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Leucemia Megacarioblástica Aguda , Humanos , Lactente , Proteínas de Fusão bcr-abl/genética , Leucemia Megacarioblástica Aguda/complicações , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras , Fatores de TranscriçãoRESUMO
BACKGROUND: Myelodysplastic syndrome (MDS) is rare in the pediatric age group and it may be associated with inheritable bone marrow failure (BMF) such as Fanconi anemia (FA). FA is a rare multi-system genetic disorder, characterized by congenital malformations and progressive BMF. Patients with FA usually present chromosomal aberrations when evolving to MDS or acute myeloid leukemia (AML). Thus, the cytogenetic studies in the bone marrow (BM) of these patients have an important role in the therapeutic decision, mainly in the indication for hematopoietic stem cell transplantation (HSCT). The most frequent chromosomal alterations in the BM of FA patients are gains of the chromosomal regions 1q and 3q, and partial or complete loss of chromosome 7. However, the significance and the predictive value of such clonal alterations, with respect to malignant progress, are not fully understood and data from molecular cytogenetic studies are very limited. CASE PRESENTATION: A five-year-old boy presented recurrent infections and persistent anemia. The BM biopsy revealed hypocellularity. G-banding was performed on BM cells and showed a normal karyotype. The physical examination showed to be characteristic of FA, being the diagnosis confirmed by DEB test. Five years later, even with supportive treatment, the patient presented severe hypocellularity and BM evolution revealing megakaryocyte dysplasia, intense dyserythropoiesis, and 11% myeloblasts. G-banded analysis showed an abnormal karyotype involving a der(9)t(9;11)(p24;q?22). The FISH analysis showed the monoallelic loss of ATM and KMT2A genes. At this moment the diagnosis was MDS, refractory anemia with excess of blasts (RAEB). Allogeneic HSCT was indicated early in the diagnosis, but no donor was found. Decitabine treatment was initiated and well tolerated, although progression to AML occurred 3 months later. Chemotherapy induction was initiated, but there was no response. The patient died due to disease progression and infection complications. CONCLUSIONS: Molecular cytogenetic analysis showed a yet unreported der(9)t(9;11)(p24;q?22),der(11)t(9;11)(p24;q?22) during the evolution from FA to MDS/AML. The FISH technique was important allowing the identification at the molecular level of the monoallelic deletion involving the KMT2A and ATM genes. Our results suggest that this chromosomal alteration conferred a poor prognosis, being associated with a rapid leukemic transformation and a poor treatment response.
RESUMO
In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR. Of the KMT2A fusion partner genes, MLLT3 was present in five patients, all with acute lymphoblastic leukemia, MLLT1 in two patients, and MLLT10, MLLT4, MLLT11, and AFF1 in one patient each. Reciprocal reading by long-distance inverse PCR also disclosed KMT2A fusions with PITPNA in one patient, with LOC100132273 in another patient, and with DNA sequences not compatible with any gene in three patients. The most common KMT2A breakpoint region was intron/exon 9 (3/8 patients), followed by intron/exon 11 and 10. Finally, multicolor banding revealed breakpoints in other chromosomes whose biological and prognostic implications remain to be determined. We conclude that the combination of molecular techniques used in this study can efficiently identify KMT2A fusion partners in complex pediatric acute leukemia karyotypes. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Criança , Pré-Escolar , Citogenética , Humanos , Lactente , Cariótipo , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , MasculinoRESUMO
Deletions in the long arm of chromosome 5 or loss of the whole chromosome are rare in childhood Acute Myeloid Leukemia (AML) patients. It is also unknown if the wide variety of breakpoints have diverging implications in the patient's outcome. Despite -5/5q- abnormalities have usually been described as a poor prognostic feature, however, the low frequency of -5/5q- in pediatric AML patients limits a full knowledge about this cytogenetic and clinical category, which is an intriguing factor for further research and new findings. Here, we report an AML child showing an uncommon deletion in 5q associated with 2 new abnormalities involving chromosome 2 within a complex karyotype well-characterized by several molecular cytogenetic approaches. Our work stimulates upcoming studies with more detailed descriptions about 5q abnormalities to better define its role in the stratification risk of such cytogenetic subgroup in childhood AML.
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BACKGROUND: Burkitt lymphoma/leukemia (BL/L) is cytogenetically characterized by the t(8;14)(q24;q32) or its variants, t(2;8)(p11;q21), and t(8;22)(q24;q11.2), which juxtapose the MYC oncogene to one of the three immunoglobulin loci. The overall cure rate of BL/L in children is 70-90%, but patients diagnosed with advanced-stage disease have a less favorable prognosis. It is possible that secondary chromosomal abnormalities contribute to this unfavorable prognosis via chemotherapy resistance, but the results of genetic studies have been inconsistent. This study aimed to identify and characterize secondary chromosomal abnormalities associated with the t(8;14) and its variants in children with French-American-British-L3 leukemia or Burkitt lymphoma with bone marrow involvement at the time of diagnosis. PROCEDURE: Chromosome analysis was based on G-banding. Fluorescence in situ hybridization technique was applied using IGH/MYC/CEP8 dual-fusion and MYC break-apart probes. Multicolor chromosome banding was performed according to standard protocol. RESULTS: We describe a group of BL/L with extreme adverse clinical outcome, in which secondary chromosomal abnormalities, particularly those involving the long arms of chromosomes 1 and 13, were found in 71% of cases. The IGH/MYC fusion showed molecular heterogeneity in 14% of cases and two cases exhibited three IGH/MYC fusion signals. CONCLUSIONS: Secondary chromosomal abnormalities were found in a high proportion of patients. We observed an extent of IGH/MYC heterogeneity not previously reported in Burkitt lymphoma, including the novel finding of three fusion signals in two cases.
Assuntos
Medula Óssea/patologia , Linfoma de Burkitt , Cromossomos Humanos/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Adolescente , Brasil , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Criança , Pré-Escolar , Coloração Cromossômica , Citogenética , Feminino , Humanos , MasculinoAssuntos
Anemia Refratária/genética , Anemia Refratária/patologia , Deleção Cromossômica , Cariótipo , Translocação Genética , Anemia Refratária/diagnóstico , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 6 , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , PrognósticoAssuntos
Cromossomos Humanos Par 11/genética , Amplificação de Genes , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Trissomia , Adolescente , Bandeamento Cromossômico , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , CariótipoRESUMO
Chromosome abnormalities that usually define high-risk acute lymphoblastic leukemia are the t(9;22)/ breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1, hypodiploid with < 44 chromosomes and 11q23/ myeloid/lymphoid leukemia gene rearrangements. The spectrum of acute lymphoblastic leukemia genetic abnormalities is nevertheless rapidly expanding. Therefore, newly described chromosomal aberrations are likely to have an impact on clinical care in the near future. Recently, the rare intrachromosomal amplification of chromosome 21 started to be considered a high-risk chromosomal abnormality. It occurs in approximately 2-5% of pediatric patients with B-cell precursor acute lymphoblastic leukemia. This abnormality is associated with a poor outcome. Hence, an accurate detection of this abnormality is expected to become very important in the choice of appropriate therapy. In this work the clinical and molecular cytogenetic evaluation by fluorescence in situ hybridization of a child with B-cell precursor acute lymphoblastic leukemia presenting the rare intrachromosomal amplification of chromosome 21 is described.
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Chromosome abnormalities that usually define high-risk acute lymphoblastic leukemia are the t(9;22)/ breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1, hypodiploid with < 44 chromosomes and 11q23/ myeloid/lymphoid leukemia gene rearrangements. The spectrum of acute lymphoblastic leukemia genetic abnormalities is nevertheless rapidly expanding. Therefore, newly described chromosomal aberrations are likely to have an impact on clinical care in the near future. Recently, the rare intrachromosomal amplification of chromosome 21 started to be considered a high-risk chromosomal abnormality. It occurs in approximately 2-5% of pediatric patients with B-cell precursor acute lymphoblastic leukemia. This abnormality is associated with a poor outcome. Hence, an accurate detection of this abnormality is expected to become very important in the choice of appropriate therapy. In this work the clinical and molecular cytogenetic evaluation by fluorescence in situ hybridization of a child with B-cell precursor acute lymphoblastic leukemia presenting the rare intrachromosomal amplification of chromosome 21 is described.
Assuntos
Humanos , Linfócitos B , Criança , /genética , Amplificação de Genes , Hibridização in Situ Fluorescente , Leucemia Aguda Bifenotípica , Leucemia Linfoide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Fatores de TranscriçãoRESUMO
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 and ETV6 gene 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 second ETV6 gene 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.
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Classical Burkitt lymphoma/leukemia (BL/L) presenting L3 morphology is found in 1% of childhood ALL. Recently, it has been described that secondary abnormalities could influence the prognosis of these patients. However, little information is available on these cytogenetic abnormalities and their prognostic importance in BL/L. Here, we report four new childhood BL/L cases associated with duplication within 1q or 13q, which exhibited a very unfavorable therapeutic response. We performed both classical and molecular cytogenetic analysis by multicolor chromosome banding of the secondary abnormalities involving the long arms of chromosome 1 or 13. These patients were previously treated with BFM-90 protocol. All of them died during or after the initial treatment. Here, for the first time, the exact breakpoints of the derivative chromosomes involved were determined at the cytogenetic level as 1q21 and 13q33 each.
Assuntos
Linfoma de Burkitt/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 8/genética , Duplicação Gênica , Rearranjo Gênico , Linfoma de Burkitt/diagnóstico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Humanos , Masculino , Prognóstico , Índice de Gravidade de DoençaRESUMO
Acute myeloid leukemia in childhood is a heterogeneous group of diseases, and different epidemiologic factors are involved in the etiopathogenesis. Genetic syndromes are one of the predisposing factors of acute myeloid leukemia (AML), including Down syndrome, Bloom syndrome, and neurofibromatosis. Acute megakaryoblastic leukemia (AMKL) is the main subtype in Down syndrome infants, and acquired chromosomal anomalies are closely related to the physiopathology of the illness. The main chromosomal anomalies in AMKL are structural, such as t(1;22); however, complex karyotypes are also common. Here we describe the case of an infant with neurofibromatosis developing AMKL with a complex karyotype including 5q and 17q deletions, TP53 deletion, and an unusual unbalanced chromosomal translocation t(11;19)(q13;p13), leading to three copies of the MLL gene.
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Hibridização in Situ Fluorescente/métodos , Leucemia Megacarioblástica Aguda/genética , Neurofibromatoses/genética , Feminino , Genes p53 , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Cariotipagem , Proteína de Leucina Linfoide-Mieloide/genéticaRESUMO
BACKGROUND: Children with Down syndrome (DS) have an increased risk of childhood acute leukemia, especially acute megakaryoblastic leukemia (AMKL) also called acute myeloid leukemia (AML) type M7. Here four yet unreported infants with such malignancies are reported. RESULTS: An unbalanced translocation involving chromosome 1 was identified by GTG banding in all cases. These were characterized in more detail by molecular cytogenetic approaches. Additional molecular analysis revealed in three of the four cases mutations in exon 2 of the GATA binding protein 1 (globin transcription factor 1), located in Xp11.23. CONCLUSION: Our results corroborate that abnormalities of chromosome 1 are common in DS-associated AMKL. Whether this chromosomal region contains gene(s) involved in hematopoietic malignant transformation remains to be determined.
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Alterations involving the short arm of chromosome 17 (17p) during the progression of chronic myeloid leukemia (CML) have been described. This chromosomal region contains the tumor suppressor gene TP53 that may be an important factor in the evolution of this disease. In this study, we used flow cytometry and western blotting to assess p53 protein expression and single stranded conformational polymorphism to examine TP53 gene alterations in three patients with CML who showed alterations in 17p. Only the case with del(17)(p11) had p53 expression positive by flow cytometry and an abnormal migration pattern by SSCP analysis. The importance of the correlation between the results obtained with these techniques, as well as the clinical course of the patients, are discussed.
Assuntos
Humanos , Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Citometria de Fluxo , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Mutação , Polimorfismo Conformacional de Fita SimplesRESUMO
We report the cytogenetic analysis of newly diagnosed Brazilian children with acute lymphocytic leukemia (ALL). We investigated 100 ALL cases from four different institutions in Rio de Janeiro. The frequency of chromosomal abnormalities was 92.3%. The karyotype profile and recurrent abnormalities found in this study do not differ essentially from those described by other groups. Although the Brazilian population is usually the product of different ethnic groups, our results show that the frequency of each recurrent abnormality is similar to that found in populations without our degree of diverse ethnic composition. Hence, our results suggest that childhood ALL in Brazil has the same biological features as that in developed countries, supporting the use of similar treatment protocols. We can therefore expect to reach the same survival rates in the coming years, depending possibly on the efficacy of the support therapy and extent of social assistance.
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Aberrações Cromossômicas , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Brasil , Criança , Pré-Escolar , Análise Citogenética , Feminino , Humanos , Imunofenotipagem , Lactente , Masculino , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
We report a new case of therapy-related acute myeloid leukemia in a child with Langerhans cell histiocytosis. This patient was previously treated with a protocol of multidrug chemotherapy, containing a relatively low dose of etoposide (total dose of 900/m(2)). Twenty-six months after the end of the therapy, the patient returned to the hospital with fever and anemia. The white blood cell count was 53 x 10(9)/L. The bone marrow examination showed massive infiltration with French-American-British acute myeloid leukemia classification M4 blast cells. The patient did not respond to an intensive treatment with high dose ARA-C and idarubicin. He died 6 months later. The cytogenetic abnormality of the blast cells was a t(11;11)(p13 -15;q23), that has not been described before in a secondary leukemia case.