Assuntos
Proteínas de Transporte/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas RepressorasRESUMO
OBJECTIVE: Cytokine receptor-like factor 2(CRLF2) plays an important role in the development of normal B lymphocytes, which can mediate early B cell proliferation and survival. The aim of this study was to investigate the mutations of CRLF2 and its clinical significance in adult patients with acute lymphoblastic leukemia(ALL). METHODS: Exons of CRLF2 were amplified, then the DNA was purified and sequenced; the frequency, position, types and clinical significance of CRLF2 mutations were analyzed. RESULTS: 6 types of genetic alterations in CRLF2 were found, among them the R186S prompted better prognosis, while L86I, F232F and W255C associated with poor prognosis. CONCLUSION: CRLF2 mutations may play an important role in the development and progressions of adult patients with ALL, and these genetic abnormalities may associate with clinical outcome.
Assuntos
Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Citocinas/genética , Adulto , Progressão da Doença , Humanos , PrognósticoRESUMO
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fator de Transcrição Ikaros/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adolescente , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina Básica/genética , Sítios de Ligação , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Fator de Transcrição Ikaros/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Regiões Promotoras Genéticas , Inibidores de Proteínas Quinases/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-bcl-6/genética , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
Genetic mutations on signaling pathways are found in patients with T-cell acute lymphoblastic leukemia (T-ALL) and act as markers of high-risk leukemia. Mutations in dynamin 2 (DNM2) have been reported in T-ALL, particularly in early T-cell precursor-ALL. In the present study, DNM2 mutations were screened by sequencing DNM2 exons obtained by polymerase chain reaction amplification and gel purification in adult T-ALL patients. A total of 4 novel DNM2 mutations were identified in adult T-ALL patients, with a mutation rate of 9.5%, and the DNM2 mutations were found to co-exist with NOTCH1 and PHD finger protein 6, and were also associated with high-risk leukemia. A high rate of silent mutation was also found in the patients, but no significant association was found between the silent mutations and patients' clinical features. The present findings suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.
RESUMO
OBJECTIVE: Interleukin 7 (IL-7) and its receptorï¼IL-7Rï¼are essential for normal T-cell development and homeostasis. This study was aimed to investigate the IL-7R mutation and its clinical significance in adult patients with adult acute lymphoblastic leukemia (ALL), particularly in T-ALL. METHODS: The exons of IL-7R were amplified, cloned and sequenced in 144 adult patients with ALL; the frequency, position and lypes of IL-7R mutation were detected and their correlation with clinical features was analyzed. RESULTS: 7.3% of T-ALL and 1.1% of B-ALL showed somatic IL-7R mutations which located at exon 6 and exon 5, respectively. Moreover, the IL-7R mutation was associated with poor clinical outcome in adult ALL patients. Furthermore, the co-existence of IL-7R mutation with NOTCH1 mutations and/or PHF6 mutation in T-ALL was observed. CONCLUSION: IL-7R mulation and its associated signaling pathways may play an important role in the pathogenesis of T-ALL.
