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1.
Blood ; 135(4): 269-273, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31697828

RESUMO

Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero.


Assuntos
Hematopoese , Leucemia/genética , Mutação , Gêmeos/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doenças em Gêmeos/genética , Feminino , Humanos , Masculino , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
2.
Blood ; 128(1): e1-9, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27121471

RESUMO

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.


Assuntos
Genômica/métodos , Neoplasias Hematológicas , Leucemia Mieloide , Síndromes Mielodisplásicas , Proteínas de Transporte/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Feminino , Forminas , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Masculino , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Tirosina Quinase 3 Semelhante a fms/genética
3.
Haematologica ; 100(2): 214-22, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25381129

RESUMO

Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples. Consequently, we were able to detect copy number changes, such as an interstitial deletion of BCOR, three MLL partial tandem duplications, and a novel KRAS amplification. With regards to coding mutations, we identified likely oncogenic variants in 41 of 42 samples. NPM1 mutations were the most frequent, followed by FLT3, DNMT3A and TET2. NPM1 and FLT3 indels were reported with good efficiency. We also showed that DNMT3A mutations can persist post-chemotherapy and in 2 cases studied at diagnosis and relapse, we were able to delineate the dynamics of tumor evolution and give insights into order of acquisition of variants. HaloPlex is a quick and reliable target enrichment method that can aid diagnosis and prognostic stratification of acute myeloid leukemia patients.


Assuntos
Variações do Número de Cópias de DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas de Neoplasias/genética , Algoritmos , Estudos de Casos e Controles , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Estadiamento de Neoplasias , Nucleofosmina , Prognóstico
4.
Nat Commun ; 14(1): 7725, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38001082

RESUMO

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Neoplasias/metabolismo , Tamoxifeno/uso terapêutico , Tamoxifeno/metabolismo , Mutação , Calreticulina/genética , Calreticulina/metabolismo
5.
Cell Rep ; 17(4): 1193-1205, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27760321

RESUMO

Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Testes Genéticos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular , Adulto , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , Reprodutibilidade dos Testes
6.
Cell Rep ; 10(8): 1239-45, 2015 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-25732814

RESUMO

Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.


Assuntos
Envelhecimento , Hematopoese/genética , Leucemia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia/patologia , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas Nucleares/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA , Ribonucleoproteína Nuclear Pequena U2/genética , Ribonucleoproteínas/genética , Análise de Sequência de DNA , Fatores de Processamento de Serina-Arginina , Adulto Jovem
7.
Exp Clin Transplant ; 10(5): 508-12, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22920230

RESUMO

We report the case of a middle-aged man who died from multiorgan failure 3 weeks after orthotopic liver transplant for fulminant hepatic failure, associated with a rare, often fatal, hematologic condition that usually presents in childhood. We discuss the importance of its diagnosis, treatment, and implications for liver transplant.


Assuntos
Falência Hepática Aguda/cirurgia , Transplante de Fígado , Linfo-Histiocitose Hemofagocítica/cirurgia , Adulto , Evolução Fatal , Humanos , Falência Hepática Aguda/complicações , Linfo-Histiocitose Hemofagocítica/complicações , Masculino , Insuficiência de Múltiplos Órgãos/etiologia
9.
Sci Transl Med ; 7(306): 306fs38, 2015 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-26400908
10.
Am J Hematol ; 76(2): 101-6, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15164373

RESUMO

The lifespan of sickle cell patients has increased substantially. We chose to compare the attributes of older sickle cell patients with younger ones within the confines of a single institutional study serving the local Bronx population. Laboratory and clinical assessments from 40 patients with sickle cell disease over 40 years of age were compared to 40 patients under 30 years of age. When the older group was compared to the younger group, hemoglobin, indirect bilirubin, and platelet counts were significantly lower. Creatinine clearances were lower and BUN levels were higher in the older group. Although the prevalence of radiographically measured cardiomegaly was significantly higher in the older group, systolic and diastolic blood pressures remained unchanged. The number of crises and number of admissions were higher in the younger group than in the older, but there was wide variation, and no significant differences could be detected; days spent in hospital over the previous 2 years did not differ. No statistically significant differences were observed for absolute reticulocyte count, MCV, % HbF, white cell count, liver function tests, or oxygen saturation. Comparing genders within age groups, younger males had higher hemoglobin levels and absolute reticulocyte counts than younger females, while only the older females had higher HbF levels than the corresponding males. Lower levels of hemoglobin associated with older age may reflect decreased hematopoietic potential that may in part be due to decreased renal function. Lower platelet counts in older sickle cell patients may be a consequence of this decreased hematopoietic potential but may also represent a secondary survival benefit effect in sickle cell anemia.


Assuntos
Envelhecimento/fisiologia , Anemia Falciforme/fisiopatologia , Adulto , Distribuição por Idade , Idoso , Anemia Falciforme/sangue , Pressão Sanguínea , Cardiomegalia/epidemiologia , Humanos , Testes de Função Renal , Testes de Função Hepática , Pessoa de Meia-Idade , Oxigênio/sangue , Contagem de Plaquetas , Estudos Retrospectivos
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