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  • 1
    In: Antioxidants, MDPI AG, Vol. 13, No. 3 ( 2024-03-01), p. 311-
    Abstract: Soybeans rank among the top five globally produced crops. Black soybeans contain anthocyanins in their seed coat, offering strong antioxidant and anti-inflammatory benefits. This study explores the protective effects of black soybean seed coat (BSSC) against acute liver injury (ALI) in mice. Mice pretreated with BSSC crude extract showed reduced liver damage, inflammation, and apoptosis. High doses (300 mg/kg) of the extract decreased levels of proinflammatory cytokines (IL-6, IFN-γ) and increased levels of anti-inflammatory ones (IL-4, IL-10), alongside mitigating liver pathological damage. Additionally, it influenced the Nrf2/HO-1 pathway and reduced levels of apoptosis-related proteins. In vitro, the compounds delphinidin-3-O-glucoside (D3G) and cyanidin-3-O-glucoside (C3G) in BSSC were found to modulate cytokine levels, suggesting their role in ALI protection. The study concludes that BSSC extract, particularly due to D3G and C3G, effectively protects against LPS-induced ALI in mice by inhibiting inflammation, oxidative stress, and apoptosis.
    Type of Medium: Online Resource
    ISSN: 2076-3921
    Language: English
    Publisher: MDPI AG
    Publication Date: 2024
    detail.hit.zdb_id: 2704216-9
    SSG: 15,3
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  • 2
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2010-2010
    Abstract: The MLL gene, located at chromosome 11q23, is fused to a variety of partner genes through chromosomal translocations in 5–10% of acute leukemias. Partial tandem duplication (PTD) of MLL gene (MLL-PTD) has been described in 10% of AML with normal karyotype. Recently, 2-hit model of leukemogenesis has been proposed for AML. However, the cooperating mutations with MLL translocations (MLL-T) or MLL-PTD have not been systematically analyzed. In the present study, we aimed to identify the fusion partners of MLL and to analyze the cooperating mutations, including FLT3 activation mutations, N-ras and CEBPα mutations in de novo AML with MLL rearrangements. The correlation between MLL fusion transcripts and clinicohematological features was also analyzed. Southern blot analysis identified 92 patients with MLL rearrangements. Their ages ranged from one day to 84 years; 44 were male. The distribution of FAB subtypes was 4 M0, 19 M1, 19 M2, 22 M4, 25 M5, 1 M6, and 2 M7. Standard RT-PCR or multiplex RT-PCR followed by Genescan analysis and/or direct sequencing, was used to detect the common MLL fusion transcripts. MLL-PTD was detected in 46 (50.0%), MLL-AF9 in 13, MLL-AF10 in 9, MLL-AF6 in 8, MLL-ELL in 7, MLL-ENL in 2, and MLL-AF1 and MLL-AF4 in one patient each. In addition, 5 rare MLL fusion transcripts, including MLL-LCX, MLL-SEPT6, MLL-CBL, MLL-MSF and MLL-LARG in one patient each, were characterized by cDNA panhandle PCR and/or long distance inverse PCR. Cytogenetic findings were available in 76 patients with MLL rearrangements, 11q23 abnormalities were detected in 27 patients. By PCR-Genescan analysis and direct sequencing, FLT3-ITD mutations were detected in 21 patients with MLL rearrangements. By PCR-RFLP and sequencing, FLT3-TKD mutations were detected in 12 patients. By DNA PCR and direct sequencing, CEBPα and N-ras mutations were found in 1 and 9 patients, respectively. Coexistence of FLT3-ITD and FLT3-TKD mutations was observed in 2 patients, FLT3-ITD and CEBPα mutations in one patient, and FLT3-TKD and N-ras mutations in another one patient. Taken together, cooperating mutations of FLT3 and/or N-ras mutations occurred in 42% (39/92) of AML with MLL rearrangements. The frequency of FLT3-ITD was significantly higher in patients with MLL-PTD than those with MLL-T (P 〈 0.001). There was no difference in the mutation status of FLT3-TKD or N-ras between MLL-PTD and MLL-T groups. Sixty patients received standard induction chemotherapy, 42 achieved a complete remission. The 5-year overall survival and relapse-free survival rates were 14.9% and 27.5%, respectively. The complete remission rate in MLL-PTD group was 56.5% (13/23) compared with 78.4% (29/37) in MLL-T group (P=0.089). Patients with MLL-PTD had a poorer 5-year survival rate than MLL-T group (0% vs. 21.9%, P=0.0623). There was no difference in relapse-free survival between the two groups (P=0.3774). In summary, the fusion partners of MLL were characterized in de novo AML. We have identified 5 rare MLL partner genes, MLL-PTD was the most common genetic subtype. MLL-PTD was highly associated with FLT3-ITD mutations. The finding of high incidence of coexistence of FLT3 or N-ras mutations in AML with MLL rearrangements supports the two-hit hypothesis for the pathogenesis of AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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    detail.hit.zdb_id: 80069-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1002-1002
    Abstract: Abstract 1002 Poster Board I-24 Background and purpose: Overexpression of BAALC, MN1, or ERG gene has been described to have adverse impact on the outcome of acute myeloid leukemia (AML) with normal karyotype. The majority of patients with partial tandem duplication of MLL gene (MLL-PTD) had normal karyotypes. The prognostic relevance of overexpression of these genes in MLL-PTD AML was not clear. Aims: We aimed to (1) measure the mRNA expression levels of FLT3, BAALC, FHIT, MN1, and ERG genes in AML patients with MLL-PTD (2) compare the expression levels of these genes with normal controls, and (3) determine their prognostic significance. Patients and methods: Bone marrow samples from 93 de novo AML patients with MLL-PTD at diagnosis were analyzed. MLL-PTD was screened by Southern blot analysis or reverse transcriptase polymerase chain reaction (RT-PCR) then confirmed by real-time quantitative PCR (RQ-PCR). RQ-PCR assay with TaqMan probe was performed to measure the expression of FLT3, BAALC, FHIT, MN1, and ERG genes in MLL-PTD AML as well as in 34 normal controls for comparison. The expression levels of target genes were calculated as the copy number of each gene normalized to the copy number of ABL control gene (NCN). Positive and negative controls as well as standard curve constructs were included in each assay. Mutational analysis was performed by DNA/cDNA PCR followed by GeneScan analysis for detection of internal tandem duplication of FLT3 gene (FLT3/ITD). The expression levels of each target genes were dichotomized at the median value to low and high expression groups. The event-free and overall survivals (EFS and OS) were compared between the 2 groups. Results: The expression levels of mRNAs for FLT3, BAALC, FHIT, MN1, and ERG genes at diagnosis in MLL-PTD AML and 34 normal controls are shown in Table. MLL-PTD patients had significantly higher expression levels of FLT3, BAALC, MN1, and ERG compared to normal controls. The expression of FHIT was also higher than that of controls, but did not reach statistic significance. FLT3/ITD was present in 26 of 52 patients (50%). The expression levels of the above genes were not different between patients with FLT3/ITD and those without. The median age of the entire cohort was 56 years. The median EFS and OS of the 52 patients who received standard induction chemotherapy were 5.8 and 11.4 months, respectively. The complete remission (CR) rate was higher in the low expression group than that of high expression group for BAALC (P = 0.011). The CR rate was not significantly different between low and high expression groups for FLT3, FHIT, MN1, or ERG, and between FLT3/ITD(+) and (-) groups. There were no significant difference in EFS or OS between patients with FLT3/ITD and those without. Patients with high expression of BAALC had a significantly shorter survival than those with low expression group; the median EFS was 10.3 mons (95% CI: 5.9-14.7 mons) vs. 0 mon, P = 0.044 and the median OS was 16.4 mons (95% CI: 8.3-25.5 mons) vs. 10.9 mons (95% CI: 6.5-15.3 mons), P = 0.031. Patients with high expression of MN1 also had a poor outcome compared with low expression group; the median EFS was 10.9 mons (95% CI: 0-28.3 mons) vs. 4.1 mons (95% CI: 0-11.7mons), P = 0.002 and the median OS was 29.7 mons (95% CI: 0-70.7mons) vs.11.0 mons (95% CI: 10.7-11.3 mons), P = 0.024. The EFS and OS were not significantly different between low and high expression groups for FLT3, BAALC, FHIT, and ERG. Conclusions: Our results showed that MLL-PTD was associated with overexpression of FLT3, BAALC, MN1, and ERG. The patients with lower expression level of BAALC had a higher CR rate and patients with overexpression of BAALC or MN1 had poor EFS and OS. FLT3/ITD had no prognostic impact. Supported by grants NSC97-2314-B-182 -011-MY3, NSC96-2314-B-195-006-MY3, and MMH-E-96009. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3487-3487
    Abstract: Background. Two-hit model of leukemogenesis has been proposed for AML; class I mutations that drive proliferation and survival, and class II mutations that block differentiation. Core-binding factor (CBF) AML consists of AML with AML1-ETO and AML with CBFβ-MYH11, that are class II mutations. Aim. We sought to determine the frequencies of cooperating mutations of class I including receptor tyrosine kinases (RTK)/Ras/JAK2 signaling pathways in CBF-AML, and to compare the patterns of cooperating mutations between AML with AML1-ETO and AML with CBFβ-MYH11. Patients and methods. By RT-PCR analysis, 130 adult and 45 children were identified to have CBF-AML, 129 with AML1-ETO and 46 with CBFβ-MYH11. Bone marrow samples at diagnosis were analyzed for FLT3-LM, FLT3-TKD, c-KIT, c-FMS, N-ras, K-ras and JAK2 mutations. Results. Sixty-six of 129 patients (51.2%) with AML1-ETO had RTK/Ras/JAK2 mutations compared with 30 of 46 patients (65.2%) with CBFβ-MYH11 (p=0.121). The frequencies of RTK/Ras/JAK2 mutations in 129 AML1-ETO AML were 3.9% (n=5) for FLT3-LM, 6.2% (n=8) for FLT3-TKD, 2.3% (n=3) for N-ras, 3.9% (n=5) for K-ras, 35.7% (n=46) for c-KIT, and1.6% (n=2) for JAK2 mutation. The frequencies of RTK/Ras/JAK2 mutations in 46 CBFβ-MYH11 AML were 2.2% (n=1) for FLT3-LM, 19.6% (n=9) for FLT3-TKD, 21.7% (n=10) for N-ras, 23.9% (n=11) for c-KIT, and none for K-ras or JAK2 mutations. No c-FMS mutations were detected in both subtypes of CBF-AML. All RTK/Ras/JAK2 mutations were mutually exclusive except three, one each with N-ras and K-ras mutations, FLT3-TKD and c-KIT mutations, c-KIT and JAK2 mutations, respectively. Patients with CBFβ-MYH11 had a significantly higher frequency of FLT3-TKD and N-ras mutations than patients with AML1-ETO (p=0.017 for FLT3-TKD, and p 〈 0.001 for N-ras). Taken together, c-KIT mutations accounted for 32.6% in CBF-AML, the frequency of c-KIT mutations in patients with AML1-ETO was significantly higher than that of CBFβ-MYH11 subtype. Of the 46 patients with AML1-ETO and c-KIT mutations, 34 had mutations located at kinase domain (exon 17), 7 in exon 8, 1 in exon 9, and 4 in exon 11. Of the 11 patients with CBFβ-MYH11 and c-KIT mutations, 5 had mutations in exon 8, 2 in exon 11 and 4 in exon 17. Patients with AML1-ETO were more frequently associated with c-KIT mutations at kinase domain compared with patients with CBFβ-MYH11 (p=0.031), whereas those with CBFβ-MYH11 had a higher frequency of c-KIT mutations in exon 8 than patients with AML1-ETO (p=0.042). Conclusion. Our results showed that occurrence of cooperating mutations of RTK/Ras/JAK2 pathways are common in patients with CBF-AML, but the patterns of mutations were different between AML1-ETO and CBFβ-MYH11 subtypes.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 5
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2363-2363
    Abstract: Two-hit model of leukemogenesis has been proposed for AML. In AML with MLL rearrangements (MLL-R), MLL gene is fused to a variety of partner genes through reciprocal chromosomal translocations (MLL/t11q23), or is rearranged to generate a partial tandem duplication (MLL-PTD). The cooperating mutations of AML with MLL-R have not been systematically analyzed. We aimed to determine the cooperating mutations, including receptor tyrosine kinase (RTK) /Ras signaling pathway, NPM1 and myeloid transcription factors in de novo AML with MLL-R. MLL-R was screened by Southern blot analysis. RT-PCR was used to detect common MLL fusion transcripts. cDNA panhandle PCR was used to identify the infrequent or unknown MLL partner genes. Mutational analysis was peformed by DNA/cDNA PCR-GeneScan analysis for FLT3/ITD, by PCR-RFLP followed by direct sequencing for FLT3/TKD, by DNA/cDNA PCR and direct sequencing for N-Ras, K-Ras, c-KIT, c-FMS, PTPN11, NPM1, AML1 and CEBPα. Of the 131 patients with MLL-R, 77 had MLL-PTD and 54 had MLL/t11q23. None of the 131 patients with MLL-R had c-FMS mutations and c-KIT mutation was present in only one patient with MLL/t11q23. NPM1 mutations occurred in one with MLL-PTD and 2 with MLL/t11q23. The frequencies of other cooperating mutations are shown in Table 1. Taken together, cooperating mutations involving RTK/Ras pathway, NPM1, and/or myeloid transcription factors occurred in 71.4% (55/77) of patients with MLL-PTD and 59.3% (32/54) of patients with MLL/t11q23. In MLL-PTD group, coexistence of two mutations occurred in 23 patients. In MLL/t11q23 group, 6 patients had two mutations. Of the 18 patients with MLL-PTD and AML1 mutations, 8 mutations were located in the Runt homology domain (RHD) and 10 in the non-RHD, 15 were frameshift or nonsense mutations and 3 were missense mutations. Fourteen patients with MLL-PTD and AML1 mutations also had mutations of RTK/Ras singling pathway. Three patients with MLL/t11q23 and AML1 mutations, one in the RHD and 2 in the non-RHD, all were missense mutations. Of the 5 patients with MLL-PTD and CEBPα mutations, 3 harbored FLT3/ITD. Patients with MLL-PTD had a significantly higher frequency of cooperating mutations with myeloid transcription factors than patients with MLL/t11q23 (20/77 vs. 3/54, P=0.002), whereas there was no difference in the frequency of mutations involving RTK/Ras pathway between MLL-PTD and MLL/t11q23 groups (51/77 vs. 29/54, P=0.202). Our results showed that patients with de novo AML and MLL-R had a high frequency of cooperating mutations with RTK/Ras signaling pathway, NPM1 or myeloid transcription factors, and the mutation patterns were different between MLL-PTD and MLL/t11q23 groups. Table 1. Comparison of cooperating mutations between MLL-PTD and MLL/t11q23 groups FLT3/ITD FLT3/TKD N-Ras K-Ras PTPN11 AML1 CEBPα MLL-PTD 35/77 11/77 5/77 0/77 3/77 18/77 5/77 MLL/t11q23 2/54 7/54 9/54 13/54 1/53 3/54 0/54 P value 〈 0.0001 1.000 0.085 〈 0.0001 0.648 0.007 0.077
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1407-1407
    Abstract: Abnormalities of genes regulating DNA methylation have been described in acute myeloid leukemia (AML). MLL protein is a transcriptional regulator and governs proper hematopoiesis through its histone methyltransferase activity. AML with partial tandem duplication of MLL (MLL-PTD) was associated with an unfavorable prognosis. The cooperating roles of MLL-PTD with other mutated genes regulating DNA methylation have not been comprehensively studied in AML. We aimed to determine the prevalence and clinical impact of mutations of DNA methylation regulators in AML with MLL-PTD. Materials and methods Bone marrow samples from 98 AML patients with MLL-PTD were analyzed for gene mutations of TET2, DNMT3A, IDH1 and IDH2. MLL-PTD was screened by RT-PCR and confirmed by real-time quantitative PCR assays. The mutational analysis was performed with PCR assays followed by direct sequencing for TET2 (whole coding exons 3–11) and IDH1/2 (hotspots exon 4). For the detection of DNMT3A mutations, the PCR products amplified for entire coding exons 2 to 23 were first screened with denaturing high-performance liquid chromatography followed by direct sequencing for the abnormal profiles. Results The frequency of TET2, IDH1, IDH2 and DNMT3A mutations in AML patients with MLL-PTD was 17.0% (16/94), 10.2% (10/98), 18.4% (18/98), and 31.6% (31/98), respectively. Taken together, 61.1% of patients with MLL-PTD had at least one mutated gene of DNA methylation regulators. TET2, IDH1 and IDH2 mutations were mutually exclusive with each other whereas DNMT3A mutations frequently co-existed with other DNA methylation modifiers:TET2 (n=8), IDH1 (n=5) and IDH2 (n=4). No differences were observed between the mutation status of the DNA methylation modifiers and clinico-hematologic features of patients with MLL-PTD except that TET2 (P=0.012) and DNMT3A (P=0.024) mutations were associated with older age. Of the 55 MLL-PTD patients who received standard chemotherapy, IDH2 mutation was associated with a lower complete remission rate (25.0% vs 67.8%, P=0.018), while DNMT3A mutations conferred an inferior event-free survival (0.0 vs 6.8 months, P=0.027) and overall survival (6.0 vs 11.5 months, P=0.032). In multivariate analysis, older age (P=0.008) and DNMT3A mutations (P=0.049) were independent adverse factors for overall survival. The crosstalk between MLL-PTD and genes involving DNA methylation in the leukemogenesis of AML warrants further investigation. Conclusions Gene mutations involving DNA methylation frequently co-existed in AML patients with MLL-PTD, especially DNMT3A mutations which conferred a poor outcome. Our study demonstrated the importance of genetic alterations involving DNA methylation in the pathogenesis of MLL-PTD AML and provided potential epigenetic-targeted therapy. Grant support The work was supported by NHRI-EX93-9011SL, NSC95-2314-B-195-001, NSC96-2314-B-195-006-MY3, NSC97-2314-B-182-011-MY3 and MMH-E-101-09. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4025-4025
    Abstract: Abstract 4025 Background. Myelodysplastic syndrome (MDS) is a heterogeneous disease group characterized by ineffective hematopoiesis, cytopenias, and various probability of acute myeloid leukemia (sAML) transformation. The molecular genetic changes from MDS to sAML are not clear. We aimed to determine the roles of gene mutations involving receptor tyrosine kinases (RTKs: FLT3/ITD, FLT3/TKD, c-KIT, or c-FMS), Ras pathways (NRAS, KRAS, or PTPN11) and JAK2V617F in the progression of MDS by analyzing matched paired high risk MDS and sAML samples. Patients and Methods. A total of 122 patients (50 RAEB1, 52 RAEB2, and 20 RCMD) were examined; 82 had sAML evolution and 68 of them had matched paired bone marrow samples (22 RAEB1, 29 RAEB2 and 17 RCMD) available for comparative analysis for at least one gene mutation. Mutational analyses were performed by DNA/cDNA PCR with GeneScan analysis for FLT3/ITD, PCR-RFLP followed by direct sequencing for FLT3/TKD, DNA/cDNA PCR and direct sequencing for c-KIT, c-FMS, NRAS, KRAS, and PTPN11 mutations, and allele-specific PCR for JAK2V617F mutation. Results. Of the 122 cases, 3 had FLT3 mutations (2 FLT3/ITD, 1 FLT3/TKD), none had c-KIT or KRAS mutations, one had c-FMS mutation, 3 each had JAK2V617F and NRAS mutations, and 2 had PTPN11 mutations. Patients harboring mutations of RTK or Ras pathways at diagnosis were not at increased risk of sAML (P=0.5501 and 1.0000, respectively). Presence of any RTK mutations at diagnosis (N=3) did not influence outcome in terms of time to sAML (P=0.6711) or overall survival (OS) (P=0.7162) compared to those who did not have any RTK mutation (N=119). Time to sAML (P=0.6093) or OS (P=0.4515) were not different between patients carrying Ras pathway mutations (N=5) and those without any mutations (N=117). The results of the mutation status for each gene in the 68 paired samples are shown in Table 1. Seven patients (10.3%) gained mutations of RTK pathways at sAML. Patients with mutations of RTKs at diagnosis had shorter time to sAML than those who did not have any mutations (3.4±2.0 vs 10.9±1.1 months, P=0.0004), but the OS was not different between these two groups (P=0.2015). For the Ras pathways, 12 patients (17.6%) acquired mutations at sAML, one of them also acquired FLT3/TKD mutation. Additional one patient gained JAK2V617F mutation. Time to sAML (P=0.2578) and OS (P=0.2637) were not different between patients with Ras pathway mutations at diagnosis and those without mutations. Taken together, 8 patients (11.8%) had mutations at diagnosis and 24 (35.3%) at sAML, one lost PTPN11 mutation and 19 patients (27.9%) acquired mutations which drive proliferation and survival of malignant clone during the progression to sAML from MDS. Conclusions. Our results showed that acquisition of mutations involving RTK, JAK2, or Ras pathways played important roles in the progression of MDS to sAML. Patients with mutations of RTKs progressed to sAML more rapidly. Supported by grants NHRI-EX99-9711SI, NSC97-2314-B-182-011-MY3 and DOH99-TD-C-111-006. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1969-1969
    Abstract: Background and Purpose: The molecular pathogenesis of progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) remains incompletely understood. We studied genemutations involving spliceosome in the transformation of MDS to sAML by comparing matched paired MDS/sAML bone marrow samples to determine the roles of SRSF2, U2AF1 SF3B1, and ZRSR2 mutations in the evolution of MDS to sAML. Patients and Methods: One hundred and forty-nine de novo MDS patients (2 RCUD, 5 RARS, 27 RCMD, 52 RAEB-1, and 63 RAEB-2) were examined forspliceosome mutations at initial diagnosis and 93 patients progressed to sAML with a median follow-up of 16.4 months. Seventy one of them had paired MDS/sAML bone marrow samples available for comparative analyses. Mutational analyses of spliceosome were performed by pyrosequencing with a detection sensitivity of 5% for U2AF1 (exons 2 and 6) and SRSF2 (P95 of exon 1) mutations and by direct sequencing for SF3B1 (exons13-16) and ZRSR2 (whole coding exons 1-11) mutations. Additional 29 gene mutations known to involve in myeloid neoplasms were also analyzed by direct sequencing or next-generation sequencing (NGS, Ion Torrent PGM) followed by Sanger sequencing validation; NGS was mainly used for mutation detection of epigenetic regulators and cohesin complex. The allele burden of targeted genes was determined by pyrosequencing and/or NGS. Results: The frequencies of U2AF1, SRSF2, SF3B1, and ZRSR2 mutations in the 149 MDS patients were 14.8% (22/149), 12.8% (19/149), 12.1% (17/141), and 7.5% (10/133), respectively. Together, spliceosome mutations occurred in 51.5% of MDS patients at initial diagnosis and were mutually exclusive. All the 5 RARS patients had SF3B1 mutations. Co-existed mutations with epigenetic regulators were detected in 36 patients (52.9%), with RUNX1 in 13 (19.1%), with cohesin complex including STAG2, SMC3, RAD21,or SMC1A, in 13 (19.1%), with signaling pathways including RAS, PTPN11, JAK2, or FLT3-TKD in 4 (5.9%), BCOR in 2, and one each with CEBPa and SETBP1. There were no differences in blood counts, percentage of blasts in bone marrow and blood, WHO subtype, cytogenetic risk group, and IPSS-R between spliceosome-mutated and -unmutated patients. Of the patients carrying spliceosome mutations, only SRSF2 mutation had prognostic impact on predicting a higher risk of sAML transformation (P = 0.025) and sAML-free survival (median 10.8 months, 95% CI 5.1-16.5 months) compared to SRSF2-unmutated patients (median 17 months, 95% CI 8.5-25.5 months, P = 0.050). Of the 71 paired MDS/sAML samples, 37 (52.1%) had spliceosome mutations at diagnosis; the mutational status and patterns remained unchanged in all the 37 matched sAML samples but allele burden was apparently increased in the sAML samples with SRSF2 (P = 0.017) or SF3B1 (P = 0.015) mutations. In addition, one ZRSR2 mutant clone and two SRSF2 mutant clones evolved during sAML progression. Acquisition of other mutated genes was found in 37 spliceosome-mutated patients at sAML phases, including RUNX1 in 5, N-RAS in 5, CEBPa in 4, K-RAS in 3, FLT3-ITD in 3, and one each with ASXL1, TET2, STAG2, WT1, PTPN11, CBL, FLT3-TKD, and C-FMS. Notably, of the 3 patients acquiring spliceosome mutations, none gained other mutated genes during sAML transformation.Clonal expansion of other mutated genes were observed in 4 cases with RUNX1, in 2 with TET2, and one each with N-RAS, CEBPa, ASXL1, SMC1A, and STAG2. Conclusions: Our results showed that spliceosome mutations occurred in more than half of de novo MDS patients at initial diagnosis. Clonal expansion, evolution, or unchanged allele burden of spliceosome mutations might occur during sAML transformation with frequent acquisition of additional mutated genes. SRSF2 mutation predicted a higher risk and more rapid sAML transformation. (Grants support: NHRI-EX103-10003NI, MOHW103-TD-B-111-09 and CMRPG3D1532) Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Journal of Pharmaceutical and Biomedical Analysis, Elsevier BV, Vol. 75 ( 2013-3), p. 7-17
    Type of Medium: Online Resource
    ISSN: 0731-7085
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 1491820-1
    SSG: 15,3
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  • 10
    In: Journal of Clinical Pathology, BMJ, Vol. 71, No. 6 ( 2018-06), p. 514-521
    Abstract: We investigated the clinical and prognostic relevance of the mutational status of driver genes with allele burden and endogenous erythroid colony (EEC) growth in 203 Taiwanese patients with primary myelofibrosis (PMF). Methods Pyrosequencing was used to detect JAK2 V617F mutational status and measure allele burden, while MPL (exon 10) mutations were analysed by PCR assay and then by direct sequencing. CALR exon 9 mutations were first screened for length changes by GeneScan followed by sequencing. The allele burden of the mutated CALR gene was measured by pyrosequencing. The EEC assay was conducted using a serum-free culture system. Results The frequencies of the three driver mutations and triple-negative status were similarly distributed between pre-PMF and overt PMF patients, except that pre-PMF patients had a higher incidence of CALR type 2/type-2 like mutations and a lower JAK2 V617F allele burden. EEC growth and CALR mutations conferred favourable overall survival (OS). A lower JAK2 V617F allele burden and grade 3 bone marrow fibrosis were associated with shorter OS and decreased leukaemia-free survival (LFS). Type 2/type 2-like CAL mutations were associated with better LFS compared with type1/type 1-like mutations. Patients with triple-negative mutation status had significantly worse OS and LFS. The allele burden of CALR mutations remained unchanged, while some JAK2 V617F mutations showed clonal expansion in patients during secondary acute myeloid leukaemia transformation. Conclusions Our study showed that EEC growth, a higher JAK2 V617F allele burden and CALR mutations, especially type 2, were independent predictors for better outcomes in PMF. The allele burden of CALR mutations remained stable, but the allele burden of JAK2 V617F mutations was variable during leukaemia transformation.
    Type of Medium: Online Resource
    ISSN: 0021-9746 , 1472-4146
    RVK:
    Language: English
    Publisher: BMJ
    Publication Date: 2018
    detail.hit.zdb_id: 2028928-5
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