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1.
Hematol Oncol ; 38(5): 808-816, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32893896

RESUMO

The high expression of brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) has been reported to influence the outcome in acute myeloid leukemia (AML), but due to limited prospective studies, their role as prognostic factors is unclear. At diagnosis, the prognostic value of BAALC and ERG expression with respect to other cytogenetic and molecular markers was analyzed in 149 AML patients. Patients were divided into quartiles which resulted in the formation of four groups (G1-G4) based on expression values of BAALC and ERG and clinical response defined across groups. Groups with similar survival probabilities were merged together and categorized subsequently as high versus low expressers. Patients with high BAALC and ERG expression had significantly lower overall survival (OS; BAALC: p = 0.001 at 5 years 29.4% vs. 69.8%; ERG: p < 0.0001 at 5 years 4% vs. 50.4%) and disease-free survival (BAALC: p = 0.001 at 5 years 19.5% vs. 69.8%; ERG: p < 0.0001 at 5 years 4.2% vs. 47%). Patients were further stratified combining BAALC and ERG expression in an integrative prognostic risk score (IPRS). After a median follow-up of 54 months (95% CI 45-63 months) among survivors, IPRS for high versus low expressers was a significant predictor for OS (BAALC + ERG: 4% vs. 71.6%, p < 0.0001) and DFS (BAALC + ERG: 4.5% vs. 74.1%, p < 0.0001). In a multivariate model, IPRS of BAALC + ERG expression retained prognostic significance for OS (hazard ratio [HR] 2.96, 95%CI 1.91-4.59, p < 0.001) and DFS (HR 3.61, 95%CI 2.26-5.76, p < 0.001).


Assuntos
Biomarcadores Tumorais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Proteínas de Neoplasias/genética , Adolescente , Adulto , Aberrações Cromossômicas , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica , Humanos , Cariotipagem , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Medição de Risco , Análise de Sobrevida , Regulador Transcricional ERG/genética , Adulto Jovem
2.
Genes Chromosomes Cancer ; 53(3): 248-54, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24310817

RESUMO

Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Loci Gênicos , Leucemia Aguda Bifenotípica/genética , Inibidores da Topoisomerase/efeitos adversos , Sequência de Bases , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Epirubicina/efeitos adversos , Feminino , Humanos , Idarubicina/efeitos adversos , Leucemia Aguda Bifenotípica/induzido quimicamente , Leucemia Promielocítica Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Dados de Sequência Molecular , Família Multigênica , Translocação Genética
3.
Br J Haematol ; 161(4): 533-40, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23480665

RESUMO

FLT3 internal tandem duplication (ITD) mutations are frequently detected at diagnosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and predict unfavourable outcome. FLT3 ITD is an unstable aberration and may be lost or acquired at relapse. Recent whole genome sequencing studies have suggested that FLT3 ITD(+)ve AML relapse may evolve from small subclones undetectable at diagnosis by routine polymerase chain reaction (PCR). We developed a patient-specific real-time quantitative-PCR (RQ-PCR) to implement FLT3 ITD detection in six AML patients whose blasts carried wild-type FLT3 at diagnosis and who relapsed with FLT3 ITD by routine PCR. Patient-specific forward primers were designed after cloning and sequencing the FLT3 ITD in each case. The assay allowed retrospective detection of FLT3 ITD in diagnostic samples of 4/6 cases and to establish the kinetics of clonal evolution preceding relapse. After conventional chemotherapy, all patients had early relapse despite having been classified as NPM1(+)ve/FLT3 ITD(-)ve at presentation, with shorter remissions being observed in four patients re-classified as FLT3 ITD(+)ve by the new assay. Notably, FLT3 ITD clone became detectable by conventional PCR in three patients tested during remission after initial treatment. Our data underscore the need of identifying low FLT3 ITD levels, which are probably associated with relapse in otherwise good prognosis CN-AML.


Assuntos
Duplicação Gênica , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Feminino , Dosagem de Genes , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Recidiva , Estudos Retrospectivos
4.
Ann Hematol ; 92(10): 1319-23, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23949315

RESUMO

NADP-dependent enzyme isocitrate dehydrogenase (IDH) mutations, IDH1 and IDH2, have been described in acute myeloid leukemia (AML) using next generation sequencing approaches. IDH2 mutations are heterozygous; they alter a single arginine residue at position 140 or 172 and have distinct prognostic significance. The current detection methods of IDH2 mutations are laborious and time consuming as they require DNA sequencing. Herein, we report a new allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) method to detect the IDH2 mutations. Analysis of leukemic DNA samples from 120 AML patients enabled to identify IDH2 mutations in 22 cases which were confirmed by direct DNA sequencing. Of these, 17 harbored IDH2 (R140Q) and 5 IDH2 (R172K) mutations. Serial dilution experiments showed that the assay enable to detect mutations in 10⁻³ dilutions. Our ASO-PCR method appears useful for routine diagnostic screening of these prognostically relevant alterations in AML and may be conveniently included in the diagnostic workup.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Reação em Cadeia da Polimerase/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reprodutibilidade dos Testes
6.
Transl Oncol ; 35: 101729, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37369156

RESUMO

Multiple myeloma (MM) is an incurable plasma cell neoplasm. Despite several effective frontline therapeutic regimens, including Bortezomib (BTZ), relapse is almost inevitable; therefore, better therapeutic modalities to improve the outcomes are needed. Cyclin-dependent kinases (CDKs) are an essential constituent of the cellular transcriptional machinery and tumors including MM are critically dependent on transcription to maintain their oncogenic state. In the present study, we explored the efficacy of THZ1, a covalent CDK7 inhibitor in MM treatment using Bortezomib resistant (H929BTZR) cells and zebrafish xenografts. THZ1 showed anti-myeloma activity in the models of MM but had no effect on healthy CD34+ cells. THZ1 suppresses phosphorylation of carboxy-terminal domain of RNA polymerase II and downregulates the transcription of BCL2 family of proteins both in H929BTZS and H929BTZR cells leading to G1/S arrest and apoptosis. THZ1 mediates inhibition of bone marrow stromal cells-induced proliferation and activation of NF-kB signaling. The data derived from zebrafish xenografts of MM demonstrate that THZ1 combined with BTZ synergistically reduces tumor growth in zebrafish embryos. Collectively, our results reveal that THZ1 alone as well as in combination with BTZ has effective anti-myeloma activity.

7.
Cytometry B Clin Cytom ; 102(6): 462-470, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36346307

RESUMO

BACKGROUND: Many novel therapies are being evaluated for the treatment of Multiple myeloma (MM). The cell-surface protein B-cell maturation antigen (BCMA, CD269) has recently emerged as a promising target for CAR-T cell and monoclonal-antibody therapies in MM. However, the knowledge of the BCMA expression-pattern in myeloma patients from the Indian subcontinent is still not available. We present an in-depth study of BCMA expression-pattern on abnormal plasma cells (aPC) in Indian MM patients. METHODS: We studied BM samples from 217 MM patients (211-new and 6-relapsed) with a median age of 56 years (range, 30-78 years & M:F-2.29) and 20 control samples. Expression levels/patterns of CD269 (clone-19f2) were evaluated in aPCs from MM patients and in normal PCs (nPC) from uninvolved staging bone marrow samples (controls) using multicolor flow cytometry (MFC). Expression-level of CD269 was determined as a ratio of mean fluorescent intensity (MFI-R) of CD269 in PCs to that of non-B-lymphocytes and expression-pattern (homogenous/heterogeneous) as coefficient-of-variation of immunofluorescence (CVIF). RESULTS: Median (range) percentage of CD269-positive abnormal-PCs in total PCs was 71.6% (0.49-99.29%). The MFI-R (median, range) of CD269 was significantly higher in aPCs (4.13, 1.12-26.88) than nPCs (3.33, 1.23-12.87), p < .0001. Median (range) MFI of CD269 at diagnosis and relapse were 2.39 (0.77-9.57) and 2.66 (2.15-3.23) respectively. CD269 levels were similar at diagnosis and relapse, p = .5529. CONCLUSIONS: We demonstrated that BCMA/CD269 is highly expressed in aPCs from a majority of MM patients, both at diagnosis and relapse. Thus, BCMA is a valuable target for therapy for Indian MM patients.


Assuntos
Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Antígeno de Maturação de Linfócitos B/metabolismo , Citometria de Fluxo , Imunoterapia Adotiva , Mieloma Múltiplo/metabolismo , Recidiva Local de Neoplasia , Masculino , Feminino
8.
Haematologica ; 96(4): 621-5, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21193421

RESUMO

We report the clinical features and treatment outcome of 33 patients with multiple sclerosis who developed acute promyelocytic leukemia. Thirty patients were previously exposed to mitoxantrone. The median latency period between treatment initiation and acute promyelocytic leukemia diagnosis was 32 months. The PML-RARA bcr1 iso-form was identified in 87% of cases. Twenty-nine (90%) patients achieved hematologic remission after all-trans retinoic acid and chemotherapy (n = 31) or arsenic trioxide and all-trans retinoic acid. Consolidation included modified chemotherapy or arsenic trioxide. At a median follow up of 26 months, 23 patients are in complete remission, 4 relapsed and one developed secondary leukemia. The 5-year cumulative incidence of relapse and overall survival were 23% and 68%, respectively. Although treatment heterogeneity and suboptimal post-remission therapy must be taken into account, overall results and development of secondary leukemia in one patient suggest that effective and less toxic agents like arsenic trioxide warrants further investigation in this context.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Esclerose Múltipla/complicações , Adulto , Idoso , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
9.
Genes Chromosomes Cancer ; 49(8): 726-32, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20544846

RESUMO

We compared genomic breakpoints at the PML and RARA loci in 23 patients with therapy-related acute promyelocytic leukemia (t-APL) and 25 de novo APL cases.Eighteen of 23 t-APL cases received the topoisomerase II poison mitoxantrone for their primary disorder. DNA breaks were clustered in a previously reported 8 bp "hot spot" region of PML corresponding to a preferred site of mitoxantrone-induced DNA topoisomerase II-mediated cleavage in 39% of t-APL occurring in patients exposed to this agent and in none of the cases arising de novo (P = 0.007). As to RARA breakpoints, clustering in a 3' region of intron 2 (region B) was found in 65% of t-APL and 28% of de novo APL patients, respectively. Scan statistics revealed significant clustering of RARA breakpoints in region B in t-APL cases (P = 0.001) as compared to de novo APL (P = 1). Furthermore, approximately 300 bp downstream of RARA region B contained a sequence highly homologous to a topoisomerase II consensus sequence. Biased distribution of DNA breakpoints at both PML and RARA loci suggest the existence of different pathogenetic mechanisms in t-APL as compared with de novo APL.


Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , DNA de Neoplasias/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/genética , Receptores do Ácido Retinoico/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Pontos de Quebra do Cromossomo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Proteína da Leucemia Promielocítica , RNA Mensageiro/genética , Receptor alfa de Ácido Retinoico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Adulto Jovem
10.
Blood ; 112(8): 3383-90, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18650449

RESUMO

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging after mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distribution of chromosome 15 breakpoints versus de novo APL, biased toward disruption within PML intron 6 (11 of 12, 92% vs 622 of 1022, 61%: P = .035). Despite this intron spanning approximately 1 kb, breakpoints in 5 mitoxantrone-treated patients fell within an 8-bp region (1482-9) corresponding to the "hotspot" previously reported in t-APL, complicating mitoxantrone-containing breast cancer therapy. Another shared breakpoint was identified within the approximately 17-kb RARA intron 2 involving 2 t-APL cases arising after mitoxantrone treatment for MS and breast cancer, respectively. Analysis of PML and RARA genomic breakpoints in functional assays in 4 cases, including the shared RARA intron 2 breakpoint at 14 446-49, confirmed each to be preferential sites of topoisomerase IIalpha-mediated DNA cleavage in the presence of mitoxantrone. This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this subtype of leukemia after exposure to this agent.


Assuntos
Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Leucemia Promielocítica Aguda/induzido quimicamente , Leucemia Promielocítica Aguda/genética , Esclerose Múltipla/terapia , Translocação Genética , Adulto , Antígenos de Neoplasias/metabolismo , DNA/química , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Mitoxantrona/efeitos adversos , Mitoxantrona/farmacologia , Modelos Genéticos
11.
Genes Chromosomes Cancer ; 48(3): 213-21, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19023877

RESUMO

The translocation t(16;21) involving RUNX1 (AML1) and resulting in the RUNX1-CBFA2T3 fusion is a rare but recurrent abnormality mostly found in therapy-related acute myeloid leukemia (t-AML) associated with agents targeting topoisomerase II (topo II). We characterized, at the genomic level, the t(16;21) translocation in a patient who developed t-AML after treatment of multiple sclerosis with mitoxantrone (MTZ). Long template nested PCR of genomic DNA followed by direct sequencing enabled the localization of RUNX1 and CBFA2T3 (ETO2) breakpoints in introns 5 and 3, respectively. Sequencing of the cDNA with specific primers showed the presence of the expected RUNX1-CBFA2T3 fusion transcript in leukemic cells. The RUNX1 intron 5 breakpoint was located at nucleotide position 24,785. This region contained an ATGCCCCAG nucleotide sequence showing approximately 90% homology to a "hotspot" DNA region ATGCCCTAG present in intron 6 of PML previously identified in therapy-related acute promyelocytic leukemia cases arising following treatment with MTZ. This study suggests a wider distribution in the human genome, and particularly at genes involved in chromosome translocations observed in t-AML, of DNA regions (hotspot) targeted by specific topo II drugs.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Mitoxantrona/efeitos adversos , Translocação Genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Análise Citogenética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Análise de Sequência de DNA , Inibidores da Topoisomerase II , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
13.
Indian J Med Res ; 129(3): 256-61, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19491417

RESUMO

BACKGROUND & OBJECTIVE: Recurrent balanced translocations are generally recognized to be a major parameter for prognostication in acute myeloid leukaemia (AML). The chromosomal translocation t(15;17) results in PML/RARalpha fusion gene, t(8;21) results in AML1/ETO fusion gene and Inv 16 generates CBFbeta/MYH11 fusion gene. Patients with these mutations have a good prognosis unlike abnormalities in chromosome 5 or 7 or FLT3 genes. Therefore, we screened the AmL patients for known specific genetic abnormalities that could lead to more definitive prognoses. METHODS: A total of 113 AML patients were evaluated at diagnosis based on routine morphology and cytochemistry and classified according to the WHO criteria. The distribution of AML subtypes was M1(1), M2(32), M3(57), M4(14), M5(1), M6(1) and seven cases where morphological subtype could not be classified. RT-PCR was performed to identify PML/RARalpha, AML1/ETO, CBFbeta/MYH11 and FLT3 nternal tandem duplication (ITD). RESULTS: Of the 57 patients with M3 subtype, 55 had the PML-RARalpha fusion transcript. The prevalence of bcr3 (short isoform) was higher (62%) than that of bcr1 (long isoform) (38%) and no correlation was found with age, sex or white blood cell count. FLT3 internal tandem duplication (ITD) mutations were more frequent in patients with APL than in other AML subtypes (17.5 vs. 8.9%), the frequency greater in patients with bcr3 isoform (70%) than in those with in bcr1 isoform (30%). Patients with FLT3/ ITD mutations had a significantly higher median white cell count than those without these mutations (55 x 10(9)/l vs. 6.3 x 10(9)/l P<0.001). More patients with FLT3/ITD mutations died early (53%) than those without these mutations (16%) (P<0.01). AML1-ETO fusion transcript was detected in 16 of 56 patients with no correlation with clinical or haematological parameters. INTERPRETATION & CONCLUSION: The results of the present study showed presence of bcr3 (short isoform) higher than bcr1 (long isoform). FLT3 internal tandem duplication (ITD) mutation was predominant in acute promyelocytic leukaemia patients with bcr3 isoform. Thus, patients with APL who have FLT3 mutation appear to have a poorer prognosis. Therefore, rapid identification of specific translocations at diagnosis is important for prognostic purposes and their detection should be incorporated into routine assessment.


Assuntos
Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Translocação Genética , Adolescente , Adulto , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Duplicação Gênica , Predisposição Genética para Doença/epidemiologia , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Prevalência , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
14.
J Mol Diagn ; 17(2): 179-84, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25554589

RESUMO

DNMT3A mutations represent one of the most frequent gene alterations detectable in acute myeloid leukemia with normal karyotype. Although various recurrent somatic mutations of DNMT3A have been described, the most common mutation is located at amino acid R882 in the methyltransferase domain of the gene. DNMT3A mutations have been reported to be stable during disease progression and are associated with unfavorable outcome in acute myeloid leukemia patients with normal karyotype. Because of their prognostic significance and high stability during disease evolution, DNMT3A mutations might represent highly informative biomarkers for minimal residual disease monitoring. We describe a new rapid diagnostic RT-PCR assay based on TauI restriction enzyme reaction to identify DNMT3A R882 mutations at diagnosis. In addition, we developed a sensitive and specific test based on peptide nucleic acid real-time PCR technology to monitor DNMT3A R882H mutation. We identified 24 DNMT3A R882H mutated patients out of 134 acute myeloid leukemia screened samples and we analyzed in these patients the kinetics of minimal residual disease after induction and consolidation therapy. This assay may be useful to better assess response to therapy in patients with acute myeloid leukemia bearing the DNMT3A R882H mutation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Análise Mutacional de DNA/métodos , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , DNA Metiltransferase 3A , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reprodutibilidade dos Testes , Adulto Jovem
15.
Best Pract Res Clin Haematol ; 27(1): 3-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24907012

RESUMO

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) associated with peculiar biologic and clinical features and requiring specific management. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARα gene fusion and chimeric protein. APL is the first example of differentiation therapy targeted to a defined genetic target i.e. PML-RARα. PML-RARα behaves as an altered retinoic acid receptor with an ability of transmitting oncogenic signaling leading to accumulation of undifferentiated promyelocytes. All-trans-retinoic acid (ATRA) induces disease remission in APL patients by triggering terminal differentiation of leukemic promyelocytes. More recently, arsenic trioxide (ATO) has been shown to contribute degradation of the PML-RARα oncoprotein through bonding the PML moiety and has shown excellent synergism with ATRA in clinical trials. Elucidating the oncogenic signaling of PML-RARα through various transcription factors and the study of APL mouse models have greatly helped to understand the molecular pathogenesis of APL. However, the precise molecular mechanism by which t(15;17) is formed and initiates leukemia remains unknown. While transforming oncogenic potential of PML-RARα has been described extensively, the mechanistic events important for the formation of t(15;17) have been taken from the model of Therapy-related APL (t-APL).


Assuntos
Transformação Celular Neoplásica/genética , Leucemia Promielocítica Aguda/etiologia , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Animais , Antineoplásicos/uso terapêutico , Trióxido de Arsênio , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Ensaios Clínicos como Assunto , Reparo do DNA por Junção de Extremidades , Modelos Animais de Doenças , Sinergismo Farmacológico , Células Precursoras de Granulócitos/efeitos dos fármacos , Células Precursoras de Granulócitos/patologia , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/fisiologia , Óxidos/farmacologia , Óxidos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Inibidores da Topoisomerase II/efeitos adversos , Tretinoína/uso terapêutico
18.
Clin Lymphoma Myeloma Leuk ; 10 Suppl 3: S139-43, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21115433

RESUMO

Acute promyelocytic leukemia (APL) is characterized by a unique genetic aberration, the t(15;17) chromosome translocation. Translocation breakpoints are located within the promyelocytic leukemia (PML) locus on chromosome 15 and the retinoic acid receptor alpha (RARA) locus on chromosome 17. In the past 2 decades, critical advances have been made in understanding the molecular pathogenesis of APL. APL represents a paradigm for molecularly targeted therapy in cancer and an extraordinary model for translational research in medicine. In fact, the release of differentiation block upon treatment of APL with all-trans-retinoic acid (ATRA) has represented the first example of targeted therapy in human cancer. More recently, the advent of arsenic trioxide (ATO) has allowed further progress in the management of this disease through improved outcomes in patients receiving this agent in combination with ATRA. Finally, optimization of therapy and minimization of toxicity is feasible in this disease through careful monitoring of residual disease using polymerase chain reaction-based approaches targeting the PML-RARA fusion gene.


Assuntos
Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Fenótipo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Trióxido de Arsênio , Arsenicais/metabolismo , Arsenicais/uso terapêutico , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Óxidos/metabolismo , Óxidos/uso terapêutico , Prognóstico , Recidiva , Translocação Genética/genética , Tretinoína/metabolismo , Tretinoína/uso terapêutico
19.
Ann Hematol ; 84(12): 781-4, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16132910

RESUMO

Thirty six patients with acute promyelocytic leukemia were studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time PCR. There was concordance between the results achieved by both the methods except in one case, which was negative by RT-PCR but positive by real-time PCR. The prevalence of bcr3 (short isoform) was found to be significantly higher than that of bcr1 (long isoform) (64 vs. 36%, P=0.03). No correlation was found between age, sex, and white blood cell (WBC) count at diagnosis. Molecular remission was achieved in 66.6% of patients with bcr3 isoform. Median WBC count at presentation was found to be higher than that in the West.


Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Promielocítica Aguda/sangue , Proteínas de Neoplasias/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Proteínas Proto-Oncogênicas c-bcr/biossíntese , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Índia , Leucemia Promielocítica Aguda/diagnóstico , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Prevalência , Isoformas de Proteínas/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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