Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Blood Adv ; 7(20): 6092-6107, 2023 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-37406166

RESUMO

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.


Assuntos
Neoplasias Hematológicas , Leucemia , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Neoplasias Hematológicas/genética , Mutação em Linhagem Germinativa , RNA Helicases DEAD-box/genética , Carcinogênese , Células Germinativas , Fator de Transcrição GATA2/genética
3.
Int J Hematol ; 106(2): 163-174, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28547672

RESUMO

Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.


Assuntos
Carcinogênese/genética , RNA Helicases DEAD-box/genética , Genes Supressores de Tumor , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/fisiologia , Humanos , Splicing de RNA/genética , RNA Mensageiro/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...