ABSTRACT
Chromosome 21 is the most affected chromosome in childhood acute lymphoblastic leukemia. Many of its numerical and structural abnormalities define diagnostically and clinically important subgroups. To obtain an overview about their types and their approximate genetic subgroup-specific incidence and distribution, we performed cytogenetic, FISH and array analyses in a total of 578 ALL patients (including 26 with a constitutional trisomy 21). The latter is the preferred method to assess genome-wide large and fine-scale copy number abnormalities (CNA) together with their corresponding allele distribution patterns. We identified a total of 258 cases (49%) with chromosome 21-associated CNA, a number that is perhaps lower-than-expected because ETV6-RUNX1-positive cases (11%) were significantly underrepresented in this array-analyzed cohort. Our most interesting observations relate to hyperdiploid leukemias with tetra- and pentasomies of chromosome 21 that develop in constitutionally trisomic patients. Utilizing comparative short tandem repeat analyses, we were able to prove that switches in the array-derived allele patterns are in fact meiotic recombination sites, which only become evident in patients with inborn trisomies that result from a meiosis 1 error. The detailed analysis of such cases may eventually provide important clues about the respective maldistribution mechanisms and the operative relevance of chromosome 21-specific regions in hyperdiploid leukemias.
ABSTRACT
Genetically-engineered mouse models (GEMMs) lacking diseased-associated gene(s) globally or in a tissue-specific manner represent an attractive tool with which to assess the efficacy and toxicity of targeted pharmacological inhibitors. Stat3 and Stat5a/b transcription factors have been implicated in several pathophysiological conditions, and pharmacological inhibition of both transcription factors has been proposed to treat certain diseases, such as malignancies. To model combined inhibition of Stat3 and Stat5a/b we have developed a GEMM harboring a flox Stat3-Stat5a/b allele (Stat5/3loxP/loxP mice) and generated mice lacking Stat3 and Stat5a/b in hepatocytes (Stat5/3Δhep/Δhep). Stat5/3Δhep/Δhep mice exhibited a marked reduction of STAT3, STAT5A and STAT5B proteins in the liver and developed steatosis, a phenotype that resembles mice lacking Stat5a/b in hepatocytes. In addition, embryonic deletion of Stat3 and Stat5a/b (Stat5/3Δ/Δ mice) resulted in lethality, similar to Stat3Δ/Δ mice. This data illustrates that Stat5/3loxP/loxP mice are functional and can be used as a valuable tool to model the combined inhibition of Stat3 and Stat5a/b in tumorigenesis and other diseases.
ABSTRACT
Spontaneous Rh blood group changes are a striking sign, reported to occur mainly in patients with hematologic disorders. Upon routine blood grouping, 2 unrelated individuals showed unexplained mixed red cell phenotype regarding the highly immunogenic c antigen (RH4), clinically relevant for blood transfusion and fetomaternal incompatibility. About half of their red cells were c-positive, whereas the other half were c-negative. These apparently hematologically healthy females had no history of transfusion or transplantation, and they tested negative for chimerism. Genotyping of flanking chromosome 1 microsatellites in blood, finger nails, hair, leukocyte subpopulations, and erythroid progenitor cells showed partial loss of heterozygosity encompassing the RHD/RHCE loci, spanning a 1p region of 26.7 or 42.4 Mb, respectively. Remarkably, in one case this was detected in all investigated tissues, whereas in the other, exclusively myeloid cells showed loss of heterozygosity. Both carried the RhD-positive haplotypes CDe and the RhD-negative haplotype cde RHD/RHCE genotypes of single erythroid colonies and dual-color fluorescent in situ hybridization analyses indicated loss of the cde haplotype and duplication of the CDe haplotype in the altered cell line. Accordingly, red cell C antigen (RH2) levels of both propositae were higher than those of heterozygous controls. Taken together, the Rhc phenotype splitting appeared to be caused by deletion of a part of 1p followed by duplication of homologous stretches of the sister chromosome. In one case, this phenomenon was confined to myeloid stem cells, while in the other, a pluripotent stem cell line was affected, demonstrating somatic mosaicism at different stages of ontogenesis.
Subject(s)
Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 1 , Mosaicism , Rh-Hr Blood-Group System/genetics , Adult , Aged , Female , Flow Cytometry , Genotype , Hematopoietic Stem Cell Transplantation , Humans , In Situ Hybridization, Fluorescence , Loss of Heterozygosity , Microsatellite Repeats , Myeloid Cells/metabolism , PhenotypeABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease in which multiple genetic abnormalities cooperate in the malignant transformation of T-lymphoid progenitors. Although in pediatric T-ALL, CDKN1B deletions occur in about 12% of the cases and represent one of the most frequent copy number alterations, neither their association with other genetic alterations nor the clinical characteristics of these patients have been determined yet. In this study, we show that loss of CDKN1B increased the prevalence of cell cycle regulator defects in immature T-ALL, usually only ascribed to CDKN2A/B deletions, and that CDKN1B deletions frequently coincide with expression of MEF2C, considered as one of the driving oncogenes in immature early T-cell precursor (ETP) ALL. However, MEF2C-dysregulation was only partially associated with the immunophenotypic characteristics used to define ETP-ALL. Furthermore, MEF2C expression levels were significantly associated with or may even be predictive of the response to glucocorticoid treatment.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p27/genetics , Gene Deletion , Gene Expression Regulation, Leukemic , Pharmacogenomic Variants , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Biomarkers , Cell Line , Child , Child, Preschool , Cluster Analysis , Cyclin-Dependent Kinase Inhibitor p27/metabolism , DNA Copy Number Variations , Female , Gene Expression Profiling , Glucocorticoids/therapeutic use , Humans , Immunophenotyping , Infant , MEF2 Transcription Factors/genetics , MEF2 Transcription Factors/metabolism , Male , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Approximately 30% of childhood acute lymphoblastic leukemia (ALL) cases are high hyperdiploid (HD). Despite their low relative recurrence risk, this group accounts for the overall largest relapse proportion. PROCEDURE: To evaluate potential risk factors in our population-based cohort of patients with HD ALL enrolled in four Austrian ALL-BFM (Berlin-Frankfurt-Münster) studies from 1986 to 2010 (n = 210), we reviewed the clinical, laboratory, and cytogenetic data of the respective cases in relation to their outcome. RESULTS: The 5-year event-free (EFS) and overall survival (OS) of the entire group was 83.1 ± 2.7% and 92.0 ± 1.9%, respectively. Univariate analysis revealed that trisomy 17 was significantly associated with a better EFS and OS, whereas trisomy 10 and a modal chromosome number (MCN) > 53 chromosomes were significantly associated with a better OS. Except for the latter, findings remained valid in multivariate analysis. CONCLUSIONS: In line with previous studies, our retrospective analysis shows that MCN and specific trisomies are relevant prognostic indicators in an ALL-BFM cohort of patients with HD ALL. However, considering the current dominant role of minimal residual disease monitoring for prognostic stratification in ALL, including this particular subgroup, it is unlikely that this information is compelling enough to be utilized for refined risk classification in future ALL-BFM treatment protocols.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Trisomy , Adolescent , Asparaginase/administration & dosage , Child , Child, Preschool , Chromosomes, Human, Pair 17 , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Disease-Free Survival , Female , Humans , Male , Mercaptopurine/administration & dosage , Methotrexate/administration & dosage , Mosaicism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prednisone/administration & dosage , Retrospective Studies , Survival Rate , Time Factors , Vincristine/administration & dosageSubject(s)
Imatinib Mesylate/therapeutic use , Oncogene Proteins, Fusion/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogene Proteins c-abl/genetics , Recurrence , Remission Induction , Salvage Therapy/methodsABSTRACT
The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.
Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Chimera/blood , Adolescent , Adult , Allografts , Child , Child, Preschool , Female , Graft Rejection , Graft vs Host Disease , Hematologic Neoplasms/complications , Humans , Infant , Lymphocyte Subsets , Male , Neoplasms, Second Primary , Recurrence , Time Factors , Transplantation Conditioning/methods , Young AdultABSTRACT
BACKGROUND: In B-cell precursor acute lymphoblastic leukemia (BCP-ALL) PAX5, a transcription factor pivotal for B-cell commitment and maintenance, is frequently affected by genetic alterations. In 2-3 % of the cases PAX5 rearrangements result in the expression of oncogenic fusion genes. The encoded chimeric proteins consist of the N-terminal PAX5 DNA-binding paired domain, which is fused to the C-terminal domains of a remarkable heterogeneous group of partner proteins. RESULTS: Employing fluorescence in situ hybridization and molecular methods PAX5-KIAA1549L was identified as novel fusion gene in a case of pediatric BCP-ALL. CONCLUSION: Our report underlines the high diversity of PAX5 fusion partners in BCP-ALL and we describe the second involvement of KIAA1549L in a genetic rearrangement in acute leukemia.
ABSTRACT
BACKGROUND: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by recurrent genetic alterations including chromosomal translocations. The transcription factor PAX5, which is pivotal for B-cell commitment and maintenance, is affected by rearrangements, which lead to the expression of in-frame fusion genes in about 2.5% of the cases. RESULTS: Using conventional cytogenetics, fluorescence in situ hybridization (FISH), and molecular methods, an additional case with a der(9)t(7;9)(q11.23;p13) resulting in the expression of a PAX5-ELN fusion gene was identified. Furthermore, a general review of leukemia harboring a t(7;9)(q11.2;p13) or der(9)t(7;9)(q11.2;p13), which occurs more often in children than in adults and shows a remarkably high male preponderance, is given. These cytogenetically highly similar translocations lead to the expression of one of three different in frame PAX5-fusions, namely with AUTS2 (7q11.22), ELN (7q11.23), or POM121 (7q11.23), which constitute the only currently known cluster of PAX5 partner genes. CONCLUSION: Our report underlines the recurrent involvement of PAX5 in different fusion genes resulting either from t(7;9)(q11.2;p13) or der(9)t(7;9)(q11.2;p13), which cannot be distinguished cytogenetically and whose discrimination requires molecular analysis.
ABSTRACT
The presence of a dicentric chromosome dic(9;20) has been reported to have an unfavourable prognosis in children with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). As outcome may be influenced by type and composition of treatment, we analyzed 19 BCP-ALL patients with dic(9;20) who have been treated with ALL-BFM (Berlin-Frankfurt-Münster) protocols that included a 4-drug induction and subsequent consolidation therapy. All patients were good responders to prednisone and in complete remission after induction therapy. Eight patients had no molecular disease after induction and another eight patients had levels < or =10(-4) after consolidation therapy. After a median follow-up of 3.4 years, probabilities of 5-year event-free and overall survival were 75 +/- 11% and 94 +/- 6%, respectively. Of note, there was a tendency for extramedullary disease in case of relapse (two of three relapses with central nervous system involvement). In conclusion, in the context of ALL-BFM protocols dic(9;20)-positivity appeared to have a favourable prognosis, which could be due to a dose- and time-intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)-positive leukemic blasts to l-asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM-like induction and consolidation therapy, may have contributed to this good outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosome Aberrations , Chromosomes, Human, Pair 20/genetics , Chromosomes, Human, Pair 9/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Asparaginase/therapeutic use , Child , Child, Preschool , Daunorubicin/therapeutic use , Female , Follow-Up Studies , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Male , Neoplasm, Residual , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prednisone/therapeutic use , Prognosis , Survival Analysis , Treatment Outcome , Vincristine/therapeutic useABSTRACT
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).
Subject(s)
Chromosomes, Human, Pair 21 , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Female , Gene Amplification , Humans , Male , Neoplasm, Residual , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Risk Factors , Survival Rate , Treatment OutcomeABSTRACT
PURPOSE: The ETV6 gene has been reported to be fused to a multitude of partner genes in various hematologic malignancies with 12p13 aberrations. Cytogenetic analysis of six cases of childhood acute lymphoblastic leukemia revealed a novel recurrent t(8;12)(q13;p13), suggesting involvement of ETV6. EXPERIMENTAL DESIGN: Fluorescence in situ hybridization was used to confirm the involvement of ETV6 in the t(8;12)(q13;p13) and reverse transcription-PCR was used to identify the ETV6 partner gene. Detailed immunologic characterization was done, and owing to their lineage promiscuity, the leukemic blast cells were analyzed for NOTCH1 mutations. RESULTS: We have identified a novel recurrent t(8;12)(q13;p13), which results in a fusion between the transcriptional repressor ETV6 (TEL) and the transcriptional coactivator NCOA2 (TIF2) in six cases of childhood leukemia expressing both T-lymphoid and myeloid antigens. The ETV6-NCOA2 transcript encodes a chimeric protein that consists of the pointed protein interaction motif of ETV6 that is fused to the COOH terminus of NCOA2, including the cyclic AMP-responsive element binding protein-binding protein (CBP) interaction and the AD2 activation domains. The absence of the reciprocal NCOA2-ETV6 transcript in one of the cases suggests that the ETV6-NCOA2 chimeric protein and not the reciprocal NCOA2-ETV6 is responsible for leukemogenesis. In addition, ETV6-NCOA2 leukemia shows a high frequency of heterozygous activating NOTCH1 mutations, which disrupt the heterodimerization or the PEST domains. CONCLUSIONS: The ETV6-NCOA2 fusion may define a novel subgroup of acute leukemia with T-lymphoid and myeloid features, which is associated with a high prevalence of NOTCH1 mutations.
Subject(s)
Nuclear Receptor Coactivator 2/genetics , Oncogene Fusion/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Adolescent , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , Female , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Male , Molecular Sequence Data , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification , Receptor, Notch1/genetics , Reverse Transcriptase Polymerase Chain Reaction , ETS Translocation Variant 6 ProteinABSTRACT
PAX5 encodes the B-cell lineage specific activator protein (BSAP) and is required for B-cell development and maintenance. In B-cell precursor acute lymphoblastic leukaemia (ALL), PAX5 is involved in several chromosome translocations that fuse the N-terminal paired DNA-binding domain of PAX5 with the C-terminal regulatory sequences of ETV6, FOXP1, ZNF521 or ELN. Herein, we describe the identification of a novel recurrent t(9;15)(p13;q24) in two cases of childhood ALL, which results in an in-frame fusion of PAX5 to the promyelocytic leukaemia (PML) gene. The putative PAX5-PML fusion gene encodes a chimaeric protein that retains the paired domain, the octapeptid and the partial homeodomain of PAX5, and virtually the whole PML protein. The steadily increasing number of PAX5 rearrangements suggests that PAX5 is not only crucial for B-cell lymphopoiesis but also for the development of B-cell malignancies.
Subject(s)
Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Oncogene Proteins, Fusion/genetics , PAX5 Transcription Factor/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Amino Acid Sequence , Base Sequence , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 9 , Cytogenetics , Humans , In Situ Hybridization, Fluorescence , Infant , Molecular Sequence Data , Promyelocytic Leukemia Protein , Reverse Transcriptase Polymerase Chain Reaction , Translocation, GeneticABSTRACT
The majority of translocations that involve the long arms of chromosomes 11 and 17 in acute myeloid leukemia appear identical on the cytogenetic level. Nevertheless, they are diverse on the molecular level. At present, two genes are known in 11q23 and four in 17q12-25 that generate five distinct fusion genes: MLL-MLLT6/AF17, MLL-LASP1, MLL-ACACA or MLL-SEPT9/MSF, and ZBTB16/PLZF-RARA. We analyzed 14 cases with a t(11;17) by fluorescence in situ hybridization and molecular genetic techniques and determined the molecular characteristics of their fusion genes. We identified six different gene fusions that comprised seven cases with a MLL-MLLT6/AF17, three with a MLL-SEPT9/MSF, and one each with MLL-LASP1, MLL-ACACA, and ZBTB16/PLZF-RARA fusions. In the remaining case, a MLL-SEPT6/Xq24 fusion suggested a complex rearrangement. The MLL-MLLT6/AF17 transcripts were extremely heterogeneous and the detection of seven different in-frame transcript and splice variants enabled us to predict the protein domains relevant for leukemogenesis. The putative MLL-MLLT6 consensus chimeric protein consists of the AT-hook DNA-binding, the methyltransferase, and the CXXC zinc-finger domains of MLL and the highly conserved octapeptide and the leucine-zipper dimerization motifs of MLLT6. The MLL-SEPT9 transcripts showed a similar high degree of variability. These analyses prove that the diverse types of t(11;17)-associated fusion genes can be reliably identified and delineated with a proper combination of cytogenetic and molecular genetic techniques. The heterogeneity of transcripts encountered in cases with MLL-MLLT6/AF17 and MLL-SEPT9/MSF fusions clearly demonstrates that thorough attention has to be paid to the appropriate selection of primers to cover all these hitherto unrecognized fusion variants.
Subject(s)
Alternative Splicing , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 17 , Leukemia, Monocytic, Acute/genetics , Leukemia, Myelomonocytic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Translocation, Genetic , Adolescent , Adult , Aged , Child , Child, Preschool , DNA-Binding Proteins/genetics , Female , Histone-Lysine N-Methyltransferase , Homeodomain Proteins/genetics , Humans , In Situ Hybridization , Infant , Male , Middle Aged , Myeloid-Lymphoid Leukemia Protein/genetics , Neoplasm Proteins/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
PURPOSE: Mixed lineage leukemia (MLL) abnormalities occur in approximately 50% of childhood pro-B acute lymphoblastic leukemia (ALL). However, the incidence and type of MLL rearrangements have not been determined in common ALL (cALL) and CD10+ or CD10- pre-B ALL. EXPERIMENTAL DESIGN: To address this question, we analyzed 29 patients with pro-B ALL, 11 patients with CD10- pre-B ALL, 23 pre-B, and 26 cALL patients with CD10 on 20% to 80%, as well as 136 pre-B and 143 cALL patients with CD10 > or = 80% of blasts. They were all enrolled in four Austrian ALL multicenter trials. Conventional cytogenetics were done to detect 11q23 abnormalities and in parallel the potential involvement of the MLL gene was evaluated with a split apart fluorescence in situ hybridization probe set. RESULTS: We found that 15 of 29 pro-B ALL, 7 of 11 CD10- pre-B ALL, and 1 of 2 French-American-British classification L1 mature B-cell leukemia cases had a MLL rearrangement. However, no 11q23/MLL translocation was identified among the CD10+ pre-B and cALL patients. MLL-rearranged pro-B and CD10- pre-B ALL cases had similar clinical and immunophenotypic (coexpression of CDw65 and CD15) features at initial diagnosis. CONCLUSIONS: The striking similarities between the two CD10- ALL subsets imply that CD10- pre-B ALL variants may represent pro-B ALL cases that maintained the propensity to rearrange and express their immunoglobulin heavy chain rather than actual pre-B ALL forms transformed at this later stage of B-cell differentiation. However, direct experimental data are needed to confirm this observation.
Subject(s)
Chromosome Aberrations , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , B-Lymphocytes , Child , Child, Preschool , Female , Humans , Immunoglobulin Heavy Chains , Immunophenotyping , In Situ Hybridization, Fluorescence , Infant , Male , Neprilysin , Phenotype , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/classification , Precursor Cell Lymphoblastic Leukemia-Lymphoma/classification , Prognosis , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Near-tetraploidy (82-94 chromosomes) makes up fewer than 1% of childhood acute lymphoblastic leukemia (ALL) cases and has been reportedly associated with a possibly poorer prognosis compared with other ploidy groups. We analyzed 783 patients enrolled in the ALL-BFM-Austria 86, -90, -95, -99/2000 and Interfant-Austria 99 trials in order to assess its incidence, biological characteristics, and prognostic relevance. Twelve of 783 patients (1.5%) had a near-tetraploid ALL. Fluorescence in situ hybridization revealed that eight of the nine B-cell precursor (BCP) cases and none of the three T-cell ALL cases had an ETV6/RUNX1 rearrangement. After a median follow-up of 11.4 years, none of the patients has relapsed or died. Thus, near-tetraploidy appears to be a specific feature of ETV6/RUNX1+ BCP ALL cases that in turn may explain its excellent outcome.
Subject(s)
Core Binding Factor Alpha 2 Subunit/analysis , Polyploidy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-ets/analysis , Repressor Proteins/analysis , Adolescent , Austria , Child , Child, Preschool , Core Binding Factor Alpha 2 Subunit/genetics , Cytogenetic Analysis , Humans , In Situ Hybridization, Fluorescence , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , ETS Translocation Variant 6 ProteinABSTRACT
Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, two of whom who suffered from a TEL/AML1+ leukemia. Based on this observation they concluded that individuals with BCP leukemia and a constitutional trisomy 21 may have similar likelihood to have a TEL/AML1 rearrangement as BCP ALL patients without this specific predisposing factor.
Subject(s)
Down Syndrome/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Adult , Austria/epidemiology , Child , Child, Preschool , Chromosomes, Human, Pair 21/genetics , Core Binding Factor Alpha 2 Subunit , Down Syndrome/complications , Down Syndrome/epidemiology , Female , Humans , In Situ Hybridization, Fluorescence , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Retrospective StudiesABSTRACT
BACKGROUND AND OBJECTIVES: The aim of this study was to determine the incidence of rearrangements of NUP98 (the gene coding for nucleoporin 98kDa protein) in childhood acute myeloid leukemia (AML) and selected patients with 11p13-15 rearrangements. This aim was achieved using a fluorescence in situ hybridization (FISH) assay that allows the detection of NUP98 aberrations independently of the partner gene involved. DESIGN AND METHODS: Screening of 59 consecutive patients enrolled in the Austrian AML-BFM93 clinical trial was performed by dual-color FISH. In addition, 14 selected cases with various hematologic malignancies and 11p13-15 aberrations were analyzed. NUP98-positive cases were further investigated by fusion gene-specific FISH and reverse transcription polymerase chain reaction assays. RESULTS: Among the 59 AML patients, one NUP98-NSD1 positive case (1.7%) was detected. Among the 14 selected patients, five new NUP98 positive cases were determined. Two cases showed an inv(11)(p15q22)/NUP98-DDX10 fusion, one each displayed a t(5;11)(q35;p15)/NUP98-NSD1 and a t(11;20)(p15;q12)/NUP98-TOP1 fusion, and one case with a putative new fusion partner gene at 3p24 was identified. INTERPRETATION AND CONCLUSIONS: The observed frequency of 1.7% confirmed the low incidence of NUP98 rearrangements in childhood AML. The low occurrence of NUP98 rearrangements in selected samples with 11p13-15 alterations suggests the existence of variable chromosomal breakpoints and affected genes in this region. The identification of a new NUP98 fusion partner region confirms the evident promiscuity of NUP98. Thus, analysis of NUP98 aberrations by FISH seems to be the method of choice for determining the presence of these genetic lesions in unselected patients, and to confirm the involvement of NUP98 in cases with 11p15 aberrations.
Subject(s)
Chromosome Aberrations , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Nuclear Pore Complex Proteins/biosynthesis , Adolescent , Adult , Aged , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , Chromosome Inversion , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Molecular Sequence Data , Translocation, GeneticABSTRACT
Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, including 2 who suffered from a TEL/AML1+ leukemia. Based on this observation we concluded that individuals with a constitutional trisomy 21 may have the similar likelihood to develop a TEL/AML1+ leukemia as BCP ALL patients without this specific predisposingfactor.