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1.
Am J Hum Genet ; 108(2): 284-294, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33421400

RESUMO

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10-15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10-12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10-9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10-14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10-11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (ß)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10-8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mastocitose/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Sistema y+ de Transporte de Aminoácidos/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , DNA Intergênico , Feminino , Humanos , Interleucina-13/genética , Íntrons , Masculino , RNA Longo não Codificante/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Telomerase/genética , Triptases/genética
2.
Blood ; 115(22): 4517-23, 2010 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-20304805

RESUMO

The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 x 10(-11)). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the "hypermutability" and "fertile ground" hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle.


Assuntos
Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Receptores de Trombopoetina/genética , Adulto , Idoso , Substituição de Aminoácidos , Sequência de Bases , Estudos de Casos e Controles , Estudos de Coortes , Primers do DNA/genética , Éxons , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutação de Sentido Incorreto , Policitemia Vera/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética
3.
Blood ; 113(24): 6182-92, 2009 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-19387008

RESUMO

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.


Assuntos
Cromossomos Humanos Par 11/genética , Mutação de Sentido Incorreto/genética , Transtornos Mieloproliferativos/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Dissomia Uniparental/genética , Processamento Alternativo , Sequência de Aminoácidos , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Repetições de Microssatélites , Dados de Sequência Molecular , Células Mieloides/metabolismo , Células Mieloides/patologia , Prognóstico , Homologia de Sequência de Aminoácidos , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
4.
Int J Hematol ; 88(2): 197-201, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18594780

RESUMO

The rare recurrent translocation of (8;9)(p22;p24) with PCM1-JAK2 fusion was recently characterized in diverse hematological malignancies. Most of them are atypical chronic myeloid leukemia (CML) or other myeloproliferative disorders (MPD), and are predominantly in the male. We report a female patient with acute myeloid leukemia (AML) initially presenting with normal karyotype and negative HLA-DR expression who achieved complete remission after standard chemotherapy. The disease relapsed 7 months later with cytogenetic change of t(8;9)(p22;p24). Flow cytometry analysis showed evolutional change of immunophenotype from negative to positive HLA-DR expression and fluorescence in situ hybridization (FISH) analysis demonstrated a PCM1-JAK2 fusion gene. We speculate that the cytogenetic change of t(8;9)(p22;p24) may induce HLA-DR immunophenotypic switch and a coordination of the two evolutional changes may play a role in leukemic cell progression.


Assuntos
Autoantígenos/genética , Proteínas de Ciclo Celular/genética , Antígenos HLA-DR/genética , Janus Quinase 2/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Aberrações Cromossômicas , Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Evolução Fatal , Feminino , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Recidiva
5.
Cancer Res ; 64(20): 7216-9, 2004 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15492236

RESUMO

We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRbeta fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRbeta. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRbeta, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.


Assuntos
Antineoplásicos/farmacologia , Eosinofilia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Fosfoproteínas/genética , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-sis/genética , Pirimidinas/farmacologia , Idoso , Sequência de Aminoácidos , Sequência de Bases , Benzamidas , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 5 , Eosinofilia/tratamento farmacológico , Humanos , Mesilato de Imatinib , Masculino , Dados de Sequência Molecular , Transtornos Mieloproliferativos/tratamento farmacológico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53
6.
Nat Genet ; 45(1): 18-24, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23222956

RESUMO

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.


Assuntos
Proteínas de Transporte/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Mutação , Proteínas Nucleares/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Substituição de Aminoácidos , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA , Exoma , Chaperonas de Histonas/genética , Chaperonas de Histonas/metabolismo , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/mortalidade , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Fosfatase 2/metabolismo , Análise de Sequência de DNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
Nat Genet ; 42(8): 722-6, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20601953

RESUMO

Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.


Assuntos
Genes Reguladores , Diferenciação Celular/genética , Proteínas de Ligação a DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Genes Supressores de Tumor , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Histonas/genética , Humanos , Lisina/genética , Masculino , Complexo Repressor Polycomb 2 , Proteínas/genética , Fatores de Transcrição
8.
Blood ; 107(8): 3339-41, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16352805

RESUMO

Imatinib and recombinant interferon alpha (rIFNalpha) can induce remission in polycythemia vera (PV) patients, but gauging the depth of responses has not been possible due to lack of a specific disease marker. We found that patients undergoing imatinib (n = 14) or rIFNalpha (n = 7) therapy remained strongly positive for V617F JAK2, although there was a significant reduction in the median percentage of mutant alleles that correlated with hematologic response (P = .001). Furthermore, individuals who achieved complete hematologic remission had lower levels of V617F than those who did not (P = .001). Of 9 imatinib-treated cases for whom pretreatment samples were available, 7 with no or partial hematologic responses showed a marginal increase (median, 1.2-fold; range, 1.0-1.5) in the percentage of V617F alleles on treatment, whereas the 2 patients who achieved complete hematologic remission showed a 2- to 3-fold reduction. Our data indicate that, although PV patients may benefit from imatinib or rIFNalpha, molecular responses are relatively modest.


Assuntos
Antineoplásicos/administração & dosagem , Interferon Tipo I/administração & dosagem , Piperazinas/administração & dosagem , Policitemia Vera/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Alelos , Substituição de Aminoácidos , Benzamidas , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Feminino , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Humanos , Mesilato de Imatinib , Janus Quinase 2 , Masculino , Pessoa de Meia-Idade , Policitemia Vera/sangue , Policitemia Vera/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Recombinantes , Indução de Remissão/métodos
9.
Blood ; 106(6): 2162-8, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15920007

RESUMO

The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n = 28), chronic or acute myeloid leukemia (n = 35), secondary erythrocytosis (n = 4), or healthy controls (n = 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. Detection of this acquired mutation is likely to have a major impact on the way patients with MPD are diagnosed, as well as serving as an obvious target for signal transduction therapy.


Assuntos
Mutação de Sentido Incorreto , Transtornos Mieloproliferativos/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Estudos de Casos e Controles , Doença Crônica , Feminino , Homozigoto , Humanos , Janus Quinase 2 , Masculino , Repetições de Microssatélites , Epidemiologia Molecular , Transtornos Mieloproliferativos/epidemiologia , Prevalência , Transdução de Sinais/genética
10.
Genes Chromosomes Cancer ; 40(1): 78-83, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15034873

RESUMO

The 8p11 myeloproliferative syndrome (EMS) is an aggressive hematological malignancy caused by the fusion of diverse partner genes to fibroblast growth factor receptor 1 (FGFR1). The partner proteins promote dimerization and ligand-independent activation of FGFR1-encoded tyrosine kinase, deregulating hemopoiesis in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here, we describe the identification of a new FGFR1 fusion gene in a patient who presented with T-cell lymphoblastic lymphoma in conjunction with an acquired ins(12;8)(p11;p11p22). Initial FISH analysis and Southern blotting confirmed that FGFR1 was disrupted. Using 5'-RACE PCR, we identified part of a novel gene, FGFR1OP2, at chromosome band 12p11 that was fused to exon 9 of FGFR1.FGFR1OP2 is predicted to be translated into an evolutionarily conserved protein containing coiled-coil domains but no other recognizable motifs. The presence of the chimeric gene was confirmed by RT-PCR, genomic DNA PCR, and FISH. These data further support the central role of deregulated FGFR1 in the pathogenesis of EMS.


Assuntos
Cromossomos Humanos Par 8/genética , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Idoso , Sequência de Aminoácidos/genética , Animais , Anopheles/genética , Sequência de Bases/genética , Cromossomos Humanos Par 12/genética , Proteínas de Drosophila/genética , Humanos , Proteínas de Insetos/genética , Masculino , Camundongos , Dados de Sequência Molecular , Ratos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Alinhamento de Sequência/métodos , Translocação Genética/genética , Proteínas de Xenopus/genética
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