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1.
Br J Haematol ; 204(5): 1844-1855, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38522849

RESUMO

Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.


Assuntos
Hematopoiese Clonal , Proteínas de Ligação a DNA , Dioxigenases , Mutação , Humanos , Hematopoiese Clonal/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Proteínas de Ligação a DNA/genética , DNA Metiltransferase 3A , Adulto , Idoso de 80 Anos ou mais , Progressão da Doença , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , DNA (Citosina-5-)-Metiltransferases/genética
2.
EJHaem ; 4(4): 1059-1070, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38024632

RESUMO

TP53 aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with TP53 aberrations. We observed no significant differences between MDS and AML regarding TP53 genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus TP53 variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, p = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, p = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, p = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, p = 0.0009). Clonal dynamic modeling showed a significant reduction in TP53 VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of TP53-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.

3.
Cancer Manag Res ; 13: 8841-8847, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858057

RESUMO

Platelet-derived growth factor-beta (PDGFRB) gene maps for the receptor tyrosine kinase PDGRFß. PDGFRB gene fusions have been implicated in multiple myeloid and lymphoid neoplasms and have shown exquisite sensitivity to tyrosine kinase inhibitors. We report a case of a 29-year-old male who presented with acute myeloid leukemia who was eventually found to harbor a unique three-way translocation t(5;7;7)(q33.2;q32;q11.2) involving the PDGFRB gene. The patient initially achieved a complete response after induction with daunorubicin and cytarabine, but when he returned for consolidation, his white cell count had increased, and he was found to have an underlying myeloproliferative neoplasm. He was given consolidation with high-dose cytarabine and imatinib with excellent response, and ultimately received a matched unrelated donor transplant. The patient remains in remission to this day more than eight years later.

4.
Leuk Lymphoma ; 62(14): 3348-3360, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34496723

RESUMO

TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Genes p53 , Perfil Genético , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Proteína Supressora de Tumor p53/genética
6.
Am J Hematol ; 94(2): 209-215, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30417942

RESUMO

An intensive "5 + 1" regimen, which included bolus high dose cytarabine (HiDAC) at 3 g/m2 once daily over 3 hours on days 1-5 and high dose mitoxantrone (HDM) 80 mg/m2 on day 2, was evaluated in 101 consecutively treated newly diagnosed acute myeloid leukemia (AML) patients at a single center since 2009. The median age was 65 (range 18-90) years. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%), respectively. The overall response (complete remission [CR] + CRi) was 76.2% (77/101). The median overall survival (OS) stratified by age group <60, 60-69 and ≥70 years were 56, 31 and 9 months respectively (log-rank, P = 0.02). 51.7% (45/84) of patients with intermediate/adverse risk category proceeded to allogeneic stem cell transplants. Among these 84 patients, the percentage of patients able to proceed to transplant in age groups <60, 60-69, and ≥ 70 years were 75% (18/24), 60.7% (17/28), and 31.2% (10/32), respectively. In conclusion, HDM-based chemotherapy regimen produces high CR rates, is well tolerated and more patients can undergo curative postremission therapy including stem cell transplant.


Assuntos
Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/administração & dosagem , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Transplante de Células-Tronco , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
7.
Cancer Genet ; 228-229: 236-250, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30554732

RESUMO

The prognostic role of cytogenetic analysis is well-established in B-cell chronic lymphocytic leukemia (CLL). Approximately 80% of patients have a cytogenetic aberration. Interphase FISH panels have been the gold standard for cytogenetic evaluation, but conventional cytogenetics allows detection of additional abnormalities, including translocations, complex karyotypes and multiple clones. Whole genome copy number assessment, currently performed by chromosomal microarray analysis (CMA), is particularly relevant in CLL for the following reasons: (1) copy number alterations (CNAs) represent key events with biologic and prognostic significance; (2) DNA from fresh samples is generally available; and (3) the tumor burden tends to be relatively high in peripheral blood. CMA also identifies novel copy number variants and copy-neutral loss-of-heterozygosity (CN-LOH), and can refine deletion breakpoints. The Cancer Genomics Consortium (CGC) Working Group for CLL has performed an extensive literature review to describe the evidence-based clinical utility of CMA in CLL. We provide suggestions for the integration of CMA into clinical use and list recurrent copy number alterations, regions of CN-LOH and mutated genes to aid in interpretation.


Assuntos
Variações do Número de Cópias de DNA , Medicina Baseada em Evidências , Leucemia Linfocítica Crônica de Células B/genética , Perda de Heterozigosidade , Humanos
8.
Mol Cytogenet ; 11: 56, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30377450

RESUMO

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.

9.
Curr Protoc Hum Genet ; 98(1): e62, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29953168

RESUMO

Amniotic fluid obtained via amniocentesis provides a source of fetal material used in prenatal diagnosis. The fluid may be used directly for biochemical analyses, fluorescence in situ hybridization (FISH), and isolation of DNA for molecular studies, including chromosomal microarray analysis (CMA). The fluid is typically cultured as a source of metaphase cells for chromosome analysis and to provide additional material for biochemical and DNA-based testing. This unit describes an in situ method for the preparation, culture, and harvest of amniotic fluid samples for metaphase chromosome analysis. Cells are grown, harvested for metaphase spreads, and analyzed on glass coverslips. The unit also describes methods to obtain cells for additional studies (such as molecular genetic analyses) by growing cells in flasks either following passaging of cells from a glass coverslip culture or by directly establishing a flask culture from the amniotic fluid specimen. When cells are grown in flasks, they must be removed from the flask with trypsin before they can be used in studies. Lastly, this unit describes a method for isolating DNA for CMA from uncultured amniotic fluid and cultured cells. © 2018 by John Wiley & Sons, Inc.

10.
Int J Surg Pathol ; 26(5): 459-463, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29228842

RESUMO

Mammary analogue secretory carcinoma (MASC) harboring ETV6 gene rearrangements was first described in the salivary gland with a relatively favorable prognosis and a possible molecular therapeutic target with pan-Trk inhibitors. Recently, primary MASC of the thyroid gland has been reported. We report a case of a 4.0 cm MASC arising from the left thyroid of a 58-year-old female with extrathyroidal extension. Initially, it was diagnosed by fine needle aspiration as suspicious for papillary thyroid carcinoma (PTC) and subsequently called a poorly differentiated carcinoma on resection. A final diagnosis of primary MASC of the thyroid was confirmed after an expanded immunohistochemical panel and identification of an ETV6 gene rearrangement by fluorescence in situ hybridization. Morphologically, the tumor was composed of solid, microcystic and focally papillary growth with dense fibrotic stroma and necrosis. Overlapping cytological features with PTC were identified, including foci of enlarged cells with irregular nuclear membranes/grooves. However, most of the cells contained prominent nucleoli with intraluminal and intracytoplasmic eosinophilic secretions. Immunohistochemically, the tumor cells were strongly positive for pancytokeratin, cytokeratin 7, PAX8, mammaglobin, and GCDFP-15, with rare staining for GATA3 and S100 and negative for TTF-1 and thyroglobulin. We report a rare case of a primary thyroid MASC, initially misdiagnosed as PTC. Pathologists should be aware of this entity and, given the similarities to PTC, have a high index of suspicion, prompting the addition of immunohistochemical and molecular studies. Furthermore, an accurate diagnosis is important because of the possible prognostic and treatment implications.


Assuntos
Carcinoma Papilar/diagnóstico , Carcinoma Secretor Análogo ao Mamário/diagnóstico , Proteínas Proto-Oncogênicas c-ets/genética , Doenças Raras/diagnóstico , Proteínas Repressoras/genética , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Quimiorradioterapia Adjuvante/métodos , Erros de Diagnóstico , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Carcinoma Secretor Análogo ao Mamário/genética , Carcinoma Secretor Análogo ao Mamário/patologia , Carcinoma Secretor Análogo ao Mamário/terapia , Pessoa de Meia-Idade , Esvaziamento Cervical , Doenças Raras/genética , Doenças Raras/patologia , Doenças Raras/terapia , Câncer Papilífero da Tireoide , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Variante 6 da Proteína do Fator de Translocação ETS
11.
Cancer Genet ; 208(11): 525-36, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26454669

RESUMO

Cytogenomic microarray analysis (CMA) offers high resolution, genome-wide copy number information and is widely used in clinical laboratories for diagnosis of constitutional abnormalities. The Cancer Genomics Consortium (CGC) conducted a multiplatform, multicenter clinical validation project to compare the reliability and inter- and intralaboratory reproducibility of this technology for clinical oncology applications. Four specimen types were processed on three different microarray platforms-from Affymetrix, Agilent, and Illumina. Each microarray platform was employed at two independent test sites. The results were compared in a blinded manner with current standard methods, including karyotype, FISH, or morphology. Twenty-nine chronic lymphocytic leukemia blood, 34 myelodysplastic syndrome bone marrow, and 30 fresh frozen renal epithelial tumor samples were assessed by all six laboratories. Thirty formalin fixed paraffin embedded renal tumor samples were analyzed at the Affymetrix and Agilent test sites only. All study samples were initial diagnostic samples. Array data were analyzed at each participating site and were submitted to caArray for central analysis. Laboratory interpretive results were submitted to the central analysis team for comparison with the standard-of-care assays and for calculation of intraplatform reproducibility and cross-platform concordance. The results demonstrated that the three microarray platforms 1) detect clinically actionable genomic changes in cancer compatible to standard-of-care methods; 2) further define cytogenetic aberrations; 3) identify submicroscopic alterations and loss of heterozygosity (LOH); and 4) yield consistent results within and between laboratories. Based on this study, the CGC concludes that CMA is a sensitive and reliable technique for copy number and LOH assessment that may be used for clinical oncology genomic analysis.


Assuntos
Hibridização Genômica Comparativa/métodos , Análise Citogenética/métodos , Neoplasias/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Aberrações Cromossômicas , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Perda de Heterozigosidade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Neoplasias/genética , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/genética , Reprodutibilidade dos Testes , Padrão de Cuidado
12.
Am J Clin Pathol ; 139(5): 662-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23596118

RESUMO

Detection of cytogenetic abnormalities requires successful culture of the clonal population to obtain metaphase chromosomes for study, and as such, has been hampered by low mitotic indices of mature B cells in culture. Our study presents data on the improved abnormality detection rate with the use of a CpG-oligonucleotide/interleukin 2 (OL/IL-2) culture protocol for mature B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and non-CLL specimens. The increased detection rate of abnormalities, compared with unstimulated culture and traditional pokeweed mitogen culture, was statistically significant for both CLL and non-CLL neoplasms. For CLL specimens, our data also showed that for cytogenetically visible aberrations, OL/IL-2 was as, if not more, sensitive than detection with interphase fluorescence in situ hybridization (iFISH). Use of OL/IL-2 allowed a number of abnormalities to be detected, which were not covered by specific iFISH panels, especially balanced translocations. Therefore, OL/IL-2 stimulation improves diagnostic sensitivity and increases discovery rate of novel prognostic findings.


Assuntos
Aberrações Cromossômicas , Citogenética/métodos , Interleucina-2/farmacologia , Leucemia Linfocítica Crônica de Células B/diagnóstico , Oligonucleotídeos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Proliferação de Células/efeitos dos fármacos , Ilhas de CpG/efeitos dos fármacos , Ilhas de CpG/genética , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/genética , Metáfase , Células Tumorais Cultivadas
14.
Am J Hematol ; 88(3): 219-24, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23440662

RESUMO

Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B-cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not-reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence-in-situ hybridization performed in four SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM-CMML and one patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (P < 0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD.


Assuntos
Neoplasias Hematológicas/patologia , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Crônica/patologia , Linfoma de Células B/patologia , Mastócitos/patologia , Mastocitose Sistêmica/patologia , Síndromes Mielodisplásicas/patologia , Cariótipo Anormal , Adulto , Fatores Etários , Idoso , Linhagem da Célula , Células Clonais , Análise Mutacional de DNA , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/mortalidade , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Masculino , Mastócitos/metabolismo , Mastocitose Sistêmica/classificação , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/mortalidade , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Proteínas Proto-Oncogênicas c-kit/genética , Taxa de Sobrevida
15.
Curr Protoc Hum Genet ; Chapter 8: Unit8.4, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22786614

RESUMO

Amniotic fluid obtained via amniocentesis provides a source of fetal material used in prenatal diagnosis. The fluid is used directly for biochemical analyses and as a source of fetal cells for biochemical assays, DNA testing, and chromosome studies. This unit describes an in situ method for the preparation, culture, and harvest of amniotic fluid samples for chromosome analysis. Cells are grown, harvested for metaphase spreads, and analyzed on glass coverslips. The unit also describes methods to obtain cells for additional studies (such as molecular genetic analyses) by growing cells in flasks either following passaging of cells from a glass coverslip culture or by directly establishing a flask culture from the amniotic fluid specimen. When cells are grown in flasks, they must be removed from the flask with trypsin before they can be used in studies.


Assuntos
Líquido Amniótico/química , Líquido Amniótico/citologia , Diagnóstico Pré-Natal/métodos , Amniocentese , Técnicas de Cultura de Células , Células Cultivadas , Aberrações Cromossômicas , Feminino , Feto , Humanos , Gravidez
16.
Nat Genet ; 44(8): 861-71, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22797726

RESUMO

A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Quinases da Família src/metabolismo , Animais , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Genes abl , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neoplásicas/patologia , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/genética , Quinases da Família src/genética
18.
Hum Pathol ; 42(10): 1562-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21497367

RESUMO

Anaplastic lymphoma kinase-positive large B-cell lymphoma is a rare non-Hodgkin lymphoma that exhibits a characteristic immunoblastic/plasmablastic morphology and is frequently associated with t(2;17)(p23;q23) and expression of Clathrin-anaplastic lymphoma kinase fusion protein. Here, we report a refractory anaplastic lymphoma kinase-positive large B-cell lymphoma in a 49-year-old human immunodeficiency virus-positive man. The neoplastic cells expressed CD138, epithelial membrane antigen, CD45, and perforin, and showed a strong granular cytoplasmic anaplastic lymphoma kinase staining pattern. Conventional chromosome analysis revealed a clone with multiple anomalies and a chromosome count of 76 to 79. Fluorescence in situ hybridization studies showed 5 copies of the ALK gene with 2 intact signals and 3 signals resulting from 2 independent, previously unreported, rearrangements. One rearrangement, seen in 2 copies, involved translocation of ALK sequences to chromosome Xq21. The second rearrangement involved translocation of ALK sequences to chromosome 12q24.1. This case broadens the cytogenetic alterations in anaplastic lymphoma kinase-positive large B-cell lymphoma, and it also demonstrates the high genetic instability of this tumor.


Assuntos
Linfoma Difuso de Grandes Células B/enzimologia , Receptores Proteína Tirosina Quinases/metabolismo , Quinase do Linfoma Anaplásico , Rearranjo Gênico , Infecções por HIV/complicações , Humanos , Imunofenotipagem , Cariotipagem , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/genética
19.
Hum Pathol ; 40(8): 1194-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19427022

RESUMO

Chronic basophilic leukemia is a rare and poorly characterized entity. Only a limited number of cases have been described. Herein, we report a patient who presented with fatigue, weight loss, leukocytosis, persistent prominent basophilia, and mild eosinophilia. The bone marrow showed features characteristic of a myeloproliferative neoplasm with a marked increase in maturing basophils. The basophils exhibited nuclear hypersegmentation, abnormal granulation, and abnormally low CD38 expression. Conventional karyotyping revealed a t(5;12)(q31;p13). ETV6 but not PDGFRB rearrangement was detected by fluorescence in situ hybridization.


Assuntos
Basófilos/patologia , Leucemia Mieloide de Fase Crônica/patologia , Idoso de 80 Anos ou mais , Células da Medula Óssea/patologia , Núcleo Celular/patologia , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 5 , Citometria de Fluxo , Rearranjo Gênico , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Leucemia Mieloide de Fase Crônica/genética , Masculino , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Translocação Genética/genética , Variante 6 da Proteína do Fator de Translocação ETS
20.
Cancer Genet Cytogenet ; 189(2): 112-7, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19215792

RESUMO

Historically, cytogenetic studies of plasma cell neoplasms have been hampered by the fact that terminally differentiated plasma cells do not proliferate well in vitro. Although the use of interphase FISH (iFISH) has greatly improved the ability to detect cytogenetic abnormalities, cases with low numbers of neoplastic cells often do not demonstrate abnormalities. Using a four-assay, nine-probe iFISH panel, we compared the abnormality detection rate for overnight unstimulated bone marrow cultures (ONC) to that for plasma-cell enriched fractions obtained with use of CD138-coated immunomagnetic beads (PCE). In the ONC, an abnormality was detected in 11 of 29 cases (38%); in the PCE, an abnormality was detected in 30 of 33 cases (91%). For 28 cases in which iFISH results from ONC were compared directly with PCE samples, the overall abnormality rate was 36% for ONC and 89% for PCE (P < 0.01). The conventional GTG-banded chromosome analysis revealed only 2 of 34 cases with an abnormal karyotype (6%); both cases were hyperdiploid. We conclude that the plasma cell enrichment step for iFISH should be incorporated into the routine cytogenetic work-up for all patients with plasma cell neoplasms.


Assuntos
Proliferação de Células , Aberrações Cromossômicas , Hibridização in Situ Fluorescente/métodos , Interfase , Paraproteinemias/patologia , Plasmócitos/patologia , Contagem de Células Sanguíneas , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 17 , Humanos , Interfase/genética , Paraproteinemias/diagnóstico , Paraproteinemias/genética , Plasmócitos/metabolismo , Sensibilidade e Especificidade
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