scholarly journals Insights into the prenatal origin of childhood acute lymphoblastic leukemia

2020 ◽  
Vol 39 (1) ◽  
pp. 161-171 ◽  
Author(s):  
Daniel Hein ◽  
Arndt Borkhardt ◽  
Ute Fischer
Keyword(s):  
Early Childhood ◽  
Acute Lymphoblastic Leukemia ◽  
Gene Fusion ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocations ◽  
Gene Fusions ◽  
Leukemic Transformation ◽  
Childhood All ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Cells Of Origin

AbstractPediatric acute lymphoblastic leukemia (ALL) is defined by recurrent chromosomal aberrations including hyperdiploidy and chromosomal translocations. Many of these aberrations originate in utero and the cells transform in early childhood through acquired secondary mutations. In this review, we will discuss the most common prenatal lesions that can lead to childhood ALL, with a special emphasis on the most common translocation in childhood ALL, t(12;21), which results in the ETV6-RUNX1 gene fusion. The ETV6-RUNX1 fusion arises prenatally and at a 500-fold higher frequency than the corresponding ALL. Even though the findings regarding the frequency of ETV6-RUNX1 were originally challenged, newer studies have confirmed the higher frequency. The prenatal origin has also been proven for other gene fusions, including KMT2A, the translocations t(1;19) and t(9;22) leading to TCF3-PBX1 and BCR-ABL1, respectively, as well as high hyperdiploidy. For most of these aberrations, there is evidence for more frequent occurrence than the corresponding leukemia incidences. We will briefly discuss what is known about the cells of origin, the mechanisms of leukemic transformation through lack of immunosurveillance, and why only a part of the carriers develops ALL.

scholarly journals Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 117-122 ◽  
Author(s):  
WM Crist ◽  
AJ Carroll ◽  
JJ Shuster ◽  
FG Behm ◽  
M Whitehead ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocations ◽  
Oncology Group ◽  
Childhood All ◽  
Pediatric Oncology Group ◽  
Worse Prognosis

Abstract The prognostic significance of chromosomal translocations, particularly t(1;19) (q23;p13), was evaluated in children with pre-B and early pre-B acute lymphoblastic leukemia (ALL). Patients were treated on a risk- based protocol of the Pediatric Oncology Group (POG) between February 1986 and May 1989. An abnormal clone was detected in 46% (130 of 285) of pre-B cases and 56% (380 of 679) of early pre-B cases. Translocation of any type was associated with a worse treatment outcome than other karyotypic abnormalities: 15 of 66 versus 3 of 64 failed therapy in the pre-B group (P = .001), and 37 of 141 versus 23 of 239 failed in the early pre-B group (P less than .001). The t(1;19) (q23;p13) occurred significantly more often in cases of pre-B ALL with a clonal abnormality than in early pre-B ALL cases (29 of 130 v 5 of 380, P less than .001). Among the 285 pre-B cases in which bone marrow was studied cytogenetically, those with t(1;19) had a significantly worse treatment outcome than all others (11 of 29 v 27 of 256 have failed therapy, P less than .001). This difference is significant (P less than .001) after adjustment for leukocyte count, age, and other relevant features. Cases with the t(1;19) also had a worse prognosis than pre-B patients with other translocations (4 of 37 have failed, P less than .01) or with any other karyotypic abnormality (7 of 101 have failed, P less than .001). We conclude that chromosomal translocations confer a worse prognosis for non-T, non-B-cell childhood ALL, and that the t(1;19) is largely responsible for the poor prognosis of the pre-B subgroup.

scholarly journals Translocation ETS leukemia-acute myeloid leukemia 1 (TEL-AML1) gene fusion in childhood acute lymphoblastic leukemia

2009 ◽  
Vol 49 (5) ◽  
pp. 270
Author(s):  
Sri Mulatsih ◽  
Yeow Liang ◽  
Allen Yeoh ◽  
Sutaryo Sutaryo ◽  
Sunarto Sunarto
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Gene Fusion ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
Molecular Characteristics ◽  
Rt Pcr ◽  
Cross Sectional ◽  
Childhood All ◽  
Diagnostic Quality ◽  
Aml1 Gene

Background Acute lymphoblastic leukemia (ALL) in childrenis a heterogeneous disease with different subtypes based on their cellular and molecular characteristics. This condition wouldinfluence the treatment outcome and subsequent risk for relapse. Accurate assignment of individual patients to risk groups is a critical issue for better outcome. TEL-AML1 gene fusion is themost frequent in childhood ALL.Objective The aim of this study was to investigate the incidenceofTEL-AML1 children with ALL in Sardjito Hospital.Methods This was a cross sectional study. In this preliminarystudy, we used nested reverse-transcriptase polymerase chainreaction (RT-PCR) to analyze the present of TEL-AML1 genefusion in bone marrow sample of childhood ALL patients.Results We analyzed 41 samples. Out of these, 30 (73%) wereamplified. Twenry three out of 30 ALL patients with good medicalrecord were analyzed for this gene fusion. Out of 30 patients, there were five patients (17%) with TEL-AML1-positive gene fusion and 25 (83%) were TEL-AML1-negative. Among five patients with TEL-AML1-positive gene fusion, four patients (80%) were one year to less than 10 year old. All of the patients (100%) were with leukocyte < 50x109/L.Conclusions TEL-AML1 gene fusion was found in 17 % ofsamples. This gene fusion was more frequent in standard risk group (based on age and leukocyte). These data must be clarified with more samples. RT-PCR must be apply in all center as one part of improving diagnostic quality, especially in managing leukemia patients.

scholarly journals Environmental Risk Factors for Childhood Acute Lymphoblastic Leukemia: An Umbrella Review

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 382
Author(s):  
Felix M. Onyije ◽  
Ann Olsson ◽  
Dan Baaken ◽  
Friederike Erdmann ◽  
Martin Stanulla ◽  
...  
Keyword(s):  
Risk Factors ◽  
Early Childhood ◽  
Acute Lymphoblastic Leukemia ◽  
Environmental Risk ◽  
Lymphoblastic Leukemia ◽  
Environmental Risk Factors ◽  
Umbrella Review ◽  
Level Of Evidence ◽  
Childhood All ◽  
High Consumption

Leukemia is the most common type of cancer among children and adolescents worldwide. The aim of this umbrella review was (1) to provide a synthesis of the environmental risk factors for the onset of childhood acute lymphoblastic leukemia (ALL) by exposure window, (2) evaluate their strength of evidence and magnitude of risk, and as an example (3) estimate the prevalence in the German population, which determines the relevance at the population level. Relevant systematic reviews and pooled analyses were identified and retrieved through PubMed, Web of Science databases and lists of references. Only two risk factors (low doses of ionizing radiation in early childhood and general pesticide exposure during maternal preconception/pregnancy) were convincingly associated with childhood ALL. Other risk factors including extremely low frequency electromagnetic field (ELF-MF), living in proximity to nuclear facilities, petroleum, benzene, solvent, and domestic paint exposure during early childhood, all showed some level of evidence of association. Maternal consumption of coffee (high consumption/>2 cups/day) and cola (high consumption) during pregnancy, paternal smoking during the pregnancy of the index child, maternal intake of fertility treatment, high birth weight (≥4000 g) and caesarean delivery were also found to have some level of evidence of association. Maternal folic acid and vitamins intake, breastfeeding (≥6 months) and day-care attendance, were inversely associated with childhood ALL with some evidence. The results of this umbrella review should be interpreted with caution; as the evidence stems almost exclusively from case-control studies, where selection and recall bias are potential concerns, and whether the empirically observed association reflect causal relationships remains an open question. Hence, improved exposure assessment methods including accurate and reliable measurement, probing questions and better interview techniques are required to establish causative risk factors of childhood leukemia, which is needed for the ultimate goal of primary prevention.

scholarly journals Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 117-122 ◽  
Author(s):  
WM Crist ◽  
AJ Carroll ◽  
JJ Shuster ◽  
FG Behm ◽  
M Whitehead ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocations ◽  
Oncology Group ◽  
Childhood All ◽  
Pediatric Oncology Group ◽  
Worse Prognosis

The prognostic significance of chromosomal translocations, particularly t(1;19) (q23;p13), was evaluated in children with pre-B and early pre-B acute lymphoblastic leukemia (ALL). Patients were treated on a risk- based protocol of the Pediatric Oncology Group (POG) between February 1986 and May 1989. An abnormal clone was detected in 46% (130 of 285) of pre-B cases and 56% (380 of 679) of early pre-B cases. Translocation of any type was associated with a worse treatment outcome than other karyotypic abnormalities: 15 of 66 versus 3 of 64 failed therapy in the pre-B group (P = .001), and 37 of 141 versus 23 of 239 failed in the early pre-B group (P less than .001). The t(1;19) (q23;p13) occurred significantly more often in cases of pre-B ALL with a clonal abnormality than in early pre-B ALL cases (29 of 130 v 5 of 380, P less than .001). Among the 285 pre-B cases in which bone marrow was studied cytogenetically, those with t(1;19) had a significantly worse treatment outcome than all others (11 of 29 v 27 of 256 have failed therapy, P less than .001). This difference is significant (P less than .001) after adjustment for leukocyte count, age, and other relevant features. Cases with the t(1;19) also had a worse prognosis than pre-B patients with other translocations (4 of 37 have failed, P less than .01) or with any other karyotypic abnormality (7 of 101 have failed, P less than .001). We conclude that chromosomal translocations confer a worse prognosis for non-T, non-B-cell childhood ALL, and that the t(1;19) is largely responsible for the poor prognosis of the pre-B subgroup.

scholarly journals Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

2021 ◽  
Vol 22 (12) ◽  
pp. 6411
Author(s):  
Agnieszka Kaczmarska ◽  
Patrycja Śliwa ◽  
Joanna Zawitkowska ◽  
Monika Lejman
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Targeted Therapies ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Genomic Analyses ◽  
Pediatric All

Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in their first remission (CR1). Over the last few years, the treatment of childhood ALL has significantly improved due to standardized research protocols. Hematopoietic stem cell transplantation (HSCT) has been the gold standard therapy in ALL Ph+ patients, but recently first-generation tyrosine kinase inhibitor (TKI)-imatinib became a major milestone in increasing overall survival. Genomic analyses give the opportunity for the investigation of new fusions or mutations, which can be used to establish effective targeted therapies. Alterations of the IKZF1 gene are present in a large proportion of pediatric and adult ALL Ph+ cases. IKZF1 deletions are present in ~15% of patients without BCR-ABL1 rearrangements. In BCR-ABL1-negative cases, IKZF1 deletions have been shown to have an independent prognostic impact, carrying a three-fold increased risk of treatment failure. The prognostic significance of IKZF1 gene aberrations in pediatric ALL Ph+ is still under investigation. More research should focus on targeted therapies and immunotherapy, which is not associated with serious toxicity in the same way as classic chemotherapy, and on the improvement of patient outcomes. In this review, we provide a molecular analysis of childhood ALL with t(9;22)(q34;q11.2), including the Ph-like subtype, and of treatment strategies.

scholarly journals Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 247-253 ◽  
Author(s):  
CH Pui ◽  
DL Williams ◽  
SC Raimondi ◽  
GK Rivera ◽  
AT Look ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Lactic Dehydrogenase ◽  
Chromosomal Translocations ◽  
Leukemic Cells ◽  
Childhood All ◽  
Patients Âgés ◽  
Serum Lactic Dehydrogenase ◽  
Leukocyte Counts

Abstract Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.

scholarly journals Clinical relevance of BCL-2 overexpression in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1140-1146 ◽  
Author(s):  
E Coustan-Smith ◽  
A Kitanaka ◽  
CH Pui ◽  
L McNinch ◽  
WE Evans ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Leukemic Cell ◽  
Trophic Factors ◽  
Chromosomal Translocations ◽  
Childhood All ◽  
Protein Levels

Enforced BCL-2 gene expression in leukemic cell lines suppresses apoptosis and confers resistance to anticancer drugs, but the clinical significance of increased BCL-2 protein levels in acute lymphoblastic leukemia (ALL) is unknown. Among 52 children with newly diagnosed ALL, BCL-2 expression in leukemic lymphoblasts ranged widely, from 4,464 to 59,753 molecules of equivalent soluble fluorochrome per cell (MESF), as determined by flow cytometry. The mean (+/- SD) level of MESF in 43 cases of B-lineage ALL (19,410 +/- 11,834) was higher than that detected in CD10+ B-lymphoid progenitors from normal bone marrow (450 +/- 314; P < .001), and CD19+ peripheral blood B lymphocytes (7,617 +/- 1,731; P = .02). Levels of BCL-2 in T-ALL cases (17,909 +/- 18,691) were also generally higher than those found in normal CD1a+ thymocytes (1,762 +/- 670), or in peripheral blood T lymphocytes (9,687 +/- 3,019). Although higher levels of BCL-2 corresponded to higher leukemic cell recoveries after culture in serum-free medium, they did not correlate with higher cell recoveries after culture on stromal layers, or with in vitro resistance to vincristine, dexamethasone, 6- thioguanine, cytarabine, teniposide, daunorubicin or methotrexate. BCL- 2 protein levels did not correlate with presenting clinical features. Unexpectedly, however, lower-than-median MESF values were significantly associated with the presence of chromosomal translocations (P = .010). Notably, all six cases with the Philadelphia chromosome, a known high- risk feature, had low levels of BCL-2 expression (P = .022). Higher levels of BCL-2 were not associated with poorer responses to therapy among 33 uniformly treated patients, and were not observed in three patients studied at relapse. In conclusion, increased BCL-2 expression in childhood ALL appears to enhance the ability of lymphoblasts to survive without essential trophic factors, and is inversely related to the presence of chromosomal translocations. However, it does not reflect increased disease aggressiveness or resistance to chemotherapy.

Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.

1991 ◽  
Vol 9 (12) ◽  
pp. 2183-2192 ◽  
Author(s):  
C M Rubin ◽  
M M Le Beau ◽  
R Mick ◽  
M A Bitter ◽  
J Nachman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Chromosomal Translocations ◽  
Leukemic Cells ◽  
Childhood All ◽  
Wbc Count

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

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