RESUMO
Human leukocyte antigen class I (HLA-I) genotype has been found to influence cancer development through the presentation of mutational neoepitopes. However, our understanding of its effect on the development of myeloproliferative neoplasms (MPNs) remains limited. We aimed to elucidate the putative protective role of HLA-I alleles in the development of JAK2 V617F-driven MPNs using a population genetics approach. The variability of the HLA-I genotype had no effect on the presence of JAK2 V617F mutation. However, three alleles were found to be inversely correlated with the presence of JAK2 V617F mutation: HLA-A*02:01 (pâ¯=â¯0.036), HLA-B*35:01 (pâ¯=â¯0.017), and HLA-C*15:02 (pâ¯=â¯0.033). The HLA-B*35:01 allele was predicted to bind to a 9-mer peptide derived from JAK2 V617F mutant protein. Gene expression analysis revealed a lower expression of HLA-A and -B in MPN CD34+ cells compared with normal CD34+ cells, which was modulated by ruxolitinib and interferon-α treatment. In summary, we provide robust evidence that specific HLA-I molecules restrict JAK2 V617F-driven oncogenesis. JAK2 V617F+ stem cells evade immune surveillance through downregulation of the HLA-I expression. Therefore, the presence of specific HLA-I alleles might be a predictive marker for response to certain immunotherapies upregulating HLA-I expression. Finally, our findings have implications in the development of mutational neoepitope-based vaccines in MPNs.
Assuntos
Alelos , Carcinogênese , Neoplasias Hematológicas , Antígenos de Histocompatibilidade Classe I , Janus Quinase 2 , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos , Substituição de Aminoácidos , Carcinogênese/genética , Carcinogênese/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/imunologiaRESUMO
Somatic mutations in JAK2, MPL and CALR are recurrently identified in most of the cases with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). We applied four molecular genetic methods for identification of CALR exon 9 mutations, including high resolution melt (HRM) analysis, Sanger sequencing, semiconductor target genes sequencing and whole exome sequencing. A total of 78 patients with myeloid malignancies were included in the study. We identified 14 CALR exon 9 mutated cases out of 78 studied patients with myeloid malignancies. All mutated patients were diagnosed with MPN being either PMF (n = 7) or ET (n = 7). Nine cases had type 1 mutations and 5 cases had type 2 mutations. CALR exon 9, MPL exon 10 and JAK2 p. V617F were mutually exclusive. There were no statistically significant differences in the hematological parameters between the cases with CALR and JAK2 or MPL mutations. Notably, all four techniques were fully concordant in the detection of CALR mutations. This is one of the few reports on the CALR mutations frequency in South-eastern populations. Our study shows that the frequency and patterns of these mutations is identical to those in the patients' cohorts from Western countries. Besides we demonstrated the utility of four different methods for their detection.
Assuntos
Biomarcadores Tumorais/genética , Calreticulina/genética , Éxons , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Idoso , Bulgária/epidemiologia , Feminino , Seguimentos , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , PrognósticoRESUMO
MicroRNAs are a class of small noncoding RNAs playing a crucial role in physiological and pathological conditions, including acute myeloid leukemia. We aimed at examining whether in clinical settings the identification of patient-specific leukemia-associated profiles (LAMPs) of overexpressed microRNAs could be used for minimal residual disease (MRD) detection. Patients with identified LAMPs at diagnosis were further tested for the presence of LAMP after induction therapy. Those with identifiable MRD defined by LAMP expression after induction showed a trend toward a shorter overall survival. Larger studies are needed to confirm the utility of patient-specific LAMPs for MRD follow-up.
Assuntos
Leucemia Mieloide Aguda/genética , MicroRNAs/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasia Residual , Prognóstico , Adulto JovemRESUMO
Somatic DNA methyl transferase 3A (DNMT3A) mutations have been recognized recently as recurrent molecular aberrations in acute myeloid leukemia (AML). The precise role of these mutations in leukemogenesis remains elusive but a number of studies have already been conducted to study their potential prognostic value in AML patients with variable results. We performed a meta-analysis on published data from over 4500 AML patients to provide robust evidence supporting DNMT3A mutation testing in clinical setting for AML patients. Our meta-analysis showed that DNMT3A mutations were associated with M4 and M5 AML subtypes. Those mutations conferred significantly worse prognosis with both shorter OS (p=0.0004) and shorter RFS (p=0.002). Notably, DNMT3A mutations appeared to be an independent adverse prognostic factor also in younger patients with normal cytogenetics AML (OS (p=0.01) and RFS (p=0.0005)) and also in the subgroup of patients with high risk genotypes defined according to the criteria of the European Leukemia Net (ELN) (OS (p=0.002)). Therefore, DNMT3A mutational status can improve the risk stratification of AML patients in the setting of integrated mutational profiling.
