS-related Gene (ERG) was found in 3 cases. ERG belongs to the ETS family of transcription factors and is implicated in chromosomal translocations associated with several cancer types including acute myeloid leukemia. The possibility of a cryptic unbalanced translocation was ruled out in the 3 cases by FISH analysis. The deletions encompassed exons 3 to 7, or 3 to 9, and the breakpoints were tightly clustered. Based on the breakpoint sequences we designed a PCR assay that allowed us to screen ERG intragenic deletions in the whole cohort. ERG deletion was identified in 9 additional cases, none of them having any of the known classifying genetic lesions, bringing up to 25% (12 out of 50) the frequency of ERG deletion in unassigned BCP-ALL of children older than 10. These results suggested that ERG deletion characterized a novel oncogenic subtype of BCP-ALL. Of note, these results were consistent with independent data of Harvey et al. (2010) that reported ERG deletions in a distinct gene-expression cluster. To confirm and extend these findings in the whole population of paediatric BCP-ALL, we used our breakpoint-specific PCR assay to screen ERG deletions in an independent cohort of 822 unselected patients aged 1 to 17, enrolled in the EORTC 58951 trial. ERG deletion was identified in 31/822 (3.7%) patients. Again, none of them had another known classifying genetic lesion, confirming that ERG deletion characterizes a distinct oncogenic subtype. Patients with ERG deletion were significantly older compared to other patients (median 7.0 vs 4.0, p=0.002), but they had similar white blood counts at diagnosis. They had a favourable outcome, with a 8-year event free survival (EFS) of 82.4% and overall survival (OS) of 96.0%, which is similar to EFS of 83.4% and OS of 91.6% obtained for patients having no very high risk initial features (i.e. no t(9;22)/BCR-ABL1, MLL rearrangement or haploidy/low hypodiploidy). IKZF1 deletion is a cooperative genetic lesion that has been recently shown to be associated with a poor outcome in BCP-ALL. Remarkably, the incidence of IKZF1 deletions in patients with ERG deletion was significantly higher than in other BCR-ABL1-negative patients, especially when considering the IKZF1 intragenic deletion Δ4-7 (10/31, 32.3% vs 34/744, 4.6%, P<0.001), and this regardless of age. Surprisingly, IKZF1 deletion had no impact on the prognosis of ERG deleted patients. Indeed, patients combining ERG and IKZF1 Δ4-7 deletions had a better outcome than other BCR-ABL1-negative patients with IKZF1 deletions (8-year EFS 83.3% vs 53.0%, hazard ratio (HR) 0.19, 95% CI 0.02–1.41; p=0.069). Altogether, we have identified a novel oncogenic subtype of BCP-ALL characterized by ERG deletion. This subtype is frequently associated with IKZF1 deletions, suggesting a preferred oncogenic cooperation. Importantly, despite having older age and frequent IKZF1 deletions, which are factors usually predictive of a poor prognosis, patients with ERG deletion have a favourable outcome. Therefore, this genetic abnormality may be systematically assessed as part of the diagnostic work-up of BCP-ALL and taken into account when considering treatment stratification. Disclosures: No relevant conflicts of interest to declare.

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).

scholarly journals Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene

2015 ◽  
Vol 63 (5) ◽  
pp. 384-390 ◽  
Author(s):  
Moneeb A. K. Othman ◽  
Beata Grygalewicz ◽  
Barbara Pienkowska-Grela ◽  
Martina Rincic ◽  
Katharina Rittscher ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Mll Gene
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