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  • Yin, Changxin  (15)
  • 2010-2014  (15)
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  • 2010-2014  (15)
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  • 1
    Online Resource
    Online Resource
    Molecular Mechanism Of Regulation Of Extramedullary Infiltration In AML1/ETO Positive Acute Myeloid Leukemia By APP/ERK/MMP-2
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3769-3769
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3769-3769
    Abstract: Amyloid precursor protein (APP) has been reported to be highly expressed in AML1/ETO positive acute myeloid leukemia (AML1/ETO+ AML), and we found it express even higher in those with extramedullary infiltration in our previous study. But it’s still unknown what role APP plays and how it works in AML1/ETO+ AML. This study was designed to investigate the effect of APP gene on the prognosis and its molecular mechanism of extramedullary infiltration in the patients with AML1/ETO+ AML. 44 cases of AML1/ETO+ AML patients with median age of 29 years old, who were admitted to our hospital from February, 2006 to February, 2012 and made the diagnosis according to WHO2008 diagnosis standard, and had completed conventional induction, consolidation and intensive therapy, were investigated in this study. They were divided into high expression group (n=22) and low one (n=22) according to APP mRNA median expression level from bone marrow cells before the first chemotherapy by QRT-PCR. Some of bone marrow samples were checked by Western Blot, and 5 biopsy specimens from extramedullary infiltration were tested by APP antibody immunohistochemistry staining. Incidence of extramedullary leukemia (EML), complete response (CR), overall survival (OS), and recurrence free survival (RFS) was differentiated between the two groups. Differences of cell ultrastructure, migration, proliferation, apoptosis and expression of ERK, MMP-2, MMP-9 and CXCR4 were studied on Kasumi-1 cell line between wild, negative control (NC) and si-APP group in which the expression levels of APP gene were down regulated with application of siRNA technology.Çå The incidence of EML was significantly different (45.5% versus 9.1%) in the two groups (P=0.007) and it was positively correlative with the expression levels of APP mRNA (rp=0.435, P=0.004). Extramedullary infiltration site also showed high expression of APP by immunohistochemistry, while the control group was negative. Not only CR rate after two courses of chemotherapy, but also OS and RFS with median follow-up of 28(4-70) months, of high expression group was all significantly lower than that of low expression group (Table 1). Compared with the wild and NC group, cell apoptosis of si-APP group was significantly increased (12.33 ± 0.75 vs 19.80 ± 1.51, P=0.000); the number of microvilli on the surface of the cell membrane significantly reduced; the ability of the cell migration by Tanswell chamber migration assay significantly decreased (P=0.004); and expression of P-ERK, c-MYC, MMP-2 decreased significantly which was confirmed by ERK and c-MYC blocker treatment (Figure 1). In sum, incidence of EML is significantly higher and the prognosis is poor in the patients with AML1/ETO+ AML with high expression of APP gene. We first describe that APP gene may mediate AML1/ETO+ leukemia cells in the development of extramedullary infiltration by up-regulation of the ERK/MMP-2 pathway. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3769.3769
    RVK:
    XA 33000
    RVK:
    XA 10000
    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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  • 2
    Online Resource
    Online Resource
    APP Gene Is Correlated with C-KIT Mutations and Indicates Poor Disease Outcome in AML1-ETO-Positive Acute Myeloid Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 942-942
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V124.21.942.942
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Online Resource
    Herpesvirus-Associated Central Nervous System Diseases After Allogeneic Hematopoietic Stem Cell Transplantation
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4139-4139
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4139-4139
    Abstract: Abstract 4139 Background Herpesvirus infections of central nervous system (CNS) are associated with encephalitis/myelitis and other neurological syndromes as well as lymphoproliferative diseases in immunocompromised individuals. Diagnosis is mainly based on the detection of virus-DNA in cerebrospinal fluid (CSF). Recently, some studies demonstrate that herpesvirus-associated diseases have increased in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), but these mainly focus on the systematic herpesvirus infections and lack of a large-sample prospective study of CNS herpesvirus infections. Methods The eligibility criteria are as following: (1)The patients after allo-HSCT; (2)The patients who were diagnosed as Epstein-Barr virus (EBV)-associated diseases; (3)The patients with other herpesvirus-associated diseases other than EBV-associated diseases accompanying CNS manifestations; (4)The patients with unexplainable CNS manifestations. According to the criteria aforementioned, fifty-four of 250 patients undergoing allo-HSCT in our single institution between July 2008 and April 2012 were enrolled in this prospective study. Moreover, 18 patients with herpesvirus-DNA-emia who did not develop herpesvirus-associated diseases volunteered to have their CSF monitored (platelet 〉 50×109/L). Herpesvirus-DNA of CSF, blood and other body fluids was monitored by polymerase chain reaction (PCR). Once herpesvirus-associated CNS diseases were considered, immunophenotypic analysis of CSF cells and magnetic resonance imaging scanning of CNS were performed. Results Twenty-four patients were diagnosed as herpesvirus-associated CNS diseases, including 8 EBV encephalitis, 7 EBV-associated CNS post-transplant lymphoproliferative diseases (PTLD), 5 herpes simplex virus type 1(HSV-1) encephalitis, 2 cytomegalovirus (CMV) encephalitis, 1 CMV myelitis and 1 varicella zoster virus(VZV) encephalitis, respectively. The EBV-DNA levels of CSF were significantly higher than that of blood (82457 ± 6126 copies/ml vs. 18517 ± 3906 copies/ml, P=0.030). The virus of CSF was consistent with the virus of blood in all patients except one patient with EBV-associated CNS-PTLD, who was EBV-DNA positive of CSF but CMV-DNA positive of blood. The median time of herpesvirus-associated CNS diseases onset was 79 days post-transplants and 70.8% cases occurred within 100 days post-transplants. The 3-year cumulative incidence of herpesvirus-associated CNS diseases and EBV-associated CNS diseases was 12.8±2.6% and 7.5±2.0%, respectively. With a median follow-up of 198 days after the diagnosis of herpesvirus-associated CNS diseases, 13 patients survived and 11 died. The causes of death were related with herpesvirus in 7 cases and not related with herpesvirus in 4 cases. Conclusions PCR detection of CSF virus-DNA is a sensitive and specific method for diagnosing herpesvirus-associated CNS diseases. EBV-associated CNS diseases are more common than other herpesvirus-associated CNS diseases in the early times of allo-HSCT. The EBV-DNA negative in blood could not exclude EBV-associated CNS diseases. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.4139.4139
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Analysis of the JAK2 Gene cDNA Full-Length In One Chinese Familial Myeloproliferative Disorders
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 5056-5056
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V116.21.5056.5056
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Online Resource
    Disrupted Toll-Like Receptor Signalling Of Intestinal Epithelium In Intestinal Graft-Versus-Host Disease
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3256-3256
    Details
    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
    URL: Article
    DOI: 10.1182/blood.V122.21.3256.3256
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Decitabine Act As Demethylation Modulators in Acute Myeloid Leukemia for Reversal of Drug Resistance
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 5218-5218
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5218-5218
    Abstract: Background and objectives The DNA methyltransferase inhibitors decitabine represent archetypal drugs for epigenetic cancer therapy. One alternative approach for the treatment of (Acute Myelocytic Leukemia) AML is the use of hypomethylating agents, including the 5-aza-2-deoxycytidine (decitabine; DAC) and other epigenetic regulators. However, the exact mechanism of DAC for drug resistance AML remains poorly understood. We conducted this study to explore how DAC regulated the sensitivity to adriamycin and aclacinomycin of AML cell line HL60/ADR and assessed the efficacy and safety of decitabine-based induction treatment patients with refractory acute myeloid leukemia. Methods In this study, we analyzing cell proliferation of HL60, HL60/ADR and KG1-¦Á cells treated by DAC against control group detected with MTS assay. Then the changes of genes methylation were determined using Methylation specific PCR (MSP), stained with anti-CD11b, before being analyzed for cell markers with flow cytometric analysis. The cell protein levels were checked with Western blotting as described elsewhere. Data were collected from refractory acute myelogenous leukemia (AML) patients treated with homoharringtonine, cytarabine, and aclarubicin after decitabine (D-HAA). Control group consisted of fludarabine, cytarabine with or without Granulocyte Colony-Stimulating Factor between 2012 and 2014. Results Different dose of DAC had proliferative inhibition effect on HL-60 cells, with time-dose dependent relationship. But the proliferative inhibition of DAC in KG1-¦Á and HL-60/ADR cells was not so effective. After been treated with 1¦ÌM DAC for 72 hours, HL-60/ADR cells were cultured with 0.5µg/ml adriamycin 1 hour. Adriamycin positive cells in DAC group were higher than control group, and the proliferative inhibition effect of adriamycin (P 〈 0.001) and aclacinomycin (P 〈 0.001) on HL60/ADR cells was increased (Figure 1). 1¦ÌM DAC significantly induced expression of CD11b on HL-60/ADR and KG1-¦Á cells, accompanied by cellular changes of differentiation (decreased nuclear¨Ccytoplasmic ratio, nuclear condensation, segmentation or lobulation, cytoplasmic granulation or vacuolization). Followed the increased the sensitivity of adriamycin, DNMT1 and SPRPs gene methylation was down-regulated. And ¦Â-catenin protein in nuclear was depressed after treatment of DAC. We enrolled 75 patients, of whom 71 were included in the intention-to-treat analysis. 65.2% patients in the D-HAA group achieved complete remission versus 29.2% in the FA/FLAG group (P=0.031). 2-year disease-free survival and overall survival were better in D-HAA group than FA/FLAG group (P=0.020, P=0.025; Figure 2). Conclusion These findings provide evidence for clinic protocols using DAC to reversed drug resistance in refractory AML cell. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.5218.5218
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 7
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    Analysis of JAK2 V617F Mutation and Its Clinical Significance in Patients with Thrombocythemia and Other Myeloproliferative Neoplasms in Chinese
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 4687-4687
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4687-4687
    Abstract: Abstract 4687 JAK2 mutation is commonly found in Philadelphia-negative myeloproliferative neoplasms (MPNs). In Western countries, this mutation is found in approximately 96 percent of people with polycythemia vera, half of individuals with essential thrombocythemia or primary myelofibrosis. We used the method of amplification refractory mutation PCR (ARMS-PCR) to investigate MPN patients in China. We focused our study on patients with essential thrombocythemia (ET). ARMS-PCR was used to detect JAK2 V617F mutation in the bone barrow (BM) or peripheral blood of 37 MPN patients, which consisting of 7 ET, 5 polycythemia vera (PV), 5 chronic myeloid leukemia (CML), 5 chronic idiopathic myelofibrosis (CIMF), as well as 15 suspected MPNs. 17 cases of JAK2 V617F mutation (45.9%) were found in 37 patients, including 4 ET (57.1%), 4 PV (80.0%), 3 CIMF (60.0%), 6 suspected MPNs (40.0%). We did not find JAK2 V617F in the patients with CML. Our results indicated that the frequency of JAK2 V617F mutation in bcr/abl-negative MPNs in Chinese is similar to that in MPN patients in Western countries. At the same time, ARMS-PCR can distinguish the mutation is heterozygous or homozygous. Most patients were heterozygous for JAK2 but only a few were homozygous. In conclusion, our study showed that JAK2 V617F mutation frequency in Chinese MPN patients is similar to that in patients with this disorder in the West. It is the major molecular genetic abnormality in bcr-abl negative MPN and it can be used for diagnosis of MPN in China. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.4687.4687
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
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    Isolated central nervous system relapse in patient with blast-crisis chronic myeloid leukemia in durable complete cytogenetic remission on dasatinib treatment: pharmacokinetics and ABL mutation analysis in cerebrospinal fluid
    Informa UK Limited ; 2013
    In:  Leukemia & Lymphoma Vol. 54, No. 7 ( 2013-07-01), p. 1557-1559
    Details
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 54, No. 7 ( 2013-07-01), p. 1557-1559
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    URL: Article
    DOI: 10.3109/10428194.2012.745933
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2013
    detail.hit.zdb_id: 2030637-4
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  • 9
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    ANKL Is Strongly EBV-Related, Frequent In Chromosome Aberrations and Gene Mutations, LMP2A/LMP1-CDK6-MDM2-CD44-Positive and Might Be Sensitive To L-Asparaginase-Containing Regimen
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3012-3012
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3012-3012
    Abstract: Aggressive natural killer leukemia (ANKL), previously being classified as large granular lymphocyte (LGL) leukemia or malignant histiocytosis, is a rare subset neoplasm with high aggressive clinical course. Until now, apart from clinical feature, the frequent chromosome aberrations, somatic genes mutations, signal pathway and the optimal treatment regimen are still poor understood. Patient and Methods A retrospective analysis was performed upon review of clinical database, including additional immunohistochemistry (IHC) staining and integrated mutation analysis on reserved samples. Twelve samples of extranodal NK/T-cell lymphoma-nasal type (ENKL-NT) were used in IHC analysis for control. Results A total of 26 cases were collected during 2001 to 2013, including 17 males and 9 females, median age of 28 years old (range 4-76 years old). Most patients presented with acute-onset high swinging fever (n=26), deteriorating jaundice (n=19) and pancytopenia (n=22) at diagnosis. The organ most frequently involved organs were bone marrow (n=25), liver (n=23), spleen (n=22) and gastrointestinal (n=6). Disseminated intravascular coagulopathy (DIC) was present in 15 out of 26 patients, significantly associated with liver involvement and jaundice (p 〈 0.01). Epstein-Barr virus (EBV) viremia was present in 7 of 8 tested cases (5.12x10*,2-5.41x10*,6 copies/mL). The characteristic morphological appearance of ANKL in bone marrow smears were deep purple-red staining granules in cytoplasm and prominent vacuoles located in cytoplasm and/or nucleus. FACS demonstrated ANKL cells were CD2+cCD3+CD7+CD11b+/-CD11c+/-CD29+CD38+/-CD45+CD56+CD86+BCL-2+, CD3-TCR-cCD79a-cMPO-CD5-CD10-CD19-CD25-CD33-CD83-CD123-. Surprisingly, ANKL cells were negative for CD21, an established EBV receptor. Additional IHC on 14 reserved bone marrow samples revealed ANKL cells were strongly positive for LMP2A (n=14), LMP1 (n=11) and EBER (n=10). In ENKL-NT, LMP2A and LMP1 were moderately positive in 5 and 4 out of 12 cases, respectively. EBERs were detected in all ENKT-NT cases. Moreover, IHC analysis showed ANKL cells were strongly stained by CDK6 (n=13), MDM2 (n=14), CD44 (n=13), IFN-γ (n=14), slightly stained by CDK4 (n=2), negative for SH2 domain-containing inositol 5’-phosphatase-1 (SHIP-1), which is responsible for 2B4-mediated inhibition in NK cells. In ENKL-NT samples, CDK6 (n=11), MDM2 (n=9) and CD44 (n=8) were positive; furthermore, SHIP-1 was slightly positive in 4 samples. Chromosome aberrations were present in 7 patients, including dup1(q22q25), inv(3)(p21p25), del(3)(p13), t(3;11)(q21;q23), i(7)(q10), del(7)(q32), del(14)(q24), der(15)t(7;15)(q10;q10), -8, -12,+13,-18,+19,-22. Multiple somatic mutations were detected in 7 cases, including TET2 (D1938E, S69R, V292L, E1207D, G1391C, T1393K, Y1998X), FBXW7 (S427L,Q428K, D431E, R505C, Q508K, G517V, D775Y), CEBPA (E57D, N292K, S85I), FLT3 (M837I, E604X), KRAS (G77R, Q22H, G13D), PAX5 (P93T, A111S), PHF6 (R15S, S155X, V5F), DNMT3A (P602H, H613D), EGFR (E736X, S155X), IDH2 (K166M),SH2B3 (E190X), c-Kit (G812C), JAK1 (D775Y), NOTCH1 (A1701S). Only 1 out of 10 patients obtained partial remission after anthracycline-based or platinum-based regimens (CHOP, CHOP-Bleomycin, CDOP, EPOCH, HyperCVAD and ESHAP). Notably, two cases rapidly achieved durable complete remission after L-asparaginase-containing regimen (CHOP/PEG-L-asp and VDLP). Two patients received allogeneic hematopoietic stem cell transplantation, one maintained durable remission and another died of invasive pulmonary infection before engraftment. The median overall survival of 26 cases was only 7.5 days (range 2-330 days). Conclusions ANKL is Trojan story about EBV and NK cells, being presented with strong evidence of EBV infection/transformation, highly aggressive clinical course and prominent chromosome/genomic instability, which deserves more research efforts to dissect the role of EBV, molecular cytogenetics make-up, signaling pathway of LMP1/LMP2A-PI3K/AKT-CDK6-MDM2 and optimal regimen such as L-asp-contained protocol for this rare leukemia subset. Disclosures: Zhou: Guangzhou Pearl River of Science & Technology New Star (No. 2011J2200069 to HS.Zhou): 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
    URL: Article
    DOI: 10.1182/blood.V122.21.3012.3012
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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    Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation For Patients With Chronic Myeloid Leukemia In Chronic Phase
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 5518-5518
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5518-5518
    Abstract: Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) scene in CML has changed dramatically. This retrospective cohort study was designed to compare medical outcomes of Imatinib mesylate and allo-HSCT for patients with CML in chronic phase. Patients and Methods From February 2002 to February 2012, 198 patients treated consecutively at the Nanfang Hospital,Southern Medical University were assigned to two groups according to treatment with imatinib or allo-HSCT. One hundred fifteen cases of imatinib group were given imatinib at an initial dose of 400mg daily and the dose was then adjusted according to the patient´s blood and therapy response. All the patients were evaluated for hematologic, cytogenetic and molecular response every 1-3months. Eighty-three cases of allo-HSCT group received myeloablative preconditioning regimen, and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease(GVHD), parts combined with mycophenolate mofetil (MMF) and antihuman thymocyte globulin(ATG). The primary end points of the study were complete cytogenetic response (CCyR), relapse rate, overall survival (OS) and progression-free survival (PFS) after therapy. Results In total, 59 (68.9%) patients treated over 12 months achieved a CCyR after 12 months in imatinib group, while 67 (95.7%) patients in allo-HSCT group. The relapse rates were 14.8% (n=17) in imatinib group and 10.8% (n=9) in allo-HSCT group (P=0.456). Ten-year cumulative OS rates were 93.9% in imatinib group and 77.1% in allo-HSCT group(P=0.015) and ten- year cumulative PFS rates of two groups were 86.1% vs.88.0%(P=0.508). For Sokal rating stratified analysis, the ten-year OS rates of two groups were 96.4% vs.68.0% (P = 0.049) for high-risk patients,92.6% vs. 57.1% (P = 0.019) for intermediate-risk patients , while the ten-year PFS rates of two groups were 89.3% vs. 88.0% for high-risk patients (P = 0.942), 70.4% vs. 85.7% for intermediate-risk patients (P = 0.405).The ten-year OS rates and PFS rates were not significant difference for low-risk patients. The cumulative OS rates of two groups were 94.7% vs. 73.5%(P=0.019)for the patients who were not less than 30 years old,and the cumulative PFS rates of two groups were 84.2% vs. 94.1% respectively (P=0.147). Conclusion Imatinib mesylate treatment is superior to allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.5518.5518
    RVK:
    XA 33000
    RVK:
    XA 10000
    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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