RESUMO
INTRODUCTION: Cutaneous composite lymphoma (CCL) is extremely rare. When 2 potentially distinct lymphoid lesions occur at one skin site, distinguishing between one neoplastic clone and a secondary reactionary lymphoid response versus a second neoplasm is difficult. In this study, we describe a unique case of CCL along with a review of reported cases in literature to identify clues and discuss issues that are relevant to the diagnosis of CCL. DESIGN: Review of a CCL case from our institution and a systematic review of reported cases of CCL in the literature. RESULTS: A total of 18 studies describing 22 cases and a case report from our institution are included. The mean age at diagnosis was 68 years. Most cases herein presented with multiple skin lesions (67%) and reported a history of immune suppression (76%). Nineteen cases (83%) had a combination of T-cell and B-cell neoplasms, whereas the remaining cases had 2 distinct B-cell clones. Clonal differentiation was confirmed based on morphology and immunohistochemistry in all cases, and by polymerase chain reaction studies in 19 cases. Complete remission was achieved in only one quarter of reported cases. CONCLUSION: Diagnosing CCL can be challenging because accurate differentiation of 2 or more clonal populations at 1 site is tedious. A stepwise approach and integration of clinical, morphologic, immunohistochemistry, and molecular data along with an understanding of the prognosis of the lymphomas in question is essential for an accurate diagnosis and necessary because of therapeutic and prognostic implications.
Assuntos
Linfoma Composto/diagnóstico , Neoplasias Cutâneas/diagnóstico , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.
Assuntos
Eritroblastos/metabolismo , Proteínas Ativadoras de GTPase/biossíntese , Regulação da Expressão Gênica , Síndromes Mielodisplásicas/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Eritroblastos/patologia , Feminino , Proteínas Ativadoras de GTPase/genética , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Therapy-related myeloid neoplasms (t-MN) are a late complication of the successful use of cytotoxic therapy for patients with cancer. A heterozygous deletions of the long arm of chromosome 5 [del(5q)], observed in 40% of patients, is associated with prior exposure to alkylating agents, and a high frequency of TP53 loss or mutation. In previous studies, we demonstrated that haploinsufficiency of 2 del(5q) genes, Egr1, and Apc, individually play a role in the pathogenesis of hematologic disease in mice. We now show that loss of one copy of Egr1 or Tp53 in an Apc haploinsufficient background (Apc (del/+)) accelerated the development of a macrocytic anemia with monocytosis, early features of t-MN. The development of anemia was significantly accelerated by treatment of mice with the alkylating agent, N-ethyl-N-nitrosourea (ENU), regardless of the levels of expression of Egr1 and Tp53. Transplantation of either wild type; Egr1(+/-); Tp53(+/-); Apc(del/+); or Egr1(+/-), Apc(del/+) bone marrow cells into lethally irradiated Apc(del/+) recipients resulted in rapid development of anemia that was further accelerated by administration of ENU to recipients, demonstrating that the Apc(del/+)-induced anemia was cell extrinsic and potentiated by ENU mutagenesis. These data emphasize the synergistic role of cell intrinsic and cell extrinsic (microenvironment) factors in the pathogenesis of t-MN, and raise awareness of the deleterious effects of cytotoxic therapy on the stromal microenvironment.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Deleção Cromossômica , Cromossomos Humanos Par 5 , Proteína 1 de Resposta de Crescimento Precoce/genética , Haploinsuficiência , Proteína Supressora de Tumor p53/genética , Alelos , Anemia Macrocítica/induzido quimicamente , Anemia Macrocítica/genética , Anemia Macrocítica/mortalidade , Animais , Apoptose/genética , Medula Óssea/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Eritroblastos/citologia , Eritroblastos/metabolismo , Eritropoese/genética , Etilnitrosoureia/efeitos adversos , Genes Letais , Genótipo , Heterozigoto , Humanos , Camundongos , Camundongos Transgênicos , Baço/metabolismo , Baço/patologiaRESUMO
An interstitial deletion of chromosome 5, del(5q), is the most common structural abnormality in primary myelodysplastic syndromes (MDS) and therapy-related myeloid neoplasms (t-MNs) after cytotoxic therapy. Loss of TP53 activity, through mutation or deletion, is highly associated with t-MNs with a del(5q). We previously demonstrated that haploinsufficiency of Egr1 and Apc, 2 genes lost in the 5q deletion, are key players in the progression of MDS with a del(5q). Using genetically engineered mice, we now show that reduction or loss of Tp53 expression, in combination with Egr1 haploinsufficiency, increased the rate of development of hematologic neoplasms and influenced the disease spectrum, but did not lead to overt myeloid leukemia, suggesting that altered function of additional gene(s) on 5q are likely required for myeloid leukemia development. Next, we demonstrated that cell intrinsic loss of Tp53 in hematopoietic stem and progenitor cells haploinsufficient for both Egr1 and Apc led to the development of acute myeloid leukemia (AML) in 17% of mice. The long latency (234-299 days) and clonal chromosomal abnormalities in the AMLs suggest that additional genetic changes may be required for full transformation. Thus, loss of Tp53 activity in cooperation with Egr1 and Apc haploinsufficiency creates an environment that is permissive for malignant transformation and the development of AML.
Assuntos
Deleção Cromossômica , Proteína 1 de Resposta de Crescimento Precoce/genética , Genes APC , Genes p53/fisiologia , Haploinsuficiência , Leucemia Mieloide Aguda/genética , Animais , Transformação Celular Neoplásica/genética , Células Cultivadas , Deleção de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Epigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated from DNMT3B7 transgenic embryos identified Apolipoprotein E (Apoe) as overexpressed. The CpG island controlling Apoe expression had lower levels of modified cytosines in DNMT3B7 transgenic HSPCs, corresponding with the observed increase in gene expression. Furthermore, we observed that spleens and bone marrows of female mice transplanted with DNMT3B7 transgenic HSPCs express very high levels of Apoe. Finally, the introduction of Apoe-overexpressing HSPCs into male recipients decreased bone marrow engraftment, recapitulating our original observations in female recipients. Our work reveals a dynamic interplay between the intrinsic epigenetic changes in HSPCs and extrinsic endocrine factors acting on these cells to regulate the efficiency of HSPC engraftment and reconstitution. We have identified a novel mechanism by which gender-specific hormones modulate HSPC function, which could serve as a target for augmenting hematopoiesis in cases with limited HSC functionality.
Assuntos
Apolipoproteínas E/biossíntese , Ilhas de CpG/fisiologia , Epigênese Genética/fisiologia , Hematopoese/fisiologia , Caracteres Sexuais , Animais , Apolipoproteínas E/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Feminino , Masculino , Camundongos , Camundongos KnockoutRESUMO
Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified.We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with -7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in -7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUX1-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Proteínas de Homeodomínio/genética , Leucemia Mieloide/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Doença Aguda , Animais , Western Blotting , Linhagem Celular Tumoral , Drosophila melanogaster/genética , Perfilação da Expressão Gênica , Haploinsuficiência , Células HeLa , Proteínas de Homeodomínio/metabolismo , Humanos , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Células K562 , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Nucleares/metabolismo , Interferência de RNA , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição , Translocação Genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Células U937 , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The drivers of abnormal DNA methylation in human cancers include widespread aberrant splicing of the DNMT3B gene, producing abnormal transcripts that encode truncated proteins that may act as dominant negative isoforms. To test whether reduced Dnmt3b dosage can alter tumorigenesis, we bred Dnmt3b(+/-) mice to Eµ-Myc mice, a mouse model susceptible to B-cell lymphomas. Eµ-Myc/Dnmt3b(+/-) mice showed a dramatic acceleration of lymphomagenesis, greater even than that observed in Eµ-Myc mice that express a truncated DNMT3B isoform found in human tumors, DNMT3B7. This finding indicates that Dnmt3b can act as a haploinsufficient tumor suppressor gene. Although reduction in both Dnmt3b dosage and expression of DNMT3B7 within the Eµ-Myc system had similar effects on tumorigenesis and DNA hypermethylation, different molecular mechanisms appear to underlie these changes. This study offers insight into how de novo DNA methyltransferases function as tumor suppressors and the sensitivity of Myc-induced lymphomas to DNA methylation.
Assuntos
Transformação Celular Neoplásica/genética , DNA (Citosina-5-)-Metiltransferases/fisiologia , Genes Supressores de Tumor/fisiologia , Haploinsuficiência/fisiologia , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , Animais , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Haploinsuficiência/genética , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Regiões Promotoras Genéticas/fisiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , DNA Metiltransferase 3BRESUMO
Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (â¼40%) and/or mutations disrupting autoregulation (â¼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.
Assuntos
Proteínas de Ligação a DNA/genética , Linfoma/genética , Linfoma/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas c-pim-1/genética , Animais , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Mutagênese Insercional/genética , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Retroviridae/genética , Análise de SobrevidaRESUMO
-7/del(7q) occurs in half of myeloid malignancies with adverse-risk cytogenetic features and is associated with poor survival. We identified the spectrum of mutations that co-occur with -7/del(7q) in 40 patients with de novo or therapy-related myeloid neoplasms. -7/del(7q) leukaemias have a distinct mutational profile characterized by low frequencies of alterations in genes encoding transcription factors, cohesin and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 50% of cases, a significantly higher frequency than other acute myeloid leukaemias and higher than previously reported. Our data provide guidance for which pathways may be most relevant in the treatment of adverse-risk myeloid leukaemia.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Leucemia Mieloide Aguda/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Fatores de Risco , Fatores de TranscriçãoRESUMO
The BCL6 gene, which is expressed in certain B- and T-cell human lymphomas, is involved with chromosomal rearrangements and mutations in a number of these neoplasms. Lymphomagenesis is believed to evolve through a multi-step accumulation of genetic alterations in these tumors. We used retroviral insertional mutagenesis in transgenic mice expressing the human BCL6 transgene in order to identify genes that cooperate with BCL6 during lymphomatous transformation. We previously reported PIM1 as the most frequently recurring cooperating gene in this model. We now report three newly identified cooperating genes-GFI1B, EVI5, and MYB-that we identified in the lymphomas of retroviral-injected BCL6 transgenic mice (but not in retroviral-injected non-transgenic controls); mRNA and protein expression of GFI1B and EVI5 were decreased in the murine tumors, whereas MYB mRNA and protein expression were increased or decreased. These findings correlated with protein expression in human lymphomas, both B- and T-cell. Improved therapy of lymphomas may necessitate the development of combinations of drugs that target the alterations specific to each neoplasm.
Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Linfoma de Células T/genética , Proteínas Oncogênicas v-myb/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteínas Ativadoras de GTPase , Vetores Genéticos , Humanos , Imuno-Histoquímica , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas v-myb/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Retroviridae/genética , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Acute myeloid leukemia and myelodysplastic syndrome with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) have a poor prognosis. Indeed, the inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has been recognized as a poor risk karyotype in the revised International Prognostic Scoring System. However, inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is not among the cytogenetic abnormalities pathognomonic for diagnosis of acute myeloid leukemia irrespective of blast percentage in the 2008 WHO classification. This multicenter study evaluated the clinico-pathological features of acute myeloid leukemia/myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and applied the revised International Prognostic Scoring System to myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2). A total of 103 inv(3)(q21q26.2)/t(3;3)(q21;q26.2) patients were reviewed and had a median bone marrow blast count of 4% in myelodysplastic syndrome (n=40) and 52% in acute myeloid leukemia (n=63) (P<0.001). Ninety-one percent of patients showed characteristic dysmegakaryopoiesis. There was no difference in overall survival between acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) (12.9 vs. 7.9 months; P=0.16). Eighty-three percent of patients died (median follow up 7.9 months). Complex karyotype, monosomal karyotype and dysgranulopoiesis (but not blast percentage) were independent poor prognostic factors in the entire cohort on multivariable analysis. The revised International Prognostic Scoring System better reflected overall survival of inv(3)(q21q26.2)/t(3;3)(q21;q26.2) than the International Prognostic Scoring System but did not fully reflect the generally dismal prognosis. Our data support consideration of myelodysplastic syndrome with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) as an acute myeloid leukemia with recurrent genetic abnormalities, irrespective of blast percentage.
Assuntos
Cariótipo Anormal , Medula Óssea/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inversão Cromossômica , Cromossomos Humanos Par 3 , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Translocação Genética , Adulto JovemRESUMO
Children with Down syndrome have a 10-20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). While a subset of pediatric AMKLs is associated with the 1;22 translocation and expression of a mutant fusion protein, the genetic alterations that promote Down syndrome-related AMKL (DS-AMKL) have remained elusive. Here we show that leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1, encoding the essential hematopoietic transcription factor GATA1 (GATA binding protein 1 or globin transcription factor 1). Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream. We show that the shorter GATA1 protein, which lacks the N-terminal activation domain, binds DNA and interacts with its essential cofactor Friend of GATA1 (FOG1; encoded by ZFPM1) to the same extent as does full-length GATA1, but has a reduced transactivation potential. Although some reports suggest that the activation domain is dispensable in cell-culture models of hematopoiesis, one study has shown that it is required for normal development in vivo. Together, these findings indicate that loss of wildtype GATA1 constitutes one step in the pathogenesis of AMKL in Down syndrome.
Assuntos
Proteínas de Ligação a DNA/genética , Síndrome de Down/complicações , Síndrome de Down/genética , Leucemia Megacarioblástica Aguda/genética , Mutação , Proteínas Proto-Oncogênicas , Fatores de Transcrição/genética , Proteínas de Transporte/metabolismo , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , DNA/metabolismo , Fatores de Ligação de DNA Eritroide Específicos , Feminino , Fator de Transcrição GATA1 , Predisposição Genética para Doença , Humanos , Lactente , Leucemia Megacarioblástica Aguda/etiologia , Masculino , Proteínas Nucleares/metabolismo , Polimorfismo Conformacional de Fita Simples , Ligação Proteica , Biossíntese de Proteínas , Estrutura Terciária de Proteína , Células Tumorais CultivadasRESUMO
Loss of a whole chromosome 5 or a deletion of the long arm of chromosome 5, -5/del(5q), is a recurring abnormality in myeloid neoplasms. The APC gene is located at chromosome band 5q23, and is deleted in more than 95% of patients with a -5/del(5q), raising the question of whether haploinsufficiency of APC contributes to the development of myeloid neoplasms with loss of 5q. We show that conditional inactivation of a single allele of Apc in mice leads to the development of severe anemia with macrocytosis and monocytosis. Further characterization of the erythroid lineage revealed that erythropoiesis is blocked at the early stages of differentiation. The long-term hematopoietic stem cell (LT-HSC) and short-term HSC (ST-HSC) populations are expanded in Apc-heterozygous mice compared with the control littermates; however, the HSCs have a reduced capacity to regenerate hematopoiesis in vivo in the absence of a single allele of Apc. Apc heterozygous myeloid progenitor cells display an increased frequency of apoptosis, and decreased in vitro colony-forming capacity, recapitulating several characteristic features of myeloid neoplasms with a -5/del(5q). Our results indicate that haploinsufficiency of Apc impairs hematopoiesis, and raise the possibility that loss of function of APC contributes to the development of myelodysplasia.
Assuntos
Proteína da Polipose Adenomatosa do Colo , Deleção Cromossômica , Cromossomos de Mamíferos , Eritropoese , Células Progenitoras Mieloides/metabolismo , Anemia Macrocítica/genética , Anemia Macrocítica/metabolismo , Animais , Apoptose/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Camundongos , Camundongos Transgênicos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismoAssuntos
Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T , Fatores de Transcrição Kruppel-Like/metabolismo , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Biópsia , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Mucosa/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica , Linfócitos T/citologia , Análise Serial de TecidosAssuntos
Peptídeos e Proteínas de Sinalização Intracelular , Leucemia Mieloide Aguda , Mutagênese Insercional , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Fatores de Terminação de Peptídeos , Proteínas , Retroviridae , Via de Sinalização Wnt/genética , Animais , Proteínas de Ligação a DNA , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Mutantes , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/metabolismo , Proteínas/genética , Proteínas/metabolismo , Fatores de TranscriçãoRESUMO
The classification and diagnostic criteria of the myeloproliferative neoplasms have changed significantly in the 2008 World Health Organization monograph on the classification of hematologic malignancies. Many of the changes arose from the findings that the different malignancies are associated with abnormal cell signaling because of translocations or mutations in genes for protein tryosine kinases involved in the normal growth and regulation of hematopoietic cells. These include ABL1, PDGFRA, PDGFRB, FGFR1, JAK2, MPL, and KIT. The new classification attempts to reflect the related molecular pathogenesis of the different entities and incorporates the identification of the molecular defects into the diagnostic criteria for some of the individual diseases. Issues concerning the new classification are discussed, and the new diagnostic criteria are reviewed and commented upon.
Assuntos
Transtornos Mieloproliferativos/classificação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Proteínas Tirosina Quinases/genética , Humanos , MutaçãoRESUMO
Although classically described as the driving oncogene in Burkitt lymphoma (BL), abnormalities of MYC have been recognized in other non-Hodgkin lymphomas as well. For example, MYC is overexpressed in approximately 10% of diffuse large B-cell lymphomas (DLBCL), conferring an adverse prognosis with chemoresistance and shortened survival; only approximately 30% of patients achieve long-term survival despite modern therapies. In contrast to BL, MYC aberrations in DLBCL are usually associated with multiple cytogenetic abnormalities and other genetic lesions, such as concurrent BCL2 translocations. Patients with so-called "double-hit" lymphomas have a worse outcome with few survivors beyond 6 months. It is unclear why MYC translocations are diagnostic in BL but prognostic in other lymphomas; different mechanisms underlying MYC abnormalities and a unique target set of genes may explain some of the variance. Furthermore, MYC possesses nontranscriptional functions other than transcriptional controls on genes regulating cell growth and may also influence the lymphoma microenvironment. Here we summarize current knowledge regarding MYC in lymphomas other than Burkitt lymphoma, with an emphasis on transcriptional, epigenetic, clinical, and microenvironmental consequences.
Assuntos
Linfoma de Burkitt/diagnóstico , Linfoma/diagnóstico , Proteínas Proto-Oncogênicas c-myc/genética , Linfoma de Burkitt/genética , Epigenômica , Humanos , Linfoma/genética , Translocação GenéticaRESUMO
We evaluated stem cell mobilization in 195 consecutive sibling donors who underwent a uniform mobilization regimen of granulocyte colony-stimulating factor (G-CSF) at 10 microg/kg/day divided into twice daily dosing. On day 5, peripheral blood (PB) CD34 cells/microL were measured immediately prior to peripheral blood stem cell (PBSC) apheresis. Failed mobilization was defined as <20 CD34 cells/microL on day 5. The median age was 52 years and 73 (37%) were 55 years or greater. Comorbid conditions by the Charlson Comorbidity Index (CCI) occurred in 13%, but only 3% had Karnofsky performance status (PS) <100%. Eight (4%) failed mobilization, defined as <20 CD34 cells/microL on day 5. Older age was associated with fewer CD34 cells/microL (P=.002). In addition, 6/73 (8.2%) older donors failed mobilization compared to 2/122 (1.6%) younger donors (P=.054). Comorbidity, sex, race, and donor weight did not influence mobilization. Although low PS was very uncommon, it was associated with reduced mobilization (P=.021), but not mobilization failure. A small fraction of older donors mobilize poorly, and this is not explained by standard measures of comorbidity or PS.
Assuntos
Fatores Etários , Fator Estimulador de Colônias de Granulócitos/farmacologia , Nível de Saúde , Mobilização de Células-Tronco Hematopoéticas/estatística & dados numéricos , Doadores Vivos , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Idoso , Contagem de Células Sanguíneas , Peso Corporal , Comorbidade , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Irmãos , Transplante Homólogo , Adulto JovemRESUMO
In the originally published version of this Article, the GAPDH loading control blot in Fig. 1a was inadvertently replaced with a duplicate of the DNMT2 blot in the same panel during assembly of the figure. This has now been corrected in both the PDF and HTML versions of the Article.