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1.
Nat Commun ; 12(1): 1334, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637765

RESUMO

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.


Assuntos
/genética , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Adolescente , Adulto , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Criança , Pré-Escolar , Fatores de Iniciação em Eucariotos/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Ribossomos/genética , Proteína Supressora de Tumor p53/genética , Adulto Jovem
2.
Am J Clin Pathol ; 154(1): 48-56, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32112088

RESUMO

OBJECTIVES: To compare the clinical significance of SF3B1/DNMT3A Comutations with SF3B1 or DNMT3A mutation alone in myelodysplastic syndrome (MDS) and clonal cytopenia of undetermined significance (CCUS). METHODS: We identified and compared 31 patients with only DNMT3A mutation, 48 patients with only SF3B1 mutation, and 16 patients with only SF3B1/DNMT3A comutations. RESULTS: SF3B1/DNMT3A comutations were found to be more common in MDS, whereas DNMT3A mutation alone was more common in CCUS. The patients with SF3B1/DNMT3A comutations were less likely to have poor cytogenetics than patients with DNMT3A mutation alone. Patients with SF3B1/DNMT3A comutations showed significantly longer median survival time and better overall survival than patients with DNMT3A mutation alone. CONCLUSIONS: Patients with SF3B1/DNMT3A comutations appear to have better clinical outcomes than patients with isolated DNMT3A mutation. These findings suggest that the favorable prognosis of SF3B1 mutation in is not abrogated by the concurrent presence of a DNMT3A mutation.


Assuntos
Doenças da Medula Óssea/genética , DNA (Citosina-5-)-Metiltransferases/genética , Síndromes Mielodisplásicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Idoso , Doenças da Medula Óssea/mortalidade , Feminino , Humanos , Masculino , Mutação , Síndromes Mielodisplásicas/mortalidade
3.
Ann Clin Lab Sci ; 50(1): 136-139, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32161023

RESUMO

Bone marrow necrosis (BMN) is a rare life-threatening condition in which the marrow is replaced by necrotic material. Half of BMN occurrences are attributed to chemotherapy or granulocyte-colony stimulating factor treatment in patients with hematolymphoid malignancies. However, we present a patient diagnosed with both multiple myeloma and extensive BMN despite being treatment-naïve. Our patient exhibited a TP53 deletion, TET2 frameshift mutation, and a single TET2 nucleotide change. He is the third such patient reported, but the first to have his cytogenetic and molecular genetic profiles investigated using conventional cytogenetics, fluorescence in situ hybridization, and next-generation sequencing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças da Medula Óssea/patologia , Proteínas de Ligação a DNA/genética , Mieloma Múltiplo/patologia , Mutação , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/genética , Doenças da Medula Óssea/tratamento farmacológico , Doenças da Medula Óssea/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Necrose , Prognóstico
4.
Rinsho Ketsueki ; 60(6): 702-707, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281163

RESUMO

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes associated with DNA repair and telomere maintenance. In addition, mutations in ribosome-related genes cause defective hematopoiesis. Patients with IBMFS exhibit a predisposition to developing hematological malignancy or solid tumor because of the defect in cellular and molecular hemostasis. The SAMD9 mutation causes the multisystem disorder, MIRAGE syndrome, characterized by congenital adrenal hypoplasia and loss of chromosome 7, providing a novel insight into the correlation between the germline and somatic mutations of SAMD9/SAMD9L and myelodysplastic syndrome (MDS) with monosomy 7. Primary immunodeficiency diseases (PID) are caused by inborn errors of the immune system. PID patients with inadequate tumor immunity are at an elevated risk of developing malignancies such as lymphoma, leukemia, and gastrointestinal cancer. Recently, monocytopenia and mycobacterial infection (MonoMAC) syndrome with the GATA2 gene mutation have been reported as PID related to bone marrow failure. Patients with MonoMAC syndrome often develop MDS and acute myeloid leukemia. Here, we present the pediatric-onset IBMFS and/or PID with cancer predisposition and briefly discuss the tumorigenesis in each monogenic disease.


Assuntos
Anemia Aplástica/complicações , Doenças da Medula Óssea/complicações , Predisposição Genética para Doença , Hemoglobinúria Paroxística/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/genética , Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Transtornos da Insuficiência da Medula Óssea , Criança , Hemoglobinúria Paroxística/genética , Humanos , Síndromes de Imunodeficiência/genética , Síndromes Mielodisplásicas
5.
Blood ; 133(10): 1071-1085, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30670445

RESUMO

Myelodysplastic syndrome (MDS) typically presents in older adults with the acquisition of age-related somatic mutations, whereas MDS presenting in children and younger adults is more frequently associated with germline genetic predisposition. Germline predisposition is increasingly recognized in MDS presenting at older ages as well. Although each individual genetic disorder is rare, as a group, the genetic MDS disorders account for a significant subset of MDS in children and young adults. Because many patients lack overt syndromic features, genetic testing plays an important role in the diagnostic evaluation. This review provides an overview of syndromes associated with genetic predisposition to MDS, discusses implications for clinical evaluation and management, and explores scientific insights gleaned from the study of MDS predisposition syndromes. The effects of germline genetic context on the selective pressures driving somatic clonal evolution are explored. Elucidation of the molecular and genetic pathways driving clonal evolution may inform surveillance and risk stratification, and may lead to the development of novel therapeutic strategies.


Assuntos
Evolução Clonal , Predisposição Genética para Doença , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Anemia de Diamond-Blackfan/genética , Doenças da Medula Óssea/genética , Criança , Disceratose Congênita/genética , Insuficiência Pancreática Exócrina/genética , Anemia de Fanconi/genética , Fator de Transcrição GATA2/genética , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Síndrome de Li-Fraumeni/genética , Lipomatose/genética , Pessoa de Meia-Idade , Proteínas/genética , Risco , Síndrome de Shwachman-Diamond , Trombocitopenia/complicações , Adulto Jovem
6.
J Pediatr Hematol Oncol ; 41(8): e542-e545, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30188351

RESUMO

Acquired pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura are rare in children. Similarly, clonal expansion of T-cell large granular lymphocytes is infrequently seen in pediatrics. Lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency is a recently described immunodeficiency syndrome that has been associated with inflammatory bowel disease and autoimmune phenomena such as Evans syndrome. Here, we describe a patient with LRBA deficiency who developed acquired pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura associated with expansion of clonal T-cell large granular lymphocytes. This has not been described in the literature previously and adds to the knowledge on the spectrum of manifestations of LRBA deficiency.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Aplasia Pura de Série Vermelha , Linfócitos T , Adolescente , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Humanos , Masculino , Púrpura Trombocitopênica/complicações , Púrpura Trombocitopênica/genética , Púrpura Trombocitopênica/metabolismo , Púrpura Trombocitopênica/patologia , Aplasia Pura de Série Vermelha/complicações , Aplasia Pura de Série Vermelha/genética , Aplasia Pura de Série Vermelha/metabolismo , Aplasia Pura de Série Vermelha/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia
7.
Genet Med ; 21(7): 1594-1602, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30523342

RESUMO

PURPOSE: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes. METHODS: We screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay. RESULTS: Pathogenic -124 and -146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging. CONCLUSION: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases.


Assuntos
Regiões Promotoras Genéticas , Telomerase/genética , Telômero/patologia , Adolescente , Adulto , Idoso , Anemia Aplástica/genética , Contagem de Células Sanguíneas , Doenças da Medula Óssea/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Fibrose Pulmonar Idiopática/genética , Hepatopatias/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Telomerase/deficiência , Adulto Jovem
8.
Mol Diagn Ther ; 23(2): 281-290, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30413969

RESUMO

Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple-organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15-20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene-based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives.


Assuntos
Doenças da Medula Óssea/genética , Insuficiência Pancreática Exócrina/genética , Lipomatose/genética , Animais , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/terapia , Modelos Animais de Doenças , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/terapia , Hematopoese/genética , Humanos , Lipomatose/diagnóstico , Lipomatose/terapia , Mutação/genética , Síndrome de Shwachman-Diamond
9.
PLoS One ; 13(10): e0205902, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30335822

RESUMO

Rheumatoid arthritis is an auto-immune disease of the synovial joints, hallmarked by chronic inflammation and subsequent progressive tissue destruction. TYRO3, AXL and MER (gene name Mertk) (TAM) receptors are part of a negative feedback signaling system in the immune reaction and mediate efferocytosis thereby tempering the inflammatory process. We have shown that Axl-/- and Mertk-/- mice develop more severe arthritis whereas activating these receptors by overexpressing their ligands Pros1 and Gas6 ameliorates arthritis. Mice genetically ablated for the three genes of the TAM receptor family Tyro3/Axl/Mertk (TAM triple knock-out or TKO) have been described to spontaneously develop macroscopic signs of arthritis. In this study we aimed to analyze arthritis development in TAM TKO mice histologically to determine the extent and sequence of pathological changes in the joint. Ankle joints of three different age groups, adolescence (14 weeks), mature adult (34 weeks) and middle-age (52 weeks), of TAM TKO or wild-type mice were examined macroscopically, histologically and immunohistochemically. Surprisingly, until the age of 52 weeks, none of the mice examined developed spontaneous macroscopic signs of arthritis. There was no synovial inflammation nor any signs of damage to the cartilage or bone. However, bone marrow edema was observed in TAM TKO mice in the two latter age groups. The infiltrate in the bone marrow was characterized by both myeloid cells and lymphocytes. This study showed that TAM TKO mice developed a pre-stage (pre-clinical phase) of arthritis marked by bone marrow edema.


Assuntos
Artrite Reumatoide/imunologia , Doenças da Medula Óssea/imunologia , Medula Óssea/imunologia , Edema/imunologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , c-Mer Tirosina Quinase/genética , Fatores Etários , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Biomarcadores/metabolismo , Medula Óssea/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Edema/genética , Edema/patologia , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Articulações/imunologia , Articulações/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases/imunologia , Transdução de Sinais , Tarso Animal/imunologia , Tarso Animal/patologia , c-Mer Tirosina Quinase/deficiência , c-Mer Tirosina Quinase/imunologia
10.
Diagn Pathol ; 13(1): 82, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30342536

RESUMO

BACKGROUND: Indolent T-cell proliferative disorder of the GIT is a rare and provisional entity in the revised WHO 2016 classification. The patients usually have prolonged survival with persistent disease even without any treatment. CASE PRESENTATION: The 46 years old male patient has been followed up for more than 6 years without chemotherapy. Repeated gastrointestinal biopsies showed expansion of the lamina propria extending to the submucosa by small to medium sized lymphocytes with minimal cytologic atypia. The lymphoid cells were positive for CD3, CD43, TIA-1, CD2, CD7 and the B-cell marker CD20; but negative for CD4, CD8, PAX5, CD56, cyclinD1, granzyme (GraB) and Epstein Barr virus-encoded RNA (EBER). Ki-67(MIB1) index was less than 10%. Molecular tests demonstrated a clonal rearrangement for T-cell receptor γ (TCR γ) gene but immunoglobulin chain (IgH, IgK, IgL) gene remained germline. Recognition of possible aberrant CD20 expression in indolent T-cell LPD is important to avoid potential diagnostic pitfall and improper treatment. CONCLUSIONS: We present an unusual case of indolent T-cell lymphoproliferative disorder with aberrant CD20 expression, Recognition of this unusual immunophenotype of indolent T-cell LPD of GI helps to eschew misdiagnosis of B-cell and other high grade lymphomas and inappropriate aggressive treatment.


Assuntos
Antígenos CD20/análise , Doenças da Medula Óssea/imunologia , Proliferação de Células , Gastroenteropatias/imunologia , Transtornos Linfoproliferativos/imunologia , Linfócitos T/imunologia , Biomarcadores/análise , Biópsia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Diagnóstico Diferencial , Endoscopia Gastrointestinal , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Imuno-Histoquímica , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Linfócitos T/patologia , Fatores de Tempo
11.
Blood ; 132(26): 2730-2743, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30361263

RESUMO

Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α-/- donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR-/- recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α-/- recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α-/- recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR-/- donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.


Assuntos
Anemia Aplástica/imunologia , Doenças da Medula Óssea/imunologia , Hemoglobinúria Paroxística/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Aloenxertos , Anemia Aplástica/genética , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Animais , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/terapia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/genética
12.
Am J Hum Genet ; 103(3): 440-447, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30146126

RESUMO

Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.


Assuntos
Doenças da Medula Óssea/genética , Medula Óssea/patologia , Células Germinativas/patologia , Mutação/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Agamaglobulinemia/genética , Anemia de Diamond-Blackfan/genética , Animais , Pré-Escolar , Eritrócitos/patologia , Feminino , Transtornos do Crescimento/genética , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Lactente , Recém-Nascido , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem , Peixe-Zebra
13.
Immunol Allergy Clin North Am ; 38(3): 379-395, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30007458

RESUMO

Mast cell disorders comprise a heterogeneous group of rare diseases, the diagnosis of which still remains a challenge. Bone marrow analysis constitutes the most appropriate site for screening systemic involvement in mastocytosis. Morphologic, immunohistochemical, flow cytometric immunophenotyping, and molecular studies should be routinely performed for diagnostic/prognostic purposes in experienced reference centers during the diagnostic workup in suspected systemic mastocytosis. The authors review the most relevant characteristics of bone marrow expression of mast cell disorders as well as the different methodological approaches to be applied to perform an objective and reproducible diagnosis and classification of mastocytosis and other mast cell disorders.


Assuntos
Doenças da Medula Óssea/imunologia , Medula Óssea/patologia , Mastócitos/fisiologia , Mastocitose/imunologia , Mutação/genética , Proteínas Proto-Oncogênicas c-kit/genética , Biomarcadores/metabolismo , Medula Óssea/metabolismo , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Células Clonais , Humanos , Imuno-Histoquímica/métodos , Mastocitose/diagnóstico , Mastocitose/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-29970384

RESUMO

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.


Assuntos
Doenças da Medula Óssea/genética , Insuficiência Pancreática Exócrina/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/fisiologia , Lipomatose/genética , Adolescente , Doenças da Medula Óssea/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Feminino , Variação Genética/genética , Humanos , Lipomatose/diagnóstico , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/fisiopatologia , Fatores de Alongamento de Peptídeos , Fenótipo , Proteínas/genética , Ribonucleoproteína Nuclear Pequena U5 , Síndrome de Shwachman-Diamond , Sequenciamento Completo do Exoma
15.
Proc Natl Acad Sci U S A ; 115(30): 7777-7782, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29987015

RESUMO

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.


Assuntos
Alelos , Doenças da Medula Óssea/metabolismo , DNA Helicases/metabolismo , Reparo do DNA , Doenças Genéticas Inatas/metabolismo , Instabilidade Genômica , Transcrição Genética , Células A549 , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , DNA Helicases/genética , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Células HeLa , Humanos , Masculino , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Síndrome
16.
Hematol Oncol Clin North Am ; 32(4): 569-580, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30047411

RESUMO

Acquired aplastic anemia and inherited bone marrow failure syndromes both present with pancytopenia and must be distinguished because they have differences in treatment decisions and continued monitoring requirements. Advances in the genetic interrogation of patient samples have led to identification of inherited germline diseases and appreciation that patients with inherited bone marrow failure disorders may be normal in appearance with few expected clinical clues. Somatic mutations in aplastic anemia may have prognostic value. Hematopoietic stem cells from inherited marrow failure diseases can correct the proliferative defect and may develop further somatic mutations that progress to myelodysplastic syndrome or acute myeloid leukemia.


Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Medula Óssea , Doenças Genéticas Inatas , Hemoglobinúria Paroxística , Leucemia Mieloide Aguda , Mutação , Síndromes Mielodisplásicas , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Anemia Aplástica/patologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Hemoglobinúria Paroxística/patologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
17.
Hematol Oncol Clin North Am ; 32(4): 643-655, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047417

RESUMO

Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes.


Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Evolução Clonal , Predisposição Genética para Doença , Hemoglobinúria Paroxística , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Anemia Aplástica/genética , Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea , Evolução Clonal/genética , Evolução Clonal/imunologia , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/imunologia , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/terapia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia
19.
Hematol Oncol Clin North Am ; 32(4): 687-700, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047420

RESUMO

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome classically associated with exocrine pancreatic dysfunction and neutropenia, with a predisposition toward progressive marrow failure, risk of myelodysplastic syndrome, and leukemia. Most patients carry biallelic mutations in the Shwachman-Bodian-Diamond Syndrome gene, which is an integral component of ribosome maturation and biogenesis. This article reviews the diagnosis, clinical characteristics, and treatment modalities of SDS, and reports advances in the understanding of the molecular pathophysiology of SDS.


Assuntos
Doenças da Medula Óssea , Insuficiência Pancreática Exócrina , Lipomatose , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/patologia , Insuficiência Pancreática Exócrina/terapia , Testes Genéticos , Humanos , Lipomatose/diagnóstico , Lipomatose/genética , Lipomatose/patologia , Lipomatose/terapia , Patologia Molecular , Síndrome de Shwachman-Diamond
20.
Hematol Oncol Clin North Am ; 32(4): 669-685, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047419

RESUMO

Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increased awareness and availability of diagnostic tests in recent years. This article summarizes the pathophysiology, evaluation, and management of hematopoietic failure in patients with DC and other TBDs.


Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Disceratose Congênita , Predisposição Genética para Doença , Hemoglobinúria Paroxística , Mutação , Neoplasias , Homeostase do Telômero , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Anemia Aplástica/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/metabolismo , Doenças da Medula Óssea/patologia , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Disceratose Congênita/genética , Disceratose Congênita/metabolismo , Disceratose Congênita/patologia , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/metabolismo , Hemoglobinúria Paroxística/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Telômero/genética , Telômero/metabolismo , Telômero/patologia
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