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Blood ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484648


Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients which we classified as causal (n=21) or unknown significance (n=7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. Median age was 69 years, most patients were males (79%). Only 9 patients (27%) had a family history of hematological malignancy, while 15 (46%) had personal history of cytopenias years prior to MDS/AML diagnosis. Most patients had normal karyotype (85%) and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n=9) or azacitidine (n=11) had an overall response rate of 100% and 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent pre-existing cytopenias, additional somatic DDX41 mutation and relatively good outcome.

Ann Biol Clin (Paris) ; 75(3): 339-347, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28540857


We report the case of a 31 year-old man diagnosed with an atypical acute leukemia difficult to characterize cytologically. The immunophenotyping identified a blastic population co-expressing myeloid, lymphoid B and lymphoid T markers suggesting the diagnosis of either a mixed phenotype acute leukemia (MPAL) or an early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Because of the poor prognosis linked to these leukemias, the patient benefited from chemotherapy targeting both myeloid and lymphoid components, followed by allogeneic hematopoietic stem cell transplantation. DNA-based techniques analyzing B and T-cell clonality identified partial rearrangements in immunoglobulin and TCR genes, allowing the monitoring of minimal residual disease. This observation highlights the difficulty to classify some atypical cases of acute leukemias. It emphasizes on the complementarity of cytomorphology, immunophenotyping by flow cytometry and molecular techniques in order to promptly characterize and treat these leukemias.

Leucemia Aguda Bifenotípica/diagnóstico , Leucemia/patologia , Doença Aguda , Adulto , Linfócitos B/patologia , Humanos , Imunofenotipagem , Leucemia/imunologia , Leucemia Aguda Bifenotípica/imunologia , Leucemia Aguda Bifenotípica/patologia , Masculino , Células Mieloides/patologia , Linfócitos T/patologia
Blood ; 127(6): 749-60, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26626993


Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin ß. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at as #NCT01718379.

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal/efeitos dos fármacos , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Anemia Macrocítica/tratamento farmacológico , Anemia Macrocítica/genética , Anemia Macrocítica/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Evolução Clonal/genética , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Células Clonais/patologia , Análise Mutacional de DNA , Eritropoetina/administração & dosagem , Feminino , Humanos , Lenalidomida , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas Recombinantes/administração & dosagem , Talidomida/administração & dosagem , Talidomida/farmacologia , Resultado do Tratamento
PLoS Negl Trop Dis ; 8(6): e2841, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24902030


BACKGROUND: Cutaneous leishmaniasis is caused by several Leishmania species that are associated with variable outcomes before and after therapy. Optimal treatment decision is based on an accurate identification of the infecting species but current methods to type Leishmania isolates are relatively complex and/or slow. Therefore, the initial treatment decision is generally presumptive, the infecting species being suspected on epidemiological and clinical grounds. A simple method to type cultured isolates would facilitate disease management. METHODOLOGY: We analyzed MALDI-TOF spectra of promastigote pellets from 46 strains cultured in monophasic medium, including 20 short-term cultured isolates from French travelers (19 with CL, 1 with VL). As per routine procedure, clinical isolates were analyzed in parallel with Multilocus Sequence Typing (MLST) at the National Reference Center for Leishmania. PRINCIPAL FINDINGS: Automatic dendrogram analysis generated a classification of isolates consistent with reference determination of species based on MLST or hsp70 sequencing. A minute analysis of spectra based on a very simple, database-independent analysis of spectra based on the algorithm showed that the mutually exclusive presence of two pairs of peaks discriminated isolates considered by reference methods to belong either to the Viannia or Leishmania subgenus, and that within each subgenus presence or absence of a few peaks allowed discrimination to species complexes level. CONCLUSIONS/SIGNIFICANCE: Analysis of cultured Leishmania isolates using mass spectrometry allows a rapid and simple classification to the species complex level consistent with reference methods, a potentially useful method to guide treatment decision in patients with cutaneous leishmaniasis.

Técnicas de Laboratório Clínico/métodos , Leishmania/química , Leishmania/classificação , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/parasitologia , Parasitologia/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , França , Humanos , Leishmania/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Viagem , Adulto Jovem