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1.
Blood ; 125(4): 639-48, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25349174

RESUMO

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.


Assuntos
Agamaglobulinemia , Doenças Autoimunes , Doenças Genéticas Inatas , Leucemia Linfocítica Granular Grande , Mutação de Sentido Incorreto , Infecções por Mycobacterium , Fator de Transcrição STAT3 , Adolescente , Adulto , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/patologia , Substituição de Aminoácidos , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/imunologia , Leucemia Linfocítica Granular Grande/patologia , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/patologia , Estrutura Terciária de Proteína , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia
2.
Blood ; 122(25): 4077-85, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24149287

RESUMO

New massively parallel sequencing technology enables, through deep sequencing of rearranged T-cell receptor (TCR) Vß complementarity-determining region 3 (CDR3) regions, a previously inaccessible level of TCR repertoire analysis. The CDR3 repertoire diversity reflects clonal composition, the potential antigenic recognition spectrum, and the quantity of available T-cell responses. In this context, T-large granular lymphocyte (T-LGL) leukemia is a chronic clonal lymphoproliferation of cytotoxic T cells often associated with autoimmune diseases and various cytopenias. Using CD8(+) T-LGL leukemia as a model disease, we set out to evaluate and compare the TCR deep-sequencing spectra of both patients and healthy controls to better understand how TCR deep sequencing could be used in the diagnosis and monitoring of not only T-LGL leukemia but also reactive processes such as autoimmune disease and infection. Our data demonstrate, with high resolution, significantly decreased diversity of the T-cell repertoire in CD8(+) T-LGL leukemia and suggest that many T-LGL clonotypes may be private to the disease and may not be present in the general public, even at the basal level.


Assuntos
Linfócitos T CD8-Positivos , Regiões Determinantes de Complementaridade/genética , Leucemia Linfocítica Granular Grande/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-Idade
3.
Blood ; 121(22): 4541-50, 2013 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-23596048

RESUMO

Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.


Assuntos
Leucemia Linfocítica Granular Grande/genética , Fator de Transcrição STAT5/genética , Domínios de Homologia de src/genética , Idoso , Estudos de Coortes , Dimerização , Exoma/genética , Feminino , Testes Genéticos , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese , Mutação , Fosforilação/genética , Estrutura Terciária de Proteína , Fator de Transcrição STAT5/química , Fator de Transcrição STAT5/metabolismo , Transcrição Gênica/genética , Proteínas Supressoras de Tumor/genética
4.
Haematologica ; 100(1): 91-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25281507

RESUMO

T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of natural killer cells are intriguing entities between benign and malignant lymphoproliferation. The molecular pathogenesis has partly been uncovered by the recent discovery of somatic activating STAT3 and STAT5b mutations. Here we show that 43% (75/174) of patients with T-cell large granular lymphocytic leukemia and 18% (7/39) with chronic lymphoproliferative disorder of natural killer cells harbor STAT3 mutations when analyzed by quantitative deep amplicon sequencing. Surprisingly, 17% of the STAT3-mutated patients carried multiple STAT3 mutations, which were located in different lymphocyte clones. The size of the mutated clone correlated well with the degree of clonal expansion of the T-cell repertoire analyzed by T-cell receptor beta chain deep sequencing. The analysis of sequential samples suggested that current immunosuppressive therapy is not able to reduce the level of the mutated clone in most cases, thus warranting the search for novel targeted therapies. Our findings imply that the clonal landscape of large granular lymphocytic leukemia is more complex than considered before, and a substantial number of patients have multiple lymphocyte subclones harboring different STAT3 mutations, thus mimicking the situation in acute leukemia.


Assuntos
Artrite Reumatoide/genética , Biomarcadores/análise , Evolução Clonal/genética , Leucemia Linfocítica Granular Grande/genética , Mutação/genética , Fator de Transcrição STAT3/genética , Linfócitos T/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Leucemia Linfocítica Granular Grande/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Adulto Jovem
5.
Case Rep Hematol ; 2021: 6641349, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824768

RESUMO

Gemtuzumab-ozogamicin (GO) is a humanized anti-CD33 antibody, which is conjugated to a cytotoxic calicheamicin. It is used to treat acute myeloid leukemia (AML) in combination with chemotherapy. We describe here two GO-treated acute myeloid leukemia (AML) cases: both patients suffered from a toxic syndrome, which manifested as impaired hemoglobin-haptoglobin scavenging and accumulation of hemolysis-related products. Our observations and earlier reports indicated that the reaction was caused by GO-targeted destruction of CD33 + CD163+ monocytes/macrophages, which are responsible for the clearance of hemoglobin-haptoglobin complexes. The rise of plasma lactate dehydrogenase was an early sign of the reaction, and both patients had high levels of free plasma hemoglobin, but plasma haptoglobin and bilirubin levels were paradoxically normal. Symptoms included septic fever and abnormalities in cardiac tests and in the case of the first patient, severe neurological symptoms which required intensive care unit admittance. Therapeutic plasma exchanges supported the patients until the recovery of normal hematopoiesis. The symptoms may be easily confounded with infectious complications-related organ damage. Regarding the increasing use of gemtuzumab-ozogamicin and other emerging CD33-targeted cell therapies, we want to highlight this mostly unknown and probably underdiagnosed toxicity.

6.
J Cancer Res Clin Oncol ; 143(8): 1543-1554, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28337541

RESUMO

PURPOSE: Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. METHODS: We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. RESULTS: Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinib-treated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. CONCLUSIONS: TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.


Assuntos
Imunidade Humoral/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Compostos de Anilina/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Dasatinibe/administração & dosagem , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , Quinolinas/administração & dosagem , Resultado do Tratamento
7.
Ann Med ; 46(3): 114-22, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24512550

RESUMO

Large granular lymphocytic (LGL) leukemia is an incurable chronic disease, characterized by clonal expansion of cytotoxic T- or NK-cells in blood and bone marrow. Cytopenias (anemia, neutropenia) and autoimmune disorders such as rheumatoid arthritis are the most common clinical manifestations of LGL leukemia. Recently, somatic activating STAT3 gene mutations were shown to be specific for LGL leukemia with a prevalence of up to 70%. Analogous mutations in the STAT5b gene were seen in a smaller proportion of patients. These gain-of-function mutations are located in the SH2 domain of STAT3 and affect the phosphotyrosine-SH2 interaction required for dimerization of STAT3. The mutations increase the phosphorylation of STAT3 and STAT5b and enhance the transcriptional activity of the mutated proteins. STAT3 and STAT5b mutations can be used as molecular markers for LGL leukemia diagnostics, and they present novel therapeutic targets for STAT3 and STAT5b inhibitors, which currently are in development for treatment of cancer and autoimmune disorders.


Assuntos
Leucemia Linfocítica Granular Grande/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT5/genética , Anemia Aplástica/genética , Animais , Humanos , Linfócitos/metabolismo , Mutação , Síndromes Mielodisplásicas/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo
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