RESUMO
Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.
Assuntos
Antineoplásicos/farmacologia , Linfoma de Efusão Primária/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Linhagem Celular Tumoral , Feminino , Humanos , Lipossomos , Linfoma de Efusão Primária/genética , Linfoma de Efusão Primária/metabolismo , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo , RNA Interferente Pequeno/genética , Proteínas Repressoras/biossínteseAssuntos
Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Idoso , Biópsia , Medula Óssea/patologia , Transformação Celular Neoplásica/genética , Análise Mutacional de DNA , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , NucleofosminaRESUMO
Deletion at 13q14 is detected by fluorescence in situ hybridization (FISH) in about 50% of chronic lymphocytic leukemia (CLL). Although CLL with 13q deletion as the sole cytogenetic abnormality (del13q-only) usually have good prognosis, more aggressive clinical courses are documented for del13q-only CLL carrying higher percentages of 13q deleted nuclei. Moreover, deletion at 13q of different sizes have been described, whose prognostic significance is still unknown. In a multi-institutional cohort of 342 del13q-only cases and in a consecutive unselected cohort of 265 CLL, we investigated the prognostic significance of 13q deletion, using the 13q FISH probes locus-specific identifier (LSI)-D13S319 and LSI-RB1 that detect the DLEU2/MIR15A/MIR16-1 and RB1 loci, respectively. Results indicated that both percentage of deleted nuclei and presence of larger deletions involving the RB1 locus cooperated to refine the prognosis of del13q-only cases. In particular, CLL carrying <70% of 13q deleted nuclei with deletions not comprising the RB1 locus were characterized by particularly long time-to-treatment. Conversely, CLL with 13q deletion in <70% of nuclei but involving the RB1 locus, or CLL carrying 13q deletion in ≥70% of nuclei, with or without RB1 deletions, collectively experienced shorter time-to-treatment. A revised flowchart for the prognostic FISH assessment of del13q-only CLL, implying the usage of both 13q probes, is proposed.
Assuntos
Transtornos Cromossômicos/genética , Leucemia Linfocítica Crônica de Células B/genética , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Estudos de Coortes , Humanos , Hibridização in Situ Fluorescente/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Prognóstico , RNA Longo não Codificante , Proteína do Retinoblastoma/genética , Deleção de Sequência , Transferases , Proteínas Supressoras de Tumor/genéticaAssuntos
Adenocarcinoma/complicações , Adenocarcinoma/genética , Síndrome Hipereosinofílica/complicações , Síndrome Hipereosinofílica/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 15/genética , Doença Crônica , Feminino , Humanos , Síndrome Hipereosinofílica/sangue , Hibridização in Situ Fluorescente , Translocação GenéticaRESUMO
The multiple cancers (MC) phenotype represents an intriguing entity from both the clinical and the biomolecular points of view. Multiple cancers can arise in a patient either synchronously or metachronously and are frequently detected in hereditary disorders. Here we report the clinical and cytogenetic characterization of 48 patients developing at least three malignancies outside the context of a known genetic condition and 30 control individuals. Medical and pathology reports were registered, blood was collected for cytogenetic studies, and the standard G-banding technique was used for chromosomal analysis of the lymphocyte cultures. Chromosomal analysis of the peripheral blood cultures revealed high cytogenetic instability in 83% of patients' karyotypes that displayed structural rearrangements most often involving chromosomes X, 1, 6, and 7. Peculiar telomeric associations and marker chromosomes were detected in patients with a suspected cancer family history. The MC condition can be observed over a wide clinical range, which includes either apparently sporadic cases or families with a strong history of tumors. These findings indicate that Xq, 6p, and 7q are likely to harbor genes of importance in cancer development, and the present cytogenetic mapping may be crucial for further molecular genetic investigations to recognize a predictive cytogenetic signature useful to detect patients with a high risk of multiple malignancies.