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2.
Blood ; 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35390143

RESUMO

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of p53 alterations in AML patients remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N=528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovered novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML, which had more deleterious TP53 mutations and copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML (sensitivity=94.49%, specificity=90.48%). Protein expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of co-mutations in TP53-mutant AML showed a muted landscape that encompassed primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provides a rationale to refine risk stratification of AML patients on the basis of integrated molecular and protein-level TP53 analyses.

3.
Ann Diagn Pathol ; 59: 151951, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35489185

RESUMO

The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients.

4.
Leuk Res ; 111: 106704, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34735934

RESUMO

Light-chain restricted hematogones (LCR HGs) detected by flow cytometry analysis can mimic bone marrow involvement by B-cell lymphoma. This phenomenon can present a diagnostic pitfall and negatively impact patient management, as misinterpretation may upgrade disease stage. In this study, we characterized the immunophenotype of LCR HGs with an aim to differentiate them from B-cell lymphoma. We analyzed 24 patients with LCR HGs, 12 (50 %) were kappa light chain restricted and 12 (50 %) were lambda light chain restricted. LCR HGs account for 51 % (range, 1.5%-99%) of B cells, and 0.5 % (range, 0.1%-3.7%) of total cells. In 15 patients in whom multiple specimens were analyzed, 10 (67 %) showed persistent LCR HGs in more than 1 specimen, and the duration of the light chain restriction ranged from 4 months to 2 years. Among 24 patients, 4 (16.6 %) cases were concurrently involved by B-cell lymphoma/myeloma in addition to LCR HGs. With the exception of light chain restriction, LCR HGs showed a similar immunophenotype as normal HGs and had a distinct location on the CD45/Side Scatter (SSC) plot. They were also consistently positive for CD10, CD19, CD38 (bright), CD43, and CD200. CD20 expression showed a spectrum from dim/negative to positive.


Assuntos
Linfócitos B/patologia , Medula Óssea/patologia , Cadeias lambda de Imunoglobulina/imunologia , Linfoma de Células B/diagnóstico , Mieloma Múltiplo/diagnóstico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Imunofenotipagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Prognóstico
5.
Hum Pathol ; 118: 60-68, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34655612

RESUMO

We report 83 cases of mantle cell lymphoma (MCL) involving the tonsil as initial manifestation (IM). The median age at the time of tonsillar involvement was 58 years (range, 35-79 years). Most (85%) patients presented similar to acute tonsillitis. Lymphadenopathy (84%) and advanced stage of disease (81%) were frequent. With a median follow-up of 6.1 years (range, 0.5-18.4 years), the median overall survival (OS) was 11.3 years for all patients. Cases with classic MCL morphology demonstrated a superior OS (median OS: 11.7 years versus 7.8 years for aggressive morphology, P = 0.0361). Approximately 20% of patients had limited stage of disease, and they had excellent outcomes (median OS: not reached versus 11.3 years for advanced-stage MCL, P = 0.0479). All the patients were alive after a median follow-up of 6.6 years (range, 1-16.2 years). There were no differences in relapse-free survival in morphology and stage (P > 0.05). When tonsils were involved by relapsed MCL, patients less commonly had acute tonsillitis-like symptoms, lymphadenopathy, and advanced stage of disease compared to MCL as IM. Patients in the relapse group had poorer OS than patients in the IM group from the time of tonsillar involvement by MCL to the date of death or last follow-up (7.8 versus 11.7 years, P = 0.003). Compared with a group of 93 patients whose initial biopsy specimen was a lymph node, patients whose initial biopsy specimen was tonsil had similar OS (11.7 versus 8.8 years, P = 0.1764). However, patients with tonsillar MCL more commonly had limited stage disease (19% versus 8%, P = 0.0385) and a low-risk Mantle Cell Lymphoma International Prognostic Index score (71% versus 47%, P = 0.0025).


Assuntos
Linfoma de Célula do Manto/patologia , Neoplasias Tonsilares/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Am J Hematol ; 96(11): 1420-1428, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34351647

RESUMO

TP53 mutations in acute myeloid leukemia (AML) are associated with resistance to standard treatments and dismal outcomes. The incidence and prognostic impact of the emergence of newly detectable TP53 mutations over the course of AML therapy has not been well described. We retrospectively analyzed 200 patients with newly diagnosed TP53 wild type AML who relapsed after or were refractory to frontline therapy. Twenty-nine patients (15%) developed a newly detectable TP53 mutation in the context of relapsed/refractory disease. The median variant allelic frequency (VAF) was 15% (range, 1.1%-95.6%). TP53 mutations were more common after intensive therapy versus lower-intensity therapy (23% vs. 10%, respectively; p = 0.02) and in patients who had undergone hematopoietic stem cell transplant versus those who had not (36% vs. 12%, respectively; p = 0.005). Lower TP53 VAF was associated with an increased likelihood of complete remission (CR) or CR with incomplete hematologic recovery (CRi) compared to higher TP53 VAF (CR/CRi rate of 41% for VAF < 20% vs. 13% for VAF ≥ 20%, respectively). The median overall survival (OS) after acquisition of TP53 mutation was 4.6 months, with a 1-year OS rate of 19%. TP53 VAF at relapse was significantly associated with OS; the median OS of patients with TP53 VAF ≥ 20% was 3.5 months versus 6.1 months for those with TP53 VAF < 20% (p < 0.05). In summary, new TP53 mutations may be acquired throughout the course of AML therapy. Sequential monitoring for TP53 mutations is likely to be increasingly relevant in the era of emerging TP53-targeting therapies for AML.


Assuntos
Leucemia Mieloide Aguda/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Frequência do Gene , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adulto Jovem
7.
Ann Diagn Pathol ; 52: 151720, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33676171

RESUMO

Transdifferentiation of follicular lymphoma to a Langerhans cell neoplasm is rarely reported and not well understood. Here we present a case, review the literature and discuss some of the biological underpinnings of lineage switch of B cells to histiocytes/Langerhans cells. A 31-year-old woman had follicular lymphoma (FL) and Langerhans cell sarcoma (LCS) co-localized above and below diaphragm. The FL was low-grade, had typical morphologic features, and was positive for CD10, BCL-2, and BCL-6. The LCS was cytologically atypical with necrosis and a high mitotic rate, and the immunophenotype supported Langerhans cell lineage positive for CD1a, CD207/langerin, and S-100 protein. Both tumors carried IGH-BCL2 and the LCS cells had immunophenotypic evidence of a residual B cell program, supporting the notion that these neoplasms are clonally related. The case reported is unusual because the patient was young and both diseases presented simultaneously, before any therapy. In addition, immunohistochemical analysis showed that the LCS was negative for BRAF V600E and phospho-ERK, suggesting that the LCS belongs to the known subset of Langerhans cell tumors lacking BRAF V600E and MAP2K1 mutations. Concurrent occurrence of FL and Langerhans cell neoplasm is an unusual phenomenon, with 10 cases reported previously: 4 Langerhans cell histiocytosis and 6 Langerhans cell sarcoma, including this case.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Sarcoma de Células de Langerhans/diagnóstico , Linfoma Folicular/diagnóstico , Segunda Neoplasia Primária/patologia , Adulto , Idoso , Linfócitos B/patologia , Desdiferenciação Celular/genética , Transdiferenciação Celular/genética , Feminino , Histiócitos/patologia , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Humanos , Imuno-Histoquímica/métodos , Imunofenotipagem/métodos , Sarcoma de Células de Langerhans/metabolismo , Sarcoma de Células de Langerhans/patologia , Células de Langerhans/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estadiamento de Neoplasias/métodos
8.
Mod Pathol ; 34(5): 854-861, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33219298

RESUMO

Hematopathologists are witnessing very exciting times, as a new era of unsurpassed technological advances is unfolding exponentially, enhancing our understanding of diseases at the genomic and molecular levels. In the evolving field of precision medicine, our contributions as hematopathologists to medical practice are of paramount importance. Social media platforms such as Twitter have helped facilitate and enrich our professional  interactions and collaborations with others in our field and in other medical disciplines leading to a more holistic approach to patient care. These platforms also have created a novel means for instantaneous dissemination of new findings and recent publications, and are proving to be increasingly useful tools that can be harnessed to expand our knowledge and amplify our presence in the medical community. In this Editorial, we share our experience as hematopathologists with Twitter, and how we leveraged this platform to boost scholarly activities within and beyond our subspecialty, and as a powerful medium for worldwide dissemination of educational material and to promote our remote teaching activities during the COVID-19 pandemic.


Assuntos
COVID-19 , Educação Médica Continuada , Hematologia/educação , Patologistas/educação , Patologia/educação , Comunicação Acadêmica , Mídias Sociais , Congressos como Assunto , Humanos , Disseminação de Informação , Especialização , Texas , Comunicação por Videoconferência
9.
Cancers (Basel) ; 12(12)2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33255818

RESUMO

RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using LY3009120 in AML cells harboring mutations upstream and downstream of RAF. LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably, LY3009120 potentiated the effect of Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect.

11.
Am J Hematol ; 93(11): 1376-1383, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30117185

RESUMO

Although ~50% of acute myeloid leukemia (AML) patients have a normal diploid karyotype by conventional cytogenetics at diagnosis, this patient subset has a variable disease course and outcome. Aberrant overexpression of the p53 protein is usually associated with TP53 alterations and a complex karyotype, but the prevalence and impact of p53 overexpression in AML with diploid cytogenetics is unknown. We examined 100 newly diagnosed AML patients to evaluate the impact of p53 expression status quantified in bone marrow core biopsy samples using immunohistochemistry and computer-assisted image analysis. A total of 24 patients had p53 overexpression defined as 3+ staining intensity in ≥5% of cells; this finding correlated with lower platelet counts (P = .002), absence of CD34 expression in blasts (P = .009), higher bone marrow blast counts (P = .04), and a higher frequency of FLT3 internal tandem duplication (P = .007). Overexpression of p53 independently predicted for shorter leukemia-free survival in patients who underwent allogeneic stem cell transplantation by univariate (P = .021) and multivariate analyses (P = .004). There was no correlation between MDM2 and p53 protein expression in this cohort. We conclude that p53 expression evaluated by immunohistochemistry in bone marrow biopsy specimens at the time of AML diagnosis may indicate distinct clinical characteristics in patients with normal diploid cytogenetics and is a potentially valuable tool that can enhance risk-stratification.


Assuntos
Leucemia Mieloide Aguda/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Medula Óssea/metabolismo , Medula Óssea/patologia , Diploide , Intervalo Livre de Doença , Feminino , Humanos , Cariótipo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Sequências de Repetição em Tandem
12.
J Cutan Pathol ; 45(1): 59-62, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28981153

RESUMO

Pleomorphic fibroma is a rare benign cutaneous neoplasm characterized by spindle-shaped cells and multinucleated giant cells scattered throughout collagenous stroma. These morphologic features can lead to diagnostic confusion, including atypical lipomatous tumor as one consideration. In contrast to atypical lipomatous tumor, previous studies have found pleomorphic fibroma to be negative for MDM2 immunohistochemical staining and MDM2 gene amplification. Here, we present a case of pleomorphic fibroma of skin with nuclear MDM2 immunoreactivity in the absence of MDM2 gene amplification, underscoring the superiority of fluorescence in situ hybridization as a diagnostic test in this differential diagnosis. The RB1 locus is also explored for differential diagnosis with pleomorphic/spindle cell lipoma and related entities.


Assuntos
Biomarcadores Tumorais/análise , Histiocitoma Fibroso Benigno/diagnóstico , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Neoplasias Cutâneas/diagnóstico , Feminino , Histiocitoma Fibroso Benigno/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lipoma/diagnóstico , Proteínas Proto-Oncogênicas c-mdm2/análise , Neoplasias Cutâneas/patologia , Adulto Jovem
13.
Mol Cancer Res ; 14(1): 56-65, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26527653

RESUMO

UNLABELLED: Mdm4 negatively regulates the p53 tumor suppressor. Mdm4 loss in mice leads to an embryonic lethal phenotype that is p53-dependent. Biochemical studies indicate that Mdm4 also binds p73, a member of the p53 family, with higher affinity than p53. In this study, the significance of the Mdm4 and p73 interaction in vivo during embryogenesis and tumorigenesis was examined. The data revealed that p73 loss did not rescue either the early Mdm4-deficient embryonic lethality or the runted phenotype of Mdm4(Δ2/Δ2) p53(+/-) embryos. Furthermore, studies in the developing central nervous system wherein both genes have prominent roles indicated that loss of p73 also did not rescue the Mdm4-null brain phenotype as did p53 loss. This p53 dependency occurred despite evidence for p73-specific transcriptional activity. In tumor studies, the combination of Mdm4 overexpression and p73 loss did not alter survival of mice or the tumor spectrum as compared with Mdm4 overexpression alone. In summary, these data demonstrate that the Mdm4-p73 axis cannot override the dominant role of p53 in development and tumorigenesis. IMPLICATIONS: Genetic characterization of the Mdm4 and p73 interaction during development and tumorigenesis suggests new insight into the role of p53 family members, which may influence treatment options for patients.


Assuntos
Carcinogênese , Proteínas de Ligação a DNA/metabolismo , Desenvolvimento Embrionário , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Proteínas de Ligação a DNA/genética , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
14.
Proc Natl Acad Sci U S A ; 111(30): 11145-50, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-25024203

RESUMO

p53(R172H/+) mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53(+/-) mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53(R172H/+) mice with metastasis to osteosarcomas from p53(+/-) mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53(R172H/+) osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformation-specific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis.


Assuntos
Neoplasias Ósseas/metabolismo , Síndrome de Li-Fraumeni/metabolismo , Mutação , Osteossarcoma/metabolismo , Fosfolipases A2 Independentes de Cálcio/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/patologia , Camundongos , Camundongos Mutantes , Invasividade Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfolipases A2 Independentes de Cálcio/genética , Elementos de Resposta , Proteínas Supressoras de Tumor/genética
15.
J Pathol ; 233(4): 380-91, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24789767

RESUMO

Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2(FM) , and a CAG-CreER tamoxifen-inducible recombination system to examine the effects of global Mdm2 loss in adult mice. Two different tamoxifen injection regimens caused 100% lethality of Mdm2(FM) (/-) ;CAG-CreER mice; both radio-sensitive and radio-insensitive tissues were impaired. Strikingly, a large number of radio-insensitive tissues, including the kidney, liver, heart, retina and hippocampus, exhibited various pathological defects. Similar tamoxifen injections in older (16-18 month-old) Mdm2(FM) (/-) ;CAG-CreER mice yielded abnormalities only in the kidney. In addition, transcriptional activation of Cdkn1a (p21), Bbc3 (Puma) and multiple senescence markers in young (2-4 month-old) mice following loss of Mdm2 was dampened in older mice. All phenotypes were p53-dependent, as Mdm2(FM) (/-) ;Trp53(-/-) ;CAG-CreER mice subjected to the same tamoxifen regimens were normal. Our findings implicate numerous possible toxicities in many normal tissues upon use of cancer therapies that aim to inhibit Mdm2 in tumours with wild-type p53.


Assuntos
Envelhecimento/patologia , Rim/patologia , Fígado/patologia , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-mdm2/deficiência , Proteínas Proto-Oncogênicas c-mdm2/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Envelhecimento/efeitos dos fármacos , Alelos , Animais , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Injeções , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout , Modelos Animais , Fenótipo , Proteínas Proto-Oncogênicas c-mdm2/genética , Retina/efeitos dos fármacos , Retina/patologia , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia
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