RESUMO
Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.
Assuntos
Cromossomos Humanos Par 14/genética , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Receptor Notch1/genética , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are recurrent but rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and various partner genes have been described. Here, we report a new series of 29 cases of BCP-ALL with IGH@ translocations. The partner gene was identified by fluorescence in situ hybridization and/or molecular cloning in 20 patients. Members of the CEBP gene family (n = 11), BCL2 (n = 3), ID4 (n = 3), EPOR (n = 2), and TRA/D@ (n = 1) were identified and demonstrated by quantitative real-time reverse transcriptase-polymerase chain reaction to be markedly up-regulated. The present cases, added to those already reported, confirm the diversity of the partner genes, which, apart from BCL2, are specific to BCP-ALL. Collectively, patients with IGH@ translocations may represent a novel sub-group of BCP-ALL occurring in adolescents and young adults.
Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 14 , Clonagem Molecular , Feminino , Humanos , Hibridização in Situ Fluorescente , Proteínas Inibidoras de Diferenciação/genética , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Eritropoetina/genéticaRESUMO
The PICALM-MLLT10 fusion gene, generated by the t(10;11)(p12-13;q14-21) translocation, is a rare but recurrent event in acute leukemias. In this study, we assessed the characteristics and outcome of 18 PICALM-MLLT10 AML patients. As compared with non PICALM-MLLT10 patients (n=72), PICALM-MLLT10 AML were characterized by more frequent extramedullary diseases, CD7 expression and higher platelet counts. Three out of four therapy-related PICALM-MLLT10 AMLs had been previously treated for diffuse large B-cell lymphoma. The complete response rate was 71% after intensive chemotherapy. PICALM-MLLT10 patients had a shorter median overall survival than patients with favorable cytogenetics (12 months vs. not reached, p=0.07) but not significantly different from those of intermediate (26 months, p=0.32) or unfavorable cytogenetic groups (8 months, p=0.13). Long term responses were achieved in a subset of patients after allogeneic stem-cell transplantation but also after high-dose cytarabine.
Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Proteínas de Fusão Oncogênica/genética , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Estudos de Coortes , Intervalo Livre de Doença , Feminino , França , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this phase 2 study was to evaluate the efficacy and safety of trastuzumab, a humanized monoclonal antibody targeted against the human epidermal growth factor receptor 2 (HER2), for adult patients with relapsed/refractory HER2-positive B-ALL. Fifteen patients, with a median age of 62 years, received trastuzumab according to the schedule approved for breast cancer patients (ie, 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly). The overall response rate was 13% with 2 patients achieving partial response and partial remission cytolytic response, respectively. Two other patients were documented with blast clearance. Only 1 reversible grade 3 cardiac toxic event occurred. This phase 2 study showed that trastuzumab monotherapy can allow for some responses in a very high-risk refractory/relapsed HER2-positive adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Trastuzumab , Resultado do Tratamento , Adulto JovemRESUMO
Isochromosome of the long arm of chromosome 20 with interstitial loss of material [ider(20q)] is a rare cytogenetic abnormality reported in myelodysplastic syndrome (MDS), with neither specific morphological pattern nor clear prognostic significance. The aim of this retrospective multicentric study is to compare the peripheral blood and bone marrow morphology of MDS patients with ider(20q) (n = 13) and del(20q) (n = 21) and controls (n = 47) in order to investigate whether the ider(20q) harbors specific morphological features. The secondary objective is to compare the outcome of patients from both groups. This study performed on the largest cohort of MDS patients with ider(20q) is the first that identifies specific morphological features (hypogranulated and vacuolized neutrophils and neutrophil erythrophagocytosis) allowing the identification of this cytogenetic abnormality with high sensitivity (70%) and specificity (85.7%). Suspected ider(20q) by morphology should therefore support targeted FISH tests in case of non informative karyotype. This combined approach will allow a better estimation of the prevalence of this underdiagnozed entity. The overall survival and progression-free survival did not statistically differ in both groups. However, hypogranulated and vacuolized neutrophils were significantly associated with survival.
Assuntos
Células Sanguíneas , Aberrações Cromossômicas , Deleção Cromossômica , Citogenética/métodos , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Sanguíneas/citologia , Células Sanguíneas/fisiologia , Células da Medula Óssea/citologia , Células da Medula Óssea/fisiologia , Cromossomos Humanos Par 20/genética , Estudos de Coortes , Feminino , Humanos , Hibridização in Situ Fluorescente , Isocromossomos/genética , Cariótipo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
The PRDM16 (1p36) gene is rearranged in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with MECOM (3q26.2) translocations. We used fluorescence in situ hybridization to study 39 haematological malignancies with translocations involving PRDM16 to assess the precise breakpoint on 1p36 and the identity of the partner locus. Reverse-transcription polymerase chain reaction (PCR) was performed in selected cases in order to confirm the partner locus. PRDM16 expression studies were performed on bone marrow samples of patients, normal controls and CD34(+) cells using TaqMan real-time quantitative PCR. PRDM16 was rearranged with the RPN1 (3q21) locus in 30 cases and with other loci in nine cases. The diagnosis was AML or MDS in most cases, except for two cases of lymphoid proliferation. We identified novel translocation partners of PRDM16, including the transcription factors ETV6 and IKZF1. Translocations involving PRDM16 lead to its overexpression irrespective of the consequence of the rearrangement (fusion gene or promoter swap). Survival data suggest that patients with AML/MDS and PRDM16 translocations have a poor prognosis despite a simple karyotype and a median age of 65 years. There seems to be an over-representation of late-onset therapy-related myeloid malignancies.
Assuntos
Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Fatores de Transcrição/genética , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Criança , Pré-Escolar , Bandeamento Cromossômico , Pontos de Quebra do Cromossomo , Feminino , Ordem dos Genes , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Linfoma/genética , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Adulto JovemRESUMO
Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (Nâ=â27) and telomeric rearrangements (Nâ=â15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (Nâ=â39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Neoplasias Hematológicas/genética , Fatores de Transcrição/genética , Linhagem Celular , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , TelômeroRESUMO
BACKGROUND: Chromosomal translocations are usually analyzed as a single entity, and are associated with a poor outcome in chronic lymphocytic leukemia. Translocations involving immunoglobulin genes are recurrent, but uncommon (<5%), and their individual prognosis is not clear. The two most frequent partners are BCL2 (18q21) and BCL3 (19q13). DESIGNS AND METHODS: Herein, 75 cases are reported of chronic lymphocytic leukemia and t(14;18) (BCL2-CLLs). Our series benefits from morphological, immunological and cytogenetical reviews. The IGHV status analyses were performed by referring laboratories. Comparison was made with our previously published series of chronic lymphocytic leukemia patients with t(14;19) (BCL3-CLLs, n=29). RESULTS: Compared with BCL3-CLLs, lymphocytosis was lower in BCL2-CLLs (p<0.008), and splenomegaly was less frequent (p<0.0001). There were more "typical" morphologies (p<0.005) and Matutes scores >4 (p<0.001) in the BCL2-CLLs group, and less CD38 expression (p<0.04). More variant BCL2-translocations were observed (t(18;22), n=11; 2t(2;18), n=2; p<0.02), and BCL2-translocation was frequently single (p<0.002). Complex karyotypes (p<0.02), trisomy 12 (p<0.03), 6q deletion (p<0.002) and TP53 deletion (p<0.02) were less frequent in BCL2-CLLs, whereas 13q deletion was more frequent (p<0.005). The IGHV gene was frequently mutated in BCL2-CLLs (p<0.0001). Treatment-free survival was longer in BCL2-CLLs (p<0.0001). CONCLUSIONS: BCL2-CLL.S express CD5 and lack expression of CD38, and have a Matutes score ≥4, frequent trisomy 12, no ATM and 6q deletions, and a mutated IGHV status. Compared to BCL3-CLLs, BCL2-CLLs are much less aggressive; indicating that identifying individual translocations and cytogenetic partners would allow improved patient stratification.
RESUMO
OBJECTIVES: Patients with near-tetraploid (karyotype: 81 - 103 chromosomes) acute lymphoblastic leukemia (NT-ALL) constitute about 1% of childhood ALL and data reported on them are limited and controversial. The aim of the study was to enlarge the knowledge on these rarely occurring ALL. METHODS: The members of the European Group for Immunophenotyping of Leukemias (EGIL) searched retrospectively their databases for NT-ALL patients. RESULTS: We collected data of 36 European children from seven European countries with NT-ALL diagnosed since 1992. All patients reached complete remission (CR) after induction chemotherapy. Their blasts were negative for peroxidase and BCR-ABL1. Ten children were diagnosed as T-cell ALL (T-ALL) EGIL categories (T-I n=2, T-II n=2, T-III n=3, T-IV n=3) and four displayed various structural chromosomal abnormalities. Eight of 10 T-ALL remained in 1st CR; one died in CR from sepsis and one is alive in 2nd CR. Median survival was 88 (7-213) months. B-cell precursor (BCP) ALL was diagnosed in 26 children. Thirteen were positive for ETV6-RUNX1 and are alive in 1st CR for 32-147 months. Ten children were ETV6-RUNX1 negative and remained in 1st CR for 16-163 months. One girl with hypodiploid and NT metaphases and ETV6-RUNX1-negative BCP-ALL and one of two boys with NT-BCP-ALL not examined for ETV6-RUNX1 died of infection after stem cell transplantation in 2nd/3rd CR. Secondary myelodysplastic syndrome developed in two patients with NT-BCP-ALL. CONCLUSIONS: Our data demonstrate immunophenotypic, cytogenetic, and molecular heterogeneity of NT-ALL and favorable prognosis of most NT-ALL across different immunophenotypic and/or genetic ALL subtypes.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Aberrações Cromossômicas , Subunidade alfa 2 de Fator de Ligação ao Core , Europa (Continente) , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Imunofenotipagem , Cariotipagem , Masculino , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
Assuntos
Análise Citogenética , Mutação/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 9/genética , Clonagem Molecular , Estudos de Coortes , Feminino , França , Regulação Leucêmica da Expressão Gênica , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adulto JovemRESUMO
Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34(+) cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.
Assuntos
Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Leucemia Mieloide Aguda/genética , MicroRNAs/metabolismo , Síndromes Mielodisplásicas/genética , Células Mieloides/citologia , Translocação Genética/genética , Transformação Celular Neoplásica/genética , Primers do DNA/genética , Humanos , Hibridização in Situ Fluorescente , Itália , Células Mieloides/fisiologia , Reação em Cadeia da Polimerase/métodos , Regulação para Cima/fisiologiaRESUMO
Gemtuzumab Ozogamicin (GO) is a humanized anti-CD33 antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin-g1. It was developed at the end of the nineties as 90% of the leukemic blast population of patients with acute myeloid leukaemia (AML) express the CD33 surface antigen (Dinndorf et al. [1] Blood 1986;67:1048-53). GO is currently approved in monotherapy for the treatment of CD33+ AML patients in first relapse, showing a 26% overall response rate and a median disease-free-survival of 5.2 months for responders (Larson et al. [2] Cancer 2005;104:1442-52). CD33 antigen expression is also observed at diagnosis (in 15% of cases) (Pui et al. [3] J Clin Oncol 1998;16:3768-73) or at relapse (Guglielmi et al. [4] Leukemia 1997; 11:1501-7) of acute lymphoblastic leukaemia (ALL), representing a potential cellular target for ALL patients. Case series have already demonstrated the efficacy of GO in children with relapsed CD33+ ALL with documentation of complete remission (CR) (Balduzzi et al. [5] Leukemia 2003;17:2247-8; Cotter et al. [6] Br J Haematol 2003;122:686-91; Zwaan et al. [7] Leukemia 2003;17:468-70). In the other hand, there is no report at our knowledge of the use of GO in the setting of adult CD33+ ALL patient. Here we report the case of a 30-year-old man with a refractory CD33+ ALL who received a salvage regimen combining chemotherapy + GO and achieved a transient CR.
Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Anticorpos Monoclonais Humanizados , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Terapia Combinada , Evolução Fatal , Gemtuzumab , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Indução de Remissão , Lectina 3 Semelhante a Ig de Ligação ao Ácido SiálicoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Monocítica Aguda/complicações , Leucemia Mielomonocítica Aguda/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/induzido quimicamente , Doença Aguda , Adulto , Evolução Fatal , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Indução de RemissãoRESUMO
BACKGROUND AND OBJECTIVES: Diffuse large B-cell lymphomas (DLBCL) are common lymphomas that have been classified into three subgroups on the basis of their patterns of gene expression. The aim of this study was to characterize the clinical, biological, immunophenotypic and cytogenetic features of DLBCL with concurrent t(14;18) and 8q24/c-MYC rearrangement. DESIGN AND METHODS: Sixteen cases of DLBCL with the dual translocation were identified between 1998 and January 2006. The clinical features of these cases were examined and morphological, immunohistochemical, flow cytometric and cytogenetic analyses were performed. RESULTS: All patients had aggressive features: B symptoms (81%), ECOG performance status >2 (81%), elevated lactate dehydrogenase (100%), stage IV disease (100%) with at least one extra-nodal localization (bone marrow, blood and central nervous system involvement in 93%, 50% and 50%, respectively) and age-adjusted IPI score of 3 in 81%. Despite intensive chemotherapy regimens (including allogeneic transplants), all patients died of disease progression. Progression-free and overall survival was 4 and 5 months, respectively. Immunophenotyping analysis (CD20, CD10, Bcl-6, Mum-1, Bcl-2 CD138, MIB1, CD19, CD5, CD38 and sIg) was performed and showed DLBCL with a germinal center (GC) profile. Ki-67 staining ranged from 70 to 90%. All cases assessed by cytogenetics analysis [conventional cytogenetic and/or fluorescence in situ hybridization (FISH)] had a complex karyotype. In one case, we identified a 8q24/c-MYC translocation variant never reported in DLBCL before: t(8;9)(q24;p13) and t(14;18)(q32;q21). The BCL-6 rearrangement was investigated by FISH and found to rearranged in four cases. INTERPRETATION AND CONCLUSIONS: In conclusion, DLBCL with concurrent t(14;18) and 8q24/c-MYC rearrangement is a subgroup of GC-DLBCLwith poor outcome. It is worth searching for the coexistence of dual translocations in Bcl-2-positive DLBCL with unusual aggressive presentation.
Assuntos
Cromossomos Humanos Par 8/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
To study the role of the JAK2-V617F mutation in leukemic transformation, we examined 27 patients with myeloproliferative disorders (MPDs) who transformed to acute myeloid leukemia (AML). At MPD diagnosis, JAK2-V617F was detectable in 17 of 27 patients. Surprisingly, only 5 of 17 patients developed JAK2-V617F-positive AML, whereas 9 of 17 patients transformed to JAK2-V617F-negative AML. Microsatellite analysis in a female patient showed that mitotic recombination was not responsible for the transition from JAK2-V617F-positive MPD to JAK2-V617F-negative AML, and clonality determined by the MPP1 polymorphism demonstrated that the granulocytes and leukemic blasts inactivated the same parental X chromosome. In a second patient positive for JAK2-V617F at transformation, but with JAK2-V617F-negative leukemic blasts, we found del(11q) in all cells examined, suggesting a common clonal origin of MPD and AML. We conclude that JAK2-V617F-positive MPD frequently yields JAK2-V617F-negative AML, and transformation of a common JAK2-V617F-negative ancestor represents a possible mechanism.
Assuntos
Transformação Celular Neoplásica/genética , Janus Quinase 2/genética , Leucemia Mieloide/genética , Mutação , Transtornos Mieloproliferativos/genética , Idoso , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/patologia , Deleção Cromossômica , Cromossomos Humanos Par 11 , Cromossomos Humanos X , Células Clonais/patologia , Feminino , Humanos , Cinesinas , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologia , Fosfoproteínas/genética , Polimorfismo GenéticoRESUMO
Chromosome 21 is frequently rearranged in hematopoietic malignancies. In order to detect new chromosomal aberrations, the Groupe Français de Cytogénétique Hématologique collected a series of 107 patients with various hematologic disorders and acquired structural abnormalities of the long arm of chromosome 21. The abnormalities were subclassified into 10 groups, according to the location of the 21q breakpoint and the type of abnormality. Band 21q22 was implicated in 72 patients (excluding duplications, triplications, and amplifications). The involvement of the RUNX1 gene was confirmed in 10 novel translocations, but the gene partners were not identified. Eleven novel translocations rearranging band 21q22 with bands 1q25, 2p21, 2q37, 3p21, 3p23, 4q31, 6p24 approximately p25, 6p12, 7p15, 16p11, and 18q21 were detected. Rearrangements of band 21q11 and 21q21 were detected in six novel translocations with 5p15, 6p21, 15q21, 16p13, and 20q11 and with 1p33, 3q27, 5p14, 11q11, and 14q11, respectively. Duplications, triplications, amplifications, and isodicentric chromosomes were detected in eight, three, eight, and three patients, respectively. The present study shows both the wide distribution of the breakpoints on the long arm of chromosome 21 in hematopoietic malignancy and the diversity of the chromosomal rearrangements and the hematologic disorders involved. The findings invite further investigation of the 21q abnormalities to detect their associated molecular rearrangements.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Doenças Hematológicas/genética , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Comportamento Cooperativo , Feminino , França/epidemiologia , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/patologia , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Most chromosomal translocations observed in T-cell acute lymphoblastic leukemia (T-ALL) often produce transcriptional activation of transcription factor oncogenes. Ectopic expression of the TLX3 (also known as HOX11L2) gene has been shown to be associated with a cryptic t(5;14)(q35;q32) translocation specific for a subtype of T-ALL. Here we report several examples of variant and alternative translocations resulting in expression of TLX3 in T-ALL, and we describe three of these translocations in detail. In particular, the CDK6 gene was rearranged in two t(5;7)(q35;q21) translocations. In two additional instances, fusion of the BCL11B (also known as CTIP2) and RANBP17/TLX3 loci were shown to result from subtle genomic insertion/deletion within these loci. This study further underscores that TLX3 expression in T-ALL is strongly associated with the presence of genomic rearrangements.
Assuntos
Proteínas de Homeodomínio/genética , Proteínas Oncogênicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Western Blotting , Linhagem Celular Tumoral , Criança , Pré-Escolar , Bandeamento Cromossômico , Cromossomos/ultraestrutura , Quinase 6 Dependente de Ciclina , Quinases Ciclina-Dependentes/genética , Feminino , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Modelos Genéticos , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas , Translocação Genética , Proteína ran de Ligação ao GTP/genética , Proteínas ras/genéticaRESUMO
Cytogenetic studies in lymphomas classically require fresh or frozen tissue, whereas in many instances only paraffin-embedded biopsies are available. We applied an interphase FISH assay on nuclei extracted from thick paraffin sections to determine accuracy of molecular cytogenetics in such samples. Twenty-three lymphoma samples and 4 reactive lymph nodes were tested with various commercially available DNA probes, and hybridization patterns were compared with those obtained on frozen nuclei counterparts. Successful hybridization with all probes tested was observed for 23/27 (85%) paraffin-embedded tissues and for all (100%) frozen samples, and cut-off levels defining positivity were superimposable for both situations. Chromosome changes were detected in the same way, without any false-positive or false-negative cases. Hybridization signals observed on dewaxed samples were either those classically expected to define the relevant chromosome change or were atypical: all atypical changes could be demonstrated also into nuclei from the frozen counterpart. Moreover, all typical and atypical chromosome changes observed on frozen nuclei were also detected in paraffin-embedded tissues. Our study shows that our interphase FISH assay performed on paraffin-embedded samples is a valuable alternate to conventional methods to ascertain diagnosis of lymphomas as to include patients into therapeutic trials.
Assuntos
Artefatos , DNA de Neoplasias/análise , Técnicas Histológicas , Linfonodos/patologia , Linfoma não Hodgkin/genética , Aberrações Cromossômicas , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Formaldeído , Secções Congeladas , Técnicas Histológicas/métodos , Humanos , Hibridização in Situ Fluorescente , Inclusão em Parafina , Fixação de TecidosRESUMO
Mutations of the AML1 gene are frequent molecular abnormalities in minimally differentiated acute myeloblastic leukemia (M0 AML), a rare type of AML. In this retrospective multicenter study, morphologic, immunophenotypical, cytogenetic, and molecular features of 59 de novo M0 AML cases were analyzed and correlated to AML1 mutations. Point mutations of AML1 gene were observed in 16 cases (27%). They were correlated with higher white blood cell (WBC) count (P =.001), greater marrow blast involvement (P =.03), higher incidence of immunoglobulin H/T-cell receptor (IgH/TCR) gene rearrangement (P <.0001), and with a borderline significant lower incidence of complex karyotypes. In the 59 patients, FLT3 mutations were the only significant prognostic factors associated with short survival.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Mutação Puntual , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Subunidade alfa 2 de Fator de Ligação ao Core , Rearranjo Gênico do Linfócito T , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Antígenos de Linfócitos T/genética , Estudos Retrospectivos , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fmsRESUMO
To draw the cytogenetic profile of childhood and adult acute megakaryoblastic leukemia (M7), the Groupe Français de Cytogénétique Hématologique collected 53 cases of M7 (30 children and 23 adults). Compared to other acute myeloid leukemias, M7 is characterized by a higher incidence of abnormalities, a higher complexity of karyotypes, and a different distribution of abnormalities among children and adults. Nine cytogenetic groups were identified: normal karyotypes (group 1), patients with Down syndrome (group 2), numerical abnormalities only (group 3), t(1;22)(p13;q13) or OTT-MAL transcript (group 4), t(9;22)(q34;q11) (group 5), 3q21q26 (group 6), -5/del(5q) or -7/del(7q) or both (group 7), i(12)(p10) (group 8), and other structural changes (group 9). Groups 1, 2, 3, and 4 were exclusively composed of children (except one adult in group 3), whereas groups 5, 6, 7, and 8 were mainly made up of adults. The main clinical and hematologic features of these groups were described. No new recurrent abnormality was identified, but mapping of all breakpoints allowed us to specify several possible hot spots of rearrangement: 17q22-23, 11q14-21, 21q21-22, and 16q21-22-23. Although 90.5% of cases had no documented antecedent hematologic disorder or exposure to chemotherapy or radiotherapy, the morphologic and the cytogenetic findings indicated that M7 might be a secondary leukemia more often than suggested by preceding history, particularly among adults. The concurrent analyses of morphologic and cytogenetic data also led us to assume that the initial precursor involved might be more immature in adult than in childhood M7.