| ObjectiveLymphoid enhancer factor 1 (LEF1) is a key transcription factor in Wingless-type (Wnt) pathway. LEF1 play an important role in tumor proliferation, differentiation, invasion and metastasis through its mediated signaling pathway. Abnormal expression of LEF1 has been reported in lymphoma, chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Adult patients with acute lymphoblastic leukemia (ALL) have different biological characteristics compared with pediatric ALL and have very poor outcome. Very few data on LEF1 has been reported in adult ALL. The present study was aimed to explore the genetic mutation and expression of LEF1, and its clinical significance in adult patients with ALL.MethodsQuantitative PCR (qPCR) was performed to detect the expression of LEF1 in 131 newly diagnosed adult patients with ALL. Genomic DNA was amplified by PCR for exon 2 and exon 3 of LEF1 gene, and the mutations of LEF1 were confirmed by direct sequencing or sequencing after cloning. Moreover, the correlations between mutations and expression of LEF1 with clinical characteristics were analyzed. Statistical analyses were carried out using the SPSS (Version 17.0). The qualitative data were made with Pearson’s chi-square test or Fisher exact probability test for differences. To estimate whether the differences in the initial percentage of blast cells, white blood cell (WBC), hemoglobin (Hb), platelet (PLT), and lactate dehydrogenase (LDH) were statistically significant between groups, we performed a nonparametric Mann-Whitney test. Kaplan-Meier curves were used to assess overall survival (OS). P values below 0.05 were considered statistically significant.ResultThe results showed that the frequency of LEF1 mutation in adult ALL is 3.1% (4/131) and all of them were point mutations located in exon 2 and exon 3. The median white blood cell count and median percentage of blasts at diagnosis were significantly higher in LEF1 high expression group than in low expression group (70.6×109/L vs 26.2×109/L, P=0.010; 81.0% vs 57.0%, P=0.014); In addition, the percentage of patients with Philadelphia chromosome positive and patients in high-risk group were significantly higher in LEF1 high expression group compared with that in low expression group (66.7% vs 36.5%, P=0.038; 79.2% vs 56.2%, P=0.044). In standard-risk patients, the percentage of HLA-DR, CD 19 positive was significantly lower in cases with LEF1 high expression than those with low expression (20.0% vs 87.5%, P=0.007; 20.0% vs 73.1%, P=0.042), while the percentage of CD7 positive was significantly higher in cases with LEF1 high expression than those with low expression (100.0% vs 44.0%, P=0.045). The frequency of splenomegaly or lymphadenectasi was higher in patients with LEF1 high expression than those with low expression (56.5% vs 29.5%, P=0.022; 69.6% vs 43.8%, P=0.034) in newly diagnosed patients.ConclusionIt is concluded that high expression of LEF1 may have important role on pathology and development of ALL. LEF1 may become a potential therapy target for Wnt signaling pathway in adult ALL.ObjectiveCytokine receptor-like factor 2 (CRLF2) play an important role in differentiation and proliferation of precursor lymphoid cells through activation of JAK signaling pathway. The correlations and underlining mechanisms between the abnormal expression of CRLF2 and JAK family members have not been fully understood. However, most of the studies were involved in pediatric ALL, and few of the data focused on adult ALL. The aim of this study was to demonstrate the characteristics of expression of CRLF2 and mutations of JAK1 and JAK2. In addition, the clinical and prognostic values of CRLF2 and JAK1 were explored.MethodsQuantitative PCR (qPCR) was performed to explore the expression of CRLF2 in 133 newly diagnosed adult patients with ALL. Genomic DNA was amplified to detect the mutations of the exon 13,14,16,18 and 19 of JAK1 and exon 16 of JAK2 by direct sequencing or sequencing after cloning. Moreover, the correlations between the expression of CRLF2 and mutations of JAK1 with clinical characteristics and survival were analyzed. Statistical analyses were carried out using the SPSS (Version 17.0). The qualitative data were made with Pearson’s chi-square test or Fisher exact probability test for differences. To estimate whether the differences in the initial percentage of blast cells, white blood cell (WBC), hemoglobin (Hb), platelet (PLT), and lactate dehydrogenase (LDH) were statistically significant between groups, we performed a nonparametric Mann-Whitney test. Kaplan-Meier curves were used to assess overall survival (OS). P values below 0.05 were considered statistically significant.ResultOverexpression of CRLF2 was detected in 22.8%(23/123) of newly diagnosed adult patients with ALL. Overexpression of CRLF2 was 55.6% in Ph+ ALL in the cohort of B-ALL patients. Percentage of patients with CD34, CD 13 or CD33 positive was significantly higher in cases with CRLF2 high expression than those with low expression (91.3% vs 62%, P=0.008; 76.2% vs 46.3%, P=0.016; 80.0% vs 37.9%, P=0.001). In present study, co-existing of CRLF2 overexpresion and IKZF1 exon 3-6 deletion (isoform Ik6) was found in 4 of 10 patients. In addition, Ik6 was found in 5 patients with Ph+ALL and 4 of them overexpressed CRLF2. Furthermore, frequency of splenomegaly was higher in patients with CRLF2 high expression than low expression (60.0% vs 32.0%, P=0.040). In present study, JAK1 mutation was confirmed in 4 cases, and all of them were point mutations with aminoacid changes.3 of JAK1 mutations located in exon 16 and the other one located in exon 13. Moreover, overexpression of CRLF2 has significant higher frequency in patients with JAK1 muatation than without JAK1 mutation (75% vs 21.3%,P=0.037). Patients with CRLF2 high expression had shorter OS and EFS than those with low expression (9.5 months vs 16 months, P=0.029; 3 months vs 9 months, P=0.030)ConclusionOverespression of CRLF2 and mutations of JAK1 have important prognostic significances in adult patients with ALL. The mutations of JAK1 observed in present study have not been reported previously. The further functional study is needed to explore deeply the role of JAK1 in development of ALL and regulatory mechanisms involving CRLF2/JAK signaling pathway. In addition, it is indicated that CRLF2, JAK1, IKZF1 and other new prognostic markers could be integrated in future prognostic model of adult ALL. |
PDF Full Text Request