Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.

Download Full-text

Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

Blood ◽

10.1182/blood.v61.1.66.66 ◽

1983 ◽

Vol 61 (1) ◽

pp. 66-70

Author(s):

T Mohanakumar ◽

TW Coffey ◽

MP Vaughn ◽

EC Russell ◽

D Conrad

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Membrane Component ◽

Childhood All ◽

Antigen Present ◽

The Common ◽

Blood Elements ◽

Human Primate

Abstract A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.

Download Full-text

Homozygous Deletion of the p16/MTS1 Gene in Pediatric Acute Lymphoblastic Leukemia Is Associated With Unfavorable Clinical Outcome

Blood ◽

10.1182/blood.v89.11.4161 ◽

1997 ◽

Vol 89 (11) ◽

pp. 4161-4166 ◽

Cited By ~ 77

Author(s):

Ursula R. Kees ◽

Paul R. Burton ◽

Changlong Lü ◽

David L. Baker

Keyword(s):

Risk Factors ◽

Acute Lymphoblastic Leukemia ◽

Clinical Outcome ◽

Lymphoblastic Leukemia ◽

Homozygous Deletion ◽

Cell Phenotype ◽

P16 Gene ◽

Childhood All ◽

Risk Of Death ◽

Increased Risk

Abstract The p16 gene (MTS1, CDKN2, p16INK4A, CDKI) encoding an inhibitor of cyclin-dependent kinase 4 (cdk4) has been found to be deleted in various types of tumors, including leukemia, and is thought to code for a tumor suppressor gene. Our preliminary findings on eight pediatric patients with acute lymphoblastic leukemia (ALL) suggested that the survival of patients carrying a homozygous p16 gene deletion was significantly inferior to that of those without a deletion. The present study on 48 patients tested the hypothesis that the clinical outcome for pediatric ALL patients is correlated with the presence or absence of the p16 gene. Overall, nine of 48 children (18.3%) carried a homozygous p16 deletion. Such deletions were significantly more common (P = .003) among T-ALL patients (five of eight, 62.5%) than among precursor-B-ALL patients (four of 40, 10.0%). Of nine patients exhibiting p16 deletions, eight (88.9%) were classified as high-risk patients by the recognized prognostic factors of age, white blood cell count, and T-cell phenotype. The 4-year event-free survival in the study population as a whole was 72.7%. Without adjustment for other risk factors (univariate model), the presence of a homozygous p16 deletion was associated with a markedly increased probability of both relapse (P = .0003) and death (P = .002). These findings raise the question of whether the p16 deletion itself confers an increased risk of relapse after adjusting for the known risk factors. In this analysis, the estimated risk multiplier factor for relapse in patients carrying the p16 deletion was 14.0 (P = .0004) and for the risk of death 15.6 (P = .0008). We therefore conclude that the presence of a homozygous p16 deletion may well be an important risk factor for both relapse and death in childhood ALL, and that its prognostic effect is not a consequence of confounding by other factors already known to influence outcome in this disease.

Download Full-text

Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽

10.1182/blood.v74.1.409.bloodjournal741409 ◽

1989 ◽

Vol 74 (1) ◽

pp. 409-415 ◽

Cited By ~ 1

Author(s):

SB Murphy ◽

SC Raimondi ◽

GK Rivera ◽

M Crone ◽

RK Dodge ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Clinical Features ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Term Survival ◽

Childhood All ◽

Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

Download Full-text

Genetic Susceptibility Loci for Childhood Acute Lymphoblastic Leukemia Among Japanese

Blood ◽

10.1182/blood.v126.23.3731.3731 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3731-3731

Author(s):

Kevin Y Urayama ◽

Masatoshi Takagi ◽

Takahisa Kawaguchi ◽

Keitaro Matsuo ◽

Yoichi Tanaka ◽

...

Keyword(s):

Genetic Variation ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Study Group ◽

Susceptibility Loci ◽

East Asians ◽

Childhood All ◽

Genome Wide

Abstract Scrutiny of the human genome through evaluation of common genetic variants has revealed hundreds of disease susceptibility loci. In childhood acute lymphoblastic leukemia (ALL), six regions that have replicated in several populations are now considered known susceptibility loci (ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, and GATA3), but their effects have yet to be fully confirmed in populations of non-European ancestry. Targeted validation attempts based on the same SNPs originally identified in European ancestral populations have been performed in East Asians, but findings have been inconsistent. This may be due to differences in linkage disequilibrium patterns, allele frequency, and/or magnitude of effect between Europeans and East Asians; thus a comprehensive characterization of genetic variation across the targeted genetic loci is required for an appropriate validation attempt in different populations. Using a large network of hospitals within the Tokyo Children's Cancer Study Group, saliva samples from previously diagnosed childhood ALL patients (aged 0-19 years) were collected between December 2012 and May 2015. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed and resulted in the inclusion of a total of 570 ALL patients, with genetic data available for up to about 500,000 SNPs after quality control exclusions. Control genome-wide data were available for 2,712 previously genotyped samples from the Nagahama Study Group and Aichi Cancer Center Study, Japan. SNP imputation was performed on the combined case-control dataset using ShapeIT and Minimac3, and the 1000 Genomes Project Phase I Version 3 as the reference population. Tests of association between childhood ALL and all available SNP genotypes across the six genes (mentioned above) implicated in previous genome-wide association studies was performed using logistic regression and assuming a log-additive model of inheritance. Of the six genomic regions examined, SNPs within the IKZF1, ARID5B, and PIP4K2A genes showed a statistically significant association with childhood ALL risk after Bonferroni correction. SNPs with the strongest evidence of association for these three genes included rs7090445 (ARID5B, OR=1.75, P =3.7x10-17), rs12533431 (IKZF1, OR=1.43, P =4.3x10-5), and rs11013045 (PIP4K2A, OR=0.76, P =9.5x10-5). Further examination of these regions indicated a second independently associated locus within ARID5B. Furthermore, we observed that the same previously reported primary ALL susceptibility SNPs for IKZF1 (e.g. rs4132601, rs11978267) and PIP4K2A (e.g. rs10828317, rs7088318) were not associated in Japanese. This highlights the importance of considering regional genetic variation comprehensively when testing the role of previously implicated candidate regions in a different racial/ethnic population. Characterization of the role of CEBPE, CDKN2A, and GATA3 genetic variation in Japanese may benefit from greater statistical power and potentially additional coverage of SNPs within these regions. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Characterization of thymocytes expressing the common acute lymphoblastic leukemia antigen

Leukemia Research ◽

10.1016/0145-2126(84)90140-1 ◽

1984 ◽

Vol 8 (2) ◽

pp. 173-179 ◽

Cited By ~ 19

Author(s):

Steven M.L. Neudorf ◽

Tucker W. Lebien ◽

John H. Kersey

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

The Common ◽

Leukemia Antigen

Download Full-text

Germ-Line Genetic Variations in TP53 and Risk for Pediatric Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v104.11.1890.1890 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1890-1890

Author(s):

Toralf Bernig ◽

Laurie Burdette ◽

Thomas Lehrnbecher ◽

Ulrike B. Graubner ◽

Monique L. den Boer ◽

...

Keyword(s):

At Risk ◽

Genetic Variation ◽

Acute Lymphoblastic Leukemia ◽

Tumor Suppressor ◽

Germ Line ◽

Lymphoblastic Leukemia ◽

Risk Haplotype ◽

Childhood All ◽

Increased Risk ◽

The Common

Abstract The tumor suppressor p53 plays an essential role in the prevention of tumor development by its ability to respond to stress signals, resulting in the inhibition of cell growth, via cell-cycle arrest or induction of apoptosis. p53 also contributes to the repair of genotoxic DNA damages and is involved in cellular senescence. Previous studies have shown that both germ-line and somatic mutations in the TP53 gene, which encodes p53, can occur in a wide spectrum of cancers, including acute lymphoblastic leukemia, ALL. Recently, we characterized the common germ-line genetic variation across TP53 by extensive re-sequence analysis (http://snp500cancer.nci.nih.gov). Patients and Methods: We conducted a genetic association study in childhood ALL to investigate the possible contribution of common single nucleotide polymorphisms, SNPs, and the common haplotypes on which they reside. For TP53, we analyzed haplotype-tagging SNPs, which are estimated to capture greater than 95% of common haplotypes across the gene (IVS2+38C, Ex4+119 (R72P), IVS4-91, Ex6-34 (R213R), IVS6+62, IVS6-36 and 1846bp 3′ of STP). Cases of ALL (n = 513) were drawn from anonymized samples from the German co-operative therapy study (COALL-06-97) and 751 healthy anonymized blood donor controls collected from regional blood banks in Germany. Genotype analysis was performed by validated Taqman assays posted on the SNP500cancer website. Haplotypes were deduced by maximization-estimation analysis of unphased genotypes using PHASEv2.0.1 (http://www.stat.washington.edu/stephens/software.html). Results: The single locus analysis revealed an increased risk for ALL for four of the seven SNPs individually: C allele at IVS2+38C (304/982 in patients vs. 399/1476 in controls, OR 1.21 95% CI 1.01 – 1.45), G allele at IVS4-91 (150/988 vs. 168/1456, OR 1.37 95% CI 1.08 – 1.75), A allele at Ex6-34 (R213R) (164/996 vs. 178/1450, OR 1.41 95% CI 1.11 – 1.78) and T allele at 1846bp 3′ of STP (185/990 vs. 203/1420, OR 1.38 95% CI 1.10 – 1.72). Individuals homozygous AA at IVS6+62 (16/350 vs. 9/556, OR 2.82, 95% CI 1.16 – 6.99) or TT at 1846bp 3′ of STP (24/334 vs. 15/522 OR 2.50, 955 CI 1.24 – 5.09) showed further risk for disease. The non-synonymous coding SNP at Ex4+119 (R72P) did not show any association with ALL. The distribution of the inferred haplotypes differed significantly between cases and controls (global haplotype test p = 0.02). Children carrying the haplotype CCGAAGT have an increased risk for ALL (138/611 vs. 155/972, OR 1.42, 95% CI 1.09 −1.83) in reference to the most common haplotype GGAAGGC. Conclusions: Our data suggest that susceptibility to pediatric ALL could be associated with at least one copy of an “at risk” haplotype. The study results imply that germ-line genetic variation in TP53, a key tumor suppressor gene, could contribute to susceptibility to childhood ALL. Additional studies are required to confirm our findings and to characterize the functional elements in the at-risk haplotypes.

Download Full-text

Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽

10.1182/blood.v74.1.409.409 ◽

1989 ◽

Vol 74 (1) ◽

pp. 409-415 ◽

Cited By ~ 41

Author(s):

SB Murphy ◽

SC Raimondi ◽

GK Rivera ◽

M Crone ◽

RK Dodge ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Clinical Features ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Term Survival ◽

Childhood All ◽

Chromosome 9P

Abstract To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

Download Full-text

Clinico-epidemiological features and response in childhood acute lymphoblastic leukemia at regional cancer center of Northeast India

South Asian Journal of Cancer ◽

10.4103/sajc.sajc_249_19 ◽

2019 ◽

Vol 08 (04) ◽

pp. 241-243

Author(s):

Bhargab Jyoti Saikia ◽

Partha Sarathi Roy ◽

Gaurav Kumar ◽

Rakesh Kumar Mishra ◽

Anupam Sarma

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Early Response ◽

Northeast India ◽

Cancer Center ◽

Childhood Cancers ◽

Related Factors ◽

Childhood All ◽

The Common ◽

Cure Rates

Abstract Introduction: Acute lymphoblastic leukemia (ALL) comprises 19.3% of all childhood cancers in Northeast India. Methods: We analyzed clinicoepidemiological features and early response to the treatment of all the cases of childhood ALL (age <15 years) diagnosed and treated at Dr. B Borooah Cancer Institute over 1 year. Results: Of 52 eligible cases, 69% were male (male:female ratio of 2.2:1) and the mean age was 7.1 years. Thirty-three children (63%) had baseline white blood cell count ≥20 × 109/L. Precursor B-cell was most the common subtype seen in 61% of children. Seven cases (14%) had high-risk (HR) cytogenetics, with t (9,22) being the most common one. Male sex and HR cytogenetics were significantly associated with poor early responses. Conclusion: ALL is a common childhood malignancy with high cure rates. However, poor socioeconomic status and the presence of higher proportions of disease-related factors lead to poor outcome in this part of the country.

Download Full-text