RESUMO
Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS.
Assuntos
Lenalidomida/administração & dosagem , Quimioterapia de Manutenção , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoenxertos , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Taxa de SobrevidaRESUMO
We describe a patient with Down syndrome whose precursor B-cell acute lymphoblastic leukemia cells expressed INPP5D-ABL1 fusion gene that resulted in a reciprocal chromosome translocation t(2;9)(q27;q34). The fusion gene was present as a small subclone in the primary disease but was first identified at relapse when the subclone had expanded into a major clone. At relapse, the patient responded poorly to conventional induction chemotherapy but a transient morphologic remission was achieved after administration of imatinib monotherapy. This case demonstrates a pathway to relapse in a Down syndrome patients with acute lymphoblastic leukemia through a rare fusion event. It highlights the significance of minor subclonal events in therapy resistance and the opportunity provided for targeted therapy.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogênicas c-abl/economia , Adolescente , Síndrome de Down/complicações , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-abl/genéticaRESUMO
T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of natural killer cells are intriguing entities between benign and malignant lymphoproliferation. The molecular pathogenesis has partly been uncovered by the recent discovery of somatic activating STAT3 and STAT5b mutations. Here we show that 43% (75/174) of patients with T-cell large granular lymphocytic leukemia and 18% (7/39) with chronic lymphoproliferative disorder of natural killer cells harbor STAT3 mutations when analyzed by quantitative deep amplicon sequencing. Surprisingly, 17% of the STAT3-mutated patients carried multiple STAT3 mutations, which were located in different lymphocyte clones. The size of the mutated clone correlated well with the degree of clonal expansion of the T-cell repertoire analyzed by T-cell receptor beta chain deep sequencing. The analysis of sequential samples suggested that current immunosuppressive therapy is not able to reduce the level of the mutated clone in most cases, thus warranting the search for novel targeted therapies. Our findings imply that the clonal landscape of large granular lymphocytic leukemia is more complex than considered before, and a substantial number of patients have multiple lymphocyte subclones harboring different STAT3 mutations, thus mimicking the situation in acute leukemia.
Assuntos
Artrite Reumatoide/genética , Biomarcadores/análise , Evolução Clonal/genética , Leucemia Linfocítica Granular Grande/genética , Mutação/genética , Fator de Transcrição STAT3/genética , Linfócitos T/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Adulto JovemRESUMO
OBJECTIVES: Previous studies indicate that 40-50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-α2b) and imatinib may increase the rate of successful discontinuation. METHODS: In this pilot study, we prospectively stopped imatinib from patients (n = 12) who had achieved major molecular response (MMR) after ≥12 months of treatment with either imatinib or imatinib+Peg-IFN-α2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed. RESULTS: In the monotherapy group, 5/6 patients lost MMR within 4 months. One patient remains to date in MR(4.0) 61 months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4 months while still receiving Peg-IFN-α2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3 months. One patient is still in sustained MR(4.0) at 58 months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells. CONCLUSIONS: A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (<2 yr) may allow for therapy discontinuation but this needs to be confirmed in larger prospective studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas/uso terapêutico , Biomarcadores Tumorais/genética , Proteínas de Fusão bcr-abl/genética , Fatores Imunológicos/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Pirimidinas/uso terapêutico , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Expressão Gênica , Humanos , Mesilato de Imatinib , Interferon alfa-2 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Recidiva , Indução de Remissão , Fatores de TempoRESUMO
Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
Assuntos
Barreira Hematoencefálica/metabolismo , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Adolescente , Adulto , Idoso , Animais , Criança , Análise Citogenética , Dasatinibe , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Indução de Remissão , Punção Espinal , Taxa de Sobrevida , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.
Assuntos
Análise Mutacional de DNA , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Acelerada/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adolescente , Adulto , Idoso , Células Clonais/patologia , Dasatinibe , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Acelerada/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , RNA Neoplásico/genética , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adolescente , Adulto , Idoso , Ácidos Borônicos/administração & dosagem , Bortezomib , Terapia Combinada/métodos , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Pirazinas/administração & dosagem , Indução de Remissão , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND: Recently, an International Scale was proposed for standardizing BCR-ABL transcript measurements and reporting in the assessment of minimal residual disease by real-time quantitative polymerase chain reaction (RQ-PCR). Here we present the setting up of the International Scale conversion factors for a national laboratory by performing both a cross-analysis of a set of standard samples from a reference laboratory and an analysis of bone marrow and peripheral blood samples at diagnosis (from 32 and 27 patients, respectively). DESIGN AND METHODS: A total of 222 bone marrow and 173 peripheral blood mononuclear cell samples from 96 patients with chronic myeloid leukemia were analyzed with RQ-PCR according to Europe Against Cancer protocols. Additionally, 291 bone marrow samples were analyzed with high mitotic index metaphase fluorescence in situ hybridization (metaphase FISH). RESULTS: Major molecular response according to the International Scale in BCR-ABL/GUS transcript levels corresponded to a ratio of 0.035% in peripheral blood and 0.034% in bone marrow, yielding the same conversion factor of 2.86 for both types of sample. Based on metaphase FISH, values of 10%/-1.0 log, 1%/-2.0 log and 0.1%/-3.0 log on the International Scale, corresponded to 13%, 2%, and 0.3% of Philadelphia chromosome positive cells in bone marrow, respectively. CONCLUSIONS: In conclusion, conversion factors can be determined either by cross-analyzing a number of samples with a laboratory that has already established the International Scale or utilizing sufficient numbers of reference samples from chronic myeloid leukemia patients at diagnosis, or using the upcoming international standards.
Assuntos
Medula Óssea/metabolismo , Proteínas de Fusão bcr-abl/biossíntese , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucócitos Mononucleares/metabolismo , Índice Mitótico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Óssea/patologia , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucócitos Mononucleares/patologia , Masculino , Metáfase , Neoplasia ResidualRESUMO
The t(5;11)(q35;p15.4) is a clinically significant marker of poor prognosis in acute myeloid leukemia (AML), which is difficult to detect due to sub-telomeric localization of the breakpoints. To facilitate the detection of this rearrangement, we studied NUP98-NSD1 transcript variants in patients with the t(5;11) using paired-end RNA sequencing and standard molecular biology techniques. We discovered three NUP98-NSD1 transcripts with two fusion junctions (NUP98 exon 11-12/NSD1 exon 6), alternative 5' donor site in NUP98 exon 7, and NSD1 exon 7 skipping. Two of the transcripts were in-frame and occurred in all t(5;11) samples (N = 5). The exonic splicing events were present in all samples (N = 23) regardless of the NUP98-NSD1 suggesting that these novel splice events are unassociated with t(5;11). In conclusion, we provide evidence of two different NUP98-NSD1 fusion transcripts in adult AML, which result in functional proteins and represent suitable molecular entities for monitoring t(5;11) AML patients.
Assuntos
Processamento Alternativo , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Adulto , Feminino , Seguimentos , Rearranjo Gênico , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Wnt4 is needed for correct development of several tissues in the mouse, and WNT4 is found here to be expressed in a temporal manner in human embryonic tissues. In addition, WNT4 mRNA is seen in several adult tissues. The 1.5 kb transcript is dominant in adult tissues, whereas the 2.4 kb transcript is the major one in embryonic tissues. The involvement of WNT4 in normal mammary gland and ovary development suggests that WNT4 germline mutations may be associated with the human cancer predisposition. Their absence in cancer families, however, implies lack of involvement of WNT4 mutations in the etiology of hereditary susceptibility to breast and ovarian cancer. Finally, the chromosomal location of WNT4 is narrowed to 1p36.12.
Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas/biossíntese , Neoplasias da Mama/etiologia , Cromossomos Humanos Par 1 , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias Ovarianas/etiologia , Linhagem , Proteínas Proto-Oncogênicas/análise , Proteínas Wnt , Proteína Wnt4Assuntos
Genes abl/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfócitos B/fisiologia , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Translocação Genética/genética , Adulto , Sequência de Aminoácidos , Dasatinibe , Fusão Gênica/genética , Humanos , Masculino , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Células Precursoras de Linfócitos B/efeitos dos fármacos , Pirimidinas/farmacologia , Tiazóis/farmacologiaRESUMO
UNLABELLED: We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3-ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Medicina de Precisão/métodos , Antineoplásicos/farmacologia , Progressão da Doença , Reposicionamento de Medicamentos , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
Imatinib, a small molecule inhibitor of ABL, PDGFR and C-KIT, has revolutionized treatment of chronic myeloid leukaemia (CML). However, resistance to treatment is of increasing importance and often is due to point mutations in the Abl kinase domain (Abl KD). Here, we analysed clinical outcome and mutation status in two independent Nordic populations (n = 77) of imatinib-resistant CML patients. We detected BCR-ABL transcripts containing point mutations of residues in the P-loop, A-loop and other kinase domain residues in 32 patients (42%). In contrast to previous data, mutations in BCR-ABL were as frequently found in patients with primary resistance (56%) as with secondary resistance (53%). No T315I mutations were found in the study cohort. BCR-ABL splice variants were identified in a significant number of our cases (19%): BCR-ABL transcripts of variable length; a variant fusion transcript joining BCR exon 14 sequences to ABL exon 4; partial, in-frame-deletion of exon 4 due to induction of a cryptic splice site by the L248V and finally, alternative splicing of ABL exon 7 sequences. Though the majority of splice variants observed in this study do not encode functional proteins, alternative splicing appears to represent a common phenomenon in the biology of CML. We conclude that Abl KD point mutations represent a major mechanism of imatinib resistance. Other sequence irregularities were also detected, but their significance in conferring resistance is unclear. Diagnostic strategies looking for imatinib-resistant clones should be designed to detect a broader profile of BCR-ABL variants than just point mutations.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação Puntual , Adulto , Idoso , Antineoplásicos/uso terapêutico , Benzamidas , Análise Mutacional de DNA , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemAssuntos
Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células Neoplásicas Circulantes , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Feminino , Seguimentos , Efeito Enxerto vs Leucemia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Metáfase , Pessoa de Meia-Idade , Neoplasia Residual , Cromossomo Filadélfia , Valor Preditivo dos Testes , Transplante HomólogoRESUMO
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Instabilidade Genômica , Mutação/genética , Proteínas Nucleares/genética , Hidrolases Anidrido Ácido , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Análise Citogenética , Feminino , Rearranjo Gênico , Genótipo , Haplótipos/genética , Humanos , Masculino , Programas de Rastreamento , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Linfócitos T/metabolismoRESUMO
OBJECTIVE: To define the clinical, radiologic, and molecular genetic characteristics of a family with early progressive osteoarthritis mimicking childhood rheumatoid arthritis, Scheuermann-like changes of the spine, tall stature, short 3 and 4 metatarsals, and moderate sensorineural hearing loss. METHODS: We describe a 22-year-old woman and her 54-year-old mother with early progressive osteoarthritis mimicking childhood rheumatoid arthritis. The index case, her mother, and 3 other family members underwent a physical examination, anthropometric measurements, and radiologic studies. Their DNA was sequenced for the procollagen type II (COL2A1) gene. RESULTS: Mild scoliosis was noticed in the proband at the age of 6 years, and at the age of 7 years large Schmorl's nodes were found in the vertebrae L1-2. At the age of 11 years, changes resembling Scheuermann's disease were seen, mostly in the thoracic vertebrae. At the same age, she began to have arthralgia in the weight-bearing joints and osteoarthritis progressed fast, necessitating a hip prosthesis at the age of 18 years. The proband and her mother had bilateral sensorineural hearing loss of moderate degree. Both mother and daughter had an Arg75-Cys mutation in the COL2A1 gene. CONCLUSION: This family is the fourth example of the Arg75-Cys mutation in the COL2A1 gene, which appears to lead to a clearly recognizable phenotype. The finding suggests that sensorineural hearing loss may be a part of this syndrome.
Assuntos
Estatura , Colágeno Tipo II/genética , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/genética , Mutação , Osteoartrite/genética , Adulto , Arginina/genética , Artrite Juvenil/diagnóstico , Colágeno Tipo II/metabolismo , Cisteína/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Vértebras Lombares/patologia , Pessoa de Meia-Idade , Escoliose/patologia , SíndromeRESUMO
The expression of apoptosis-related genes BCL2, BAX, BCL2L1, BCL2A1, MCL1, DAPK1 and MYC was studied by quantitative real-time polymerase chain reaction on total RNA samples from patients with acute lymphoblastic leukaemia (ALL, n = 16), acute myeloid leukaemia (AML, n = 27), chronic myeloid leukaemia (CML, n = 12), mantle cell lymphoma (MCL, n = 19) and chronic lymphoid leukaemia (CLL, n = 32). BCL2, BAX, BCL2A1, MCL1, DAPK1 and MYC were overexpressed in all patient groups. BCL2L1 was underexpressed in CLL and CML, but not in AML, ALL and MCL. MCL1 levels were significantly higher in CD13 and CD33-positive ALL, and in CD56-positive AML samples. BCL2, BCL2L1, BCL2A1 and MCL1 were overexpressed and DAPK1 was underexpressed in CLL samples with a 11q23 deletion. MYC overexpression was significantly associated with shorter overall survival in MCL (P < 0.01). AML patients with a normal karyotype showed a higher frequency of BCL2A1 overexpression (P < 0.001) than those with an abnormal karyotype.