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  • 1
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-12)
    Abstract: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. Methods We detected the expression of autophagy markers in FLT3-ITD-positive leukemic cells after vs. before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. Results Sorafenib-resistant cells markedly overpresented autophagy markers in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to mediate FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame resistance to FLT3 inhibitors. Conclusions Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance.
    Type of Medium: Online Resource
    ISSN: 1479-5876
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5170-5170
    Abstract: AML1/ETO-positive acute myeloid leukemia (AML) is a heterogeneous malignancy. Up until now, the difference between adult ( 〉 14-year old) and pediatric (≤14-year old) AML1/ETO+ AML remains unclear. In this retrospective multi-center study we analyzed 173 AML1/ETO+ AML patients including 98 adults and 75 kids, and found that AML-M2 phenotype was the most common morphology, especially higher in adult patients with an incidence of 92.9%, as compared with 82.7% (P=0.005) in pediatric patients. Furthermore, higher incidence of extramedulary leukemia (29.6% vs. 13.3%, P=0.001) and C-KIT mutation (21/67, 31.3% vs. 12/66, 18.2%, P=0.079) were observed in adult patients than pediatric patients. No significant difference in gender ratio, peripheral white blood cells count, immunology and cytogenetic abnormality including affiliated cytogenetic abnormalities and lose of sex chromosmoe between the two age groups. Among adult patients, idarubicin combined with cytarabine (IA) or daunorubicin combined with cytarabine (DA) was the major induction regimens, while FLAG (fludalabin,cytarabine and G-CSF) combined with idarubicin or DA combined with etoposid (DAE) was the main regimens in pediatric patients for one to two cycles. Not only the first-cycle complete remission (CR) rate (69/74, 93.2% vs. 56/95, 58.9%, P 〈 0.001), but also the second-course cumulative CR rate (73/74, 98.6% vs. 82/95, 86.3%, P=0.004) in pediatric patients was much better than that in adult patients. After obtaining CR, standard dose cytarabine (SDAC)-based or medium dose cytarabine (MDAC)-based regimens were given to the adult patients as the major consolidation regimens, while pediatric patients received MDAC or homoharringtonine combined with cytarabine and etoposid (HAE). With a median of 23.5(2-126) months follow-up, cumulatively 35/87(40.2%) patients relapsed and 39/98(39.8%) cases died in adult group, which were much higher than that in pediatric patients, with the cumulative incidence of recurrence of 18/74(24.3%) (P=0.032) and cumulative death rate of 13/75(17.3%) (P=0.001). Survival analysis showed that EML [RFS: HR 3.20(1.63-6.28), P=0.001; OS: HR 2.92(1.55-5.51), P=0.001] and C-KIT mutation [RFS: HR 3.17(1.47-6.93), P=0.003; OS: HR 2.24(1.03-4.86), P=0.041] were the adverse factors for relapse free survival (RFS) and overall survival (OS). Nevertheless, neither these two factor were negative for the survival of pediatric patients. Taking together, significant difference in bone marrow morphology, incidence of EML and C-KIT mutation, also prognostic factors were observed between the adult and pediatric AML1/ETO+ AML patients. Intensive induction might be a main reason for higher CR rate and better survival in pediatric patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 3
    Online Resource
    Online Resource
    Elsevier BV ; 2012
    In:  Journal of Rare Earths Vol. 30, No. 3 ( 2012-3), p. 197-201
    In: Journal of Rare Earths, Elsevier BV, Vol. 30, No. 3 ( 2012-3), p. 197-201
    Type of Medium: Online Resource
    ISSN: 1002-0721
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
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  • 4
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3256-3256
    Abstract: The intestine is preferentially damaged in acute graft-versus-graft disease (aGVHD). Patients with intestinal GVHD are usually associated with drug-resistant diarrhea and microflora disturbance. Recent studies suggest that toll-like receptor (TLR) signaling can protect the intestinal epithelial barrier and confer commensal tolerance in health. But less is known about how functional versus dysfunctional TLR pathway opposes or favours the intestinal GVHD. Methods In the current study, BALB/c mice were transplanted whole spleen and T cell deleted (TCD) bone marrow cells from C57BL/6 mice as GVHD group, and transplanted TCD bone marrow cells as control group. The jejunum, ileum, colon and rectum epithelium were harvested and total RNA of the intestinal epithelium were extracted in two groups. The mRNA expression of classical TLR pathway TLRx/MYD88/IRAK4 signaling molecules (TLR2, TLR4, MYD88, IRAK4 and Tollip) and cytokines (IFN-γ, TNF-α and TGF-β) were detected by RT-PCR. Results The intestine of aGVHD recipients showed severe mucosal edema and erythema with histologic changes of apoptotic epithelial cells and crypt cell dropout, while the intestine of recipients in the control group did not show any intestinal GVHD evidence. TLR2 expression was markedly down-regulated and little TLR4 expression was observed in GVHD intestinal epithelium in comparison to control group. MYD88 and IRAK4 expression were lower in the entire intestinal epithelium of GVHD group but only significant in colon and rectum epithelium between the two groups. Tollip, a TLR signaling inhibitor by interfering IRAK, was found much higher in the GVHD group. For cytokines, both of IFN-γ and TNF-α expression were markedly up-regulated from proximal to distal intestine in GVHD group as compared to control group. There was no difference in TGF-β expression between the two groups. Conclusions We propose TLR signaling in the intestinal epithelium, especially in colon and rectum, presents disruption in intestinal graft-versus-host disease. IFN-γ and TNF-α might contribute to accelerate TLR pathway alteration. Disclosures: Liu: It was supported by 863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017).: Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding. Wu:It was supported by 863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017).: Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding. Zhao:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017).: Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding. Wu:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Zhang:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Fan:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Fan:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Yin:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Zheng:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Yi:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding. Liu:863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation ( No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174): Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
    Online Resource
    Online Resource
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 5056-5056
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 5056-5056
    Abstract: Abstract 5056 Introduction: JAK2V617F point mutation have been confirmed to be one of the major molecular mechanism of BCR/ABL negative myeloproliferative disorders(MPD). Besides, some other gene mutations such as JAK2 exon12, MPL W515L/K, c-mpl and EPOR have extended the scope of the research in this field. Most of the MPD patients are sporadic and there are seldom reports in Chinese familial MPD. 2008 ASH metting we have reported in a Chinese family of MPD's findings, the two brothers in our hospital diagnosis for MPD (one is a PV, another is ET), then we investigated the 15 members of the family. We discovered that there were three male members carried the JAK2V617F mutation in this family, including the two MPD patients and their father, which affected in two generations. All the family members were confirmed as BCR/ABL, MPL W515L/K, c-mpl, and EPOR negative. Subsequently, in order to understand the existence of family members in addition to the gene JAK2 V617F mutation, the existence of JAK2 gene mutations in other parts of the? if other mutations in existence and the high incidence of family members of MPD? We focus on the cDNA full-length of JAK2 gene to provide some theory basis on the pathogenesis in MPD. Methods: A total of 15 family members were enrolled in our study, including 2 brothers of MPD patients (the older one was thrombocythemia (ET), and another is polycythemia vera (PV)) and the other members in the same family. The mRNA of mononuclear cells from peripheral blood sample was extracted according to the manufacturer's instruction (TAKARA). RT-PCR and DNA sequencing have been used to analyze the cDNA full-length of the JAK2 gene. Results: All of the samples can be analyzed for JAK2 cDNA full-length. 3 members carried the JAK2V617F mutation (1849G®T) in this family, including the two MPD patients and their father. And the older brother was homozygous mutation and the other two were heterozygous mutation. All of the 15 samples were JAK2 exon12 gene mutation negative. 2 persons who were the male ET patient's children had a heterozygous mutation (380G®A) in JAK2 exon 3, caused a glycine-to-asparticacid substitution at position 127. Besides, 13 persons had 489C®T mutation in exon 4 and 14 persons had 2490G→A mutation in exon 17 in this family, But they were both same-sense mutation. Conclusion: It is necessary to do routine analysis of blood and other related inspection for MPD patient's family members, so as to make diagnosis earlier. However, we are not sure that the sequencing results are unique to all the familial MPD and need to be confirmed by more cases. We still do not determine the current discovery point mutations have biological significance, still need to be further explored. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 942-942
    Abstract: Amyloid precursor protein (APP) has been reported to be highly expressed in AML1-ETO-positive acute myeloid leukemia (AML1-ETO-positive AML), and we found it correlate with extramedullary infiltration regulated of by APP/ERK/MMP-2 signal pathway in our previous study. It is also known that C-KIT mutations highly expressed in AML1-ETO-positive AML and cooperates with full-length AML1-ETO to induce AML in mice. In this study we further described a close correlation of APP gene with C-KIT mutations, as well as APP related clinical and prognostic significance in 65 patients with AML1-ETO-positive AML. 65 cases of AML1-ETO-positive AML patients with median age of 30 years old, who were admitted to our hospital from February, 2006 to June, 2013 and made the diagnosis according to WHO2008 diagnosis standard, were enrolled into this study. APP expression in bone marrow cells before the first chemotherapy was assessed by quantitative reverse transcriptase (QRT)-PCR method. These cases were accordingly divided into APP-H group (n=33, with high level of APP by QRT-PCR) and APP-L group (n=32, with lower level of APP by QRT-PCR) according to median APP expression. Incidence of C-KIT mutations, clinical characteristics and prognosis including complete response (CR), overall survival (OS), and recurrence free survival (RFS) with median 35 (6-96) months followed-up was differentiated between the two groups. Furthermore, expression of APP and AML1/ETO fusion gene were simultaneously monitored at the time of 3, 6, 12 and 24 months or relapse after CR by QRT-PCR method. The incidence of C-KIT mutations was significantly increased in the APP-H group, as compared with the APP-L group (39.4% versus 12.5%) and it was positively correlative with APP expression (rp=0.435, P=0.004). Of the 17 patients harboring C-KIT mutations, 13 patients overexpressed APP gene (P=0.014) (Figure 1). Clinically, APP-H patients exhibited significantly elevated white blood cells count, increased extramedullary infiltration (P=0.039 and P=0.019, respectively). Moreover, APP overexpression was related to low rate of two-cycle CR, RFS and OS (P=0.020, P=0.001 and P=0.029, respectively) (Table 1). In addition, the change of APP expression was consistent with that of AML1-ETO fusion gene monitored by QRT-PCR method at different status of leukemia, though APP expressed differently in different patients with the same AML1-ETO expression. Taken together, these data suggest that APP gene is correlated with C-KIT mutations and indicates poor disease outcome and dynamic monitoring APP expression could be another choice of minimal residual disease monitoring in AML1-ETO-positive AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 7
    In: Clinical and Experimental Medicine, Springer Science and Business Media LLC
    Type of Medium: Online Resource
    ISSN: 1591-9528
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2054398-0
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  • 8
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2021-12)
    Abstract: Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. Methods Cell growth was assessed with CCK-8 assay, and apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models. Results In this study, we investigated the antileukemia effects of HDAC inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo. Conclusions Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.
    Type of Medium: Online Resource
    ISSN: 1479-5876
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 9
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2014-05-23)
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2553671-0
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  • 10
    Online Resource
    Online Resource
    Hindawi Limited ; 2018
    In:  International Transactions on Electrical Energy Systems Vol. 28, No. 8 ( 2018-08), p. e2570-
    In: International Transactions on Electrical Energy Systems, Hindawi Limited, Vol. 28, No. 8 ( 2018-08), p. e2570-
    Type of Medium: Online Resource
    ISSN: 2050-7038
    URL: Issue
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2018
    detail.hit.zdb_id: 2702272-9
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