Aven and Survivin Expression in Egyptian Acute Leukemia and Their Relation to Apoptosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4717-4717
Author(s):  
Magda Assem ◽  
Thoraya Mohamed Abdel Hamid ◽  
Gihan Abedel Basset ◽  
Amany Hilal ◽  
Mahmoud Kamel ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Dna Fragmentation ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mammalian Species ◽  
Mrna Level ◽  
Survivin Expression ◽  
Fragmentation Pattern ◽  
Group Iii ◽  
Group I

Abstract Abstract 4717 Background Several anti apoptotic signals have been recently identified. Aven and Survivin are broadly expressed and are conserved in mammalian species. Patients and Methods Sixty-four patients with acute leukemia [39 with acute myeloblastic leukemia (AML) and 25 with acute lymphoblastic leukemia (ALL)] were used as the study group. Reverse transcriptase (RT –PCR) was used, Aven and Survivin expression were detected at the messenger (mRNA) level .DNA fragmentation was carried out on daily basis before &24 hours after the therapeutic dose every day for 4 times during the initial induction of chemotherapy (everyday for ALL& every otherday for AML). Results Survivin expression was found in (66%) of acute leukemia, near significantly (p=0.06) more in AML (74%) than in ALL (52%). While, Aven expression was (40.6%) in acute leukemia equally expressed in AML (41%) and ALL (40%).Patients were categorized into 3 groups based on DNA fragmentation, whereby group I: DNA fragmentation found on day 1 or day 1+day 2, group II: DNA fragmentation found on days 1, 2 and 3, group III where fragmentation was found on days 1+2+3+4 or/and day5. Absence of Aven expression significantly (p<0.001) contributed to DNA fragmentation as 24 /35 (68.6%) of acute leukemia with Aven negative were in group III (the best group). Absence of Survivin did not contribute as much, Where 18 out of 31 (58%) of group III were Survivin positive (P= 0.1).None of the concordant both positive Survivin and Aven were in group III (the good 5 day fragmentation), this was statistically highly significant (P< 0.001) relation. Survivin was statistically related to CD7 expression (P<0.001) in AML only, while Aven was statistically related to CD34 expression (P<0.014) in the whole acute leukemia cases. Aven was statistically correlated to alkaline phosphatase (P< 0.036).There was a significant dissociation between Aven and Survivin in AML (p=0.03) and near significant dissociation in ALL (p=0.07). Conclusion Aven seems to be more important as an inhibitor of apoptosis than survivin in acute leukemia. The presence of both Aven & survivin confers a survival disadvantage & a significantly worse DNA fragmentation pattern, thus suggesting a synergistic inhibition of apoptosis when present together, although, they tend not to be expressed together. The highly significant relation between CD7 & surviving expression, might suggest their involvement in a common signal transduction pathway. Key words: Survivin, Aven, AML, ALL and DNA fragmentation. Disclosures: No relevant conflicts of interest to declare.

Application of SENP-1, HIF-1α and VEGF Gene Expressions in Prognostic Prediction for Normal Karyotypic Acute Leukemia Patients with NPM1 + and FLT3-ITD-.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4723-4723
Author(s):  
Binbin Huang ◽  
Bing Xiu ◽  
Aibin Liang
Keyword(s):  
Regression Analysis ◽  
Linear Regression ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Linear Regression Analysis ◽  
Mrna Level ◽  
Large Population ◽  
Vegf Gene ◽  
Vegf Mrna ◽  
Prognostic Prediction

Abstract Abstract 4723 In our study, 26 BM species from 23 normal karyotypic acute leukemia patients (non-APL) with NPM+ and FLT3-ITD- gene mutation were collected in our department. Compared to healthy controls, SENP1, HIF-1alpha and VEGF mRNA expression in ALL and AML patients were elevated to 10.0, 13.2, 16.6 and 43.1, 97.75, 240.0 folds, respectively, by RT-real time PCR. The levels of SENP1, HIF-1αand VEGF mRNA in AML patients were greatly higher than those in ALL (p<0.05). SENP1 and HIF-1alpha expression levels were positively and significantly correlated (linear regression analysis, r = 0.88, p<0.05) both in ALL and AML. The correlation between HIF-1alpha and VEGF mRNA level was statistically significant (linear regression analysis, r = 0.34, p<0.05). Among AML patients, SENP1, HIF-1alpha and VEGF gene expressive level in non-response (NR) patients (n=7) were higher than patients with CR (n=9), p<0.01. For ALL patients, the expressive level (‘X±S) of SENP1, HIF-1alpha, VEGF gene in NR(n=3)were slightly higher than those in CR (n=4): 10.5±2.7, 6.8±3.4; 13.2±16.6, 3.9±3.0; 13.1±10.1,11.1±12.1. Elevated gene expression of SENP1, HIF-1alpha and VEGF indicate shorter survival time of patients, p<0.01.The levels of SENP1, HIF-1alpha and VEGF gene decreased after treatment in 3 AML patients. Thus, higher SENP1, HIF-1alpha and VEGF gene levels might be associated with shortened survival and worse clinical process. Therefore, although higher expression of SENP1, HIF-1alpha and VEGF gene might throw an impact on the prognostic prediction in acute leukemia patients, confirmation of this hypothesis need to be done in more large population. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of a Novel Biomarker, Serum Soluble LR11 on Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2717-2717
Author(s):  
Chikako Ohwada ◽  
Masahiro Takeuchi ◽  
Shio Sakai ◽  
Daijiro Abe ◽  
Yusuke Takeda ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Laboratory Data ◽  
Type I ◽  
Prognostic Impact ◽  
Soluble Lr11

Abstract Abstract 2717 Introduction: LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding. LR11 plays a key role in the migration of undifferentiated vascular smooth muscle cells, and circulating sLR11 is known to be a biomarker of carotid intima-media thickness. Along with the fact that circulating sLR11 levels represent the accumulation of vascular immature cells, human CD34+CD38− immature hematopoietic precursors have been reported to express high levels of LR11 mRNA. We have recently found that LR11 is specifically and highly expressed on cell surface of acute leukemia cells in addition to normal leukocytes (unpublished data). These facts prompted us to evaluate the serum sLR11 level in patients with acute leukemia and other hematological malignancies to validate sLR11 as a novel circulating marker for treatment outcome and prognosis. Patients and Methods: Serum sLR11 levels were measured by ELISA method in 139 patients with acute leukemia and other hematological malignancies treated at a single institution from 1999 to 2010. Patients' laboratory data and treatment outcome were collected retrospectively in 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Results: sLR11 levels of acute leukemia patients were significantly increased [ALL, 73.5±93.5 ng mld−1 (range, 5.7–407.0), P<0.0001; AML, 26.8±29.1 ng ml−1 (range, 5.0–157.5), P<0.0001] in comparison to the control subjects (9.2±3.3 ng ml−1), while sLR11 levels in patients with chronic myeloid leukemia (17.9±11.1 ng ml−1), chronic lymphocytic leukemia (12.7±11.6 ng ml−1), multiple myeloma (10.5±4.8 ng ml−1), and POEMS syndrome (9.0±2.7 ng ml−1) were not significantly different from controls. sLR11 levels were significantly higher in ALL than those in other leukemias. Paired sample analysis of patients with AML and ALL at complete remission (CR) after chemotherapy showed significantly decreased sLR11 levels compared to the time of diagnosis (AML: 30.9±37.5 ng ml−1 vs. 10.4±4.3 ng ml−1, P=0.015, ALL: 39.1±126.0 ng ml−1 vs. 11.2±5.0 ng ml−1, P=0.0029). The multiple stepwise liner regression analysis showed that the peripheral blast proportion in both ALL and AML patients were independently associated with sLR11 at diagnosis (AML: r2= 0.21, P=0.0026, ALL: r2= 0.34, P=0.0043). Among 42 AML patients, sLR11 levels of subjects in the highest tertile of peripheral blast proportion (>67.5% of WBC) were 2.44- and 3.05-fold higher than those in the middle (23.0-64.0% of WBC) and lowest tertiles (<20.0% of WBC), respectively. Twenty out of 21 AML patients with <20 ng ml−1 sLR11 at diagnosis achieved CR after induction chemotherapy, and the CR rate was significantly higher in patients with <20 ng ml−1 sLR11 than in patients with ≥20 ng ml−1 (95.2% vs 65.5%, P=0.02). The probability of overall 5-year survival was significantly lower in AML patients with ≥20 ng ml−1 sLR11 at diagnosis than in those with <20 ng ml−1 [Figure1, 36.8% vs 63.7%, P = 0.04; hazard ratio (HR): 2.74; 95% confidence interval (CI): 1.04–8.01]. Conclusions: Serum sLR11 levels in patients with acute leukemia were significantly elevated and were associated with the peripheral blast population but not in other chronic proliferative hematological malignancies. These findings suggest that the serum sLR11 levels are predictive for pathogenic properties of immature blasts, including their migration and attachment activities, rather than simply associating with proliferating cell numbers. Especially in AML patients, serum sLR11 levels at diagnosis significantly affect CR rate and OS. Although larger scale studies including karyotype or FAB classification would be required for its patho-clinical significance, serum sLR11 is a promising novel biomarker for acute leukemia and it could play an important role as prognostic factor. Disclosures: No relevant conflicts of interest to declare.

SALL4 Is a Key Survival Factor in Acute B-Cell Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2428-2428
Author(s):  
Shikiko Ueno ◽  
Jiayun Lu ◽  
He Jie ◽  
Ailing Li ◽  
XiaoXian Zhang ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Down Regulation ◽  
Immunodeficient Mice ◽  
Donor Cells ◽  
Reh Cells ◽  
And Control

Abstract Abstract 2428 SALL4 is a zinc-finger transcriptional factor and a member of the SALL gene family. It plays an essential role in the maintenance of ESC pluripotent and self-renewal properties by interacting with other two key regulators in ESCs, Nanog and Oct4. We previously have shown that stem cell factor SALL4 is aberrantly expressed in 75% of acute B-cell lymphoblastic leukemia (B-ALL). We have also shown that SALL4 is aberrantly expressed in AML, and down-regulation of SALL4 in AML leads to significant cell death. In this study, we focused on investigating the functional role of SALL4 in human B-ALL leukemogenesis. We first assessed the SALL4 mRNA level in four B-ALL cell lines (REH, Nalm6, 697, Blin-1) and five primary patient samples by qRT-PCR. We observed SALL4 mRNA in these four cell lines increased when compared to normal human CD34 negative BM cells. Moreover 4 of 5 primary samples showed high level expression of SALL4, suggesting that SALL4 might play a role in B-ALL pathogenesis. Then, we selected a SALL4 expressing B-ALL cell line (REH and Nalm6) and attenuated SALL4 expression through GFP-labeled shRNA approach in these cell lines. We monitored the growth of SALL4 knockdown and control REH and Nalm6 cells through MTS assay. SALL4 knockdown cells had a decreased growth rate compared to that of the control cells. We also stained SALL4 knockdown and control cells with Annexin V and 7-AAD by flow cytometric quantitation of apoptotic cells. The percentages of apopotic cells in SALL4 knockdown cells were much higher than these in controls. These data demonstrated that inhibition of SALL4 in REH cells and Nalm6 cells led to reduced proliferation and increased apoptosis. We then examined the oncogenesis ability of SALL4 knockdown REH cells in a mouse xenotransplantation model. SALL4 knockdown or control REH cells were injected intravenously into immunodeficient mice. All the recipients succumbed to fatal leukemia within 4 to 6 weeks post transplantation. In both BM and spleen of SALL4 knockdown recipients the engrafted proportion of GFP+ cells was significantly decreased compared to the initial donor cells. Whereas, in both BM and spleen control recipients the percentage of GFP+ REH cells engrafted was similar to that of initial donor cells. This suggests that down-regulation of SALL4 is essential for B-ALL engraftment. To rule out the observed engraftment defect was due to homing, we next performed homing assay. SALL4 knockdown or control cells were injected intravenously into immunodeficient mice as well. Three hours of the injection, mice were sacrificed and analyzed the percentage of GFP+ cells in BM and spleen by flow cytometry. There was no difference among SALL4 knockdown and the control. Furthermore, we performed gene expression profiling on apoptosis-related genes in SALL4 knockdown and control REH cells. The result showed that in SALL4-knockdown REH, TNF mediated cell apoptosis pathways was up-regulated as well as multiple caspase members. The expression of Caspase 3, Caspase 8, FADD was up-regulated in both SALL4 knockdown REH and Nalm6 when compared to these controls, and was verified by real time RT-PCR. This suggests that SALL4 could repress apoptosis through the TNF signal pathway. In summary, we report a novel SALL4/TNF pathway in maintaining cell survival in B-ALL. Disclosures: No relevant conflicts of interest to declare.

Genetic and Clinical Characterization of 45 Acute Leukemia Patients with MLL Gene Rearrangements From a Single Institution.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2477-2477
Author(s):  
Nuno Cerveira ◽  
Susana Lisboa ◽  
Cecília Correia ◽  
Susana Bizarro ◽  
Joana Santos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Consecutive Series ◽  
Gene Rearrangements ◽  
Fusion Partner ◽  
Older Children ◽  
Single Institution ◽  
Mll Gene

Abstract Abstract 2477 Background: MLL gene rearrangements are found in more than 70% of the cases of infant leukemia, both acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), but are less frequent in leukemia from older children. MLL translocations are also found in approximately 10% of adult AML and in a small proportion of patients with therapy-related leukemia. Independently of their association with other high-risk features at presentation, MLL rearrangements are in most cases predictive of poor clinical outcome. In this study, we report the clinical characterization and frequency and type of MLL rearrangements present in a consecutive series of 45 patients that were diagnosed with acute leukemia in the Portuguese Oncology Institute, Porto, Portugal, over the last 13 years (1998–2011). Patients and Methods: Conventional cytogenetic, fluorescence in situ hybridization (FISH), and molecular genetic studies (RT-PCR and LDI-PCR) were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. Additionally, a detailed patient clinical characterization was also performed and statistical analysis using the Kaplan-Meier method as used to evaluate patient survival. Results: In 43 patients (96% of the cases) we could identify the fusion partner, the most common being the MLLT3, AFF1, MLLT1, MLLT10, ELL, and MLLT4 genes, accounting for 88% of all cases. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloblastic leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype and treatment protocol. However, patients that received a bone marrow transplant had a better survival than patients that received chemotherapy alone. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. Conclusions: The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant. Disclosures: No relevant conflicts of interest to declare.

MLL genomic DNA Breakpoints In Infant Acute Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1350-1350
Author(s):  
Grigory Tsaur ◽  
Claus Meyer ◽  
Alexander Popov ◽  
Olga Plekhanova ◽  
Anatoly Kustanovich ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Genomic Dna ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Chromosome 11 ◽  
Long Distance ◽  
Mll Gene ◽  
Stable Pattern ◽  
Breakpoint Location

Abstract Background Infant acute leukemia is characterized by high incidence of MLL gene rearrangements. Purpose To evaluate the distribution of MLL genomic DNA breakpoints and their relation to several diagnostic parameters among infant acute leukemia. Methods 72 infants with MLL-rearranged acute lymphoblastic leukemia (ALL) (n=52), acute myeloid leukemia (AML) (n=19) and mixed phenotype acute leukemia (n=1) were included in this study based on the availability of DNA material at diagnosis. In the observed group there were 28 boys (39%) and 44 girls (61%) with median age of 4.9 mo (range 0.03-11.9). Genomic DNA breakpoint detection in MLL gene and translocation partner genes (TPG) was performed by long-distance inverse PCR (LDI-PCR). Exon-intron numbering of MLL gene was done according to I. Nilson et al, 1996. Results Majority of ALL cases (n=28; 54%) was characterized by presence of MLL-AF4 fusion gene (FG), less frequently MLL-MLLT1 (n=12; 23%), MLL-MLLT3 (n=7; 13%) and others were found (Table 1). The most common breakpoint location within MLL gene in ALL patients was intron 11, detected in 25 cases (48%). The highest variability of MLL breakpoints was found in MLL-AF4-positive patients: only 11 of 28 (39%) had breakpoints in intron 11. The most stable pattern of MLL genomic DNA breakpoints was observed in MLL-MLLT1-positive patients: 8 of 12 (67%) had breakpoints in intron 11. In AML patients two the most prevalent FGs were MLL-MLLT3 (n=7, 37%) and MLL-MLLT10 (n=5, 26%). The remaining ones are listed in Table 1. The most frequent breakpoints location was intron 8 (8 out of 19, 42%). The most stable pattern was revealed for MLL-MLLT10 FG: MLL breakpoints in 4 of 5 (80%) cases were found in intron 9 (Table 1). ALL patients who had breakpoints in intron 11 were significantly younger (median 3.0 mo, range 0.03-11.6) than all others (median 5.6 mo, range 0.7-11.9) (p=0.025) and than patients with MLL breakpoints in intron 9 (median 6.6 mo, range 3.1-11.9) (p=0.017). For AML cases we did not find any relation between age and breakpoints locations. Distribution of MLL DNA breakpoints was similar in boys and girls and did not depend on type of TPG. Genetic recombinations involving MLL gene predominantly resulted in reciprocal chromosomal translocations (n=62; 86%). Beside them, 6 (11%) insertions were identified in all MLL-MLLT10-positive cases and MLL-SEPT6-positive one. In 11 (15%) patients we found breakpoints within the regions located from 0.7 Kb to 25.4 Kb 3' of the first exon of TPGs (MLLT1 n=9; EPS15 n=1; MYO1F n=1), however fusion transcripts at cDNA level were identified and sequenced in all these cases, indicating a spliced fusion mechanism. 3-way translocations were found in 5 patients and in 1 case we found combination of insertion with interstitial deletion of chromosome 11. The list of reciprocal genes involved in these 6 cases was as follows: CEP164, DNAH6, DCPA1, MCL1 as well as non-coding regions of 2q21.2 and 2p21. We also analyzed breakpoints in TPGs. Except above mentioned spliced fusion cases, the remaining 3 breakpoints in MLLT1 as well as 3 of 4 breakpoints in EPS15 and all breakpoints in MLLT11 were within intron 1 of corresponding genes. In AF4 the major breakpoint region included intron 3 (n=19), intron 4 (n=6) and intron 5 (n=2). We also revealed 2 rare breakpoints in intron 6 and 10. In MLLT3 the most frequent breakpoint location was intron 5 (n=12), additionally 2 cases in intron 5 were identified. In MLLT10 two separate breakpoint locations were found: intron 3 (n=1) and intron 8 (n=3) in combination with intron 9 (n=1). We estimated prognostic significance of MLL breakpoint locations in 31 cases of infant ALL treated by MLL-Baby protocol. 3-year cumulative incidence of relapse was remarkably higher in patients with breakpoints in intron 11 (n=18) in comparison to patients with breakpoint localized from intron 7 to exon 11, inclusively (n=13) (0.85±0.01 and 0.57±0.02, respectively), although difference between these two groups did not achieve statistical significance (p=0.261). Median follow-up time in the observed group was 30 months (range 6–42). Conclusion In the current study we estimated clinical and prognostic significance of MLL and TPG genomic DNA breakpoints in infant acute leukemia. Our data provide additional information of molecular genetic features of MLL-rearranged infant acute leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Silencing HDAC3 Enhances Apoptosis of Acute B Lymphoblastic Leukemia Cells smurf2 Inducing By Inhibiting JAK/STAT3 Signal Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5128-5128
Author(s):  
Yongling Guo ◽  
Dan Ma ◽  
Zhengchang He ◽  
Jie Xiong ◽  
Xingyi Kuang ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Therapeutic Targets ◽  
Signal Pathway ◽  
Lymphocytic Leukemia ◽  
Clinical Prognosis ◽  
Stat3 Pathway ◽  
Healthy Donors

Abstract Purpose Smad ubiquitin regulatory factor 2(Smurf2) as a member of ubiquitinated E3 ligase was certificated to regulate the ubiquitination level of target gene. In this study, smurf2 as tumor suppressor was studied in acute B lymphoblastic leukemia, Histone deacetylases 3(HDAC3) which was connected with smurf2 was related with poor prognosis. It is further proved that smurf2 and HDAC3 were expected to be therapeutic targets for B-ALL cells and improve the prognosis of patients with B-ALL. Methods Realtime-PCR and westernblot were used to detect the expression of smurf2 and HDAC3 in healthy donors and B-ALL patients by us. Sup-B15 and CCRF-SB were treated with MG-132, small interfering RNA of smurf2 or HDAC3. Up-regulating smurf2 plasmid was also transfected to B-ALL cells by lipo3000. Flow cytometry and westernblot were used to validate the difference of apoptosis and cell cycle. Results Smurf2 mRNA in B-ALL patients was significantly lower than that in healthy donors. HDAC3 was higher in B-ALL patients than that in healthy donors. Protein level of smurf2 and HDAC3 was consistent with mRNA level. Up-regulating smurf2 by plasmid or MG-132 and silencing smurf2 could influence HDAC3, which further depressed JAK/STAT3 signal pathway inducing apoptosis of B-ALL cells. Sup-B15 and CCRF-SB were treated with siHDAC3 and MG-132 for 24h, we discovered that silencing HDAC3 enhanced the apoptosis level of B-ALL cells MG-132 inducing by depressing JAK/STAT3 pathway. It was expected to become a therapeutic target for improving the clinical prognosis of B-ALL patients. On the other hand, we found that MG-132 caused G2/M phase arrest in B-ALL cells and successfully inhibited the JAK/STAT3 pathway leading to apoptosis. Conclusions Silencing HDAC3 inhibited the JAK/STAT3 pathway and further enhanced apoptosis in B-ALL cells MG-132 inducing. HDAC3 and smurf2 were expected to become therapeutic targets for clinical treatment of acute B lymphocytic leukemia and improve survival rate of leukemia patients. Key words Smurf2; HDAC3; Apoptosis; Prognosis; Disclosures No relevant conflicts of interest to declare.

scholarly journals Low Prevalence of T-Cell Lymphoblastic Leukemia/Lymphoma in an Adult Hispanic Population: A Report of the Acute Leukemia Working Group (GTLA)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Luis Felipe Rubalcava-Lara ◽  
Emmanuel Almanza Huante ◽  
Roberta Demichelis ◽  
Juan Rangel-Patiño ◽  
Andres Gomez-De Leon ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Rank Test ◽  
Induction Treatment ◽  
P Value ◽  
Cell Transplant ◽  
Hispanic Population

Introduction: The proportion of Acute lymphoblastic T cell leukemia/lymphoma (T-ALL/LBL) in Latinamerica (LA) is about 13% [Quiroz, 2018], compared with 25% of other publications [Litzow,2015]. In the largest leukemia series of adult Mexican population, the incidence of T-ALL was merely 2.9% with a -SG. The main objective of this study was to describe the epidemiological characteristic and survival of T-ALL in 4 reference oncology centers in Mexico. Methods: Retrospective cohort study from 2014 to 2019 in all consecutive, newly diagnosed T-ALL patients defined by flow cytometry (FC). The primary end point was to assess the survival of T-ALL in a Hispanic population. Baseline characteristics were grouped in tables and summarized as medians and ranges. Sub-groups were compared using chi-square test for binary variables and Mann-Whitney U test for quantitative variables. The Overall Survival (OS) analysis was made using Kaplan-Meier curves and comparison between groups was performed using the log-rank test with a significant P value less than 0.05 with 95% confidence interval. Results: A total of 47 patients were identified, which represent 11.1% of all acute leukemia the median of age was 30 years. The 83.7% being identified in the adolescent young-adult (AYA) group. Counterintuitively a 44.9% had a previous comorbidity (diabetes, hypertension, dyslipidemia) considering the range of age. The 85% had a low risk of mortality using the modified Charlson index, the median count of leukocytes was 36 x 109 (range 6.78-117) and 28% presented with initial hyperleukocytosis, the median LDH was 605 UI/l (range 343-1451). Applying the European Group for the Immunological Classification of Leukemias criteria: 28% were cortical T, 41.7% were mature and approximately 30% were be classified as early. Applying the early T-P (ETP) definition a total of 10 cases were identified (22.2% prevalence). The use of hyperCVAD and pediatric inspired regimens shared the same rate (41.3%), strikingly there is still a 17.4% of patients that received other type of chemotherapy for diverse reasons (economic, shortage of treatment, patient or physician preference) being the CHOP-inspired schemes the most used. The rate of complete response (CR) at 4 weeks after induction was 68.2% with 54.2% having a negative minimal residual disease (MRD). After 8 weeks a total of 34 (77.3%) patients achieved CR, with 63.6% and 66.7 % maintaining negative MRD at 16 weeks and after consolidations, respectively. Only 38.3% were able to complete the full induction treatment without a dose adjustment due to toxicity. A total of 8 (19.5%) were refractory to initial frontline treatment and eventually 23 (60.5%) relapsed, with a total of 10 patients presenting with CNS infiltration at relapse. A total of 6 patients received an allogenic stem cell transplant (ASCT), with 4 of them being alive and in CR at the 100 days cutoff. The median OS was 16 months (CI 95% 11.4-21.09) and 38.8% of our population was alive at the 24 months cutoff. This time period was drastically reduced for the non-AYA population who had a OS of 7.69 months (CI 95% 0-21.24) and 21.9% a 24 months progression free survival (PFS), compared with 16.6 months (CI 7.41-25.81) and 41.6% 24 months PFS. In the univariate analysis refractoriness to induction (p 0.039) and higher number of cycles (p 0.02) were associated with worse outcome. Conclusions: The T-ALL predominantly affects AYA populations while its incidence in our country appears to be lower even in large oncologic concentration centers. The proportion of ETP was slightly higher than that reported in other studies. Lower CR rates with a low frequency of ASCT in comparison to those reported in high income countries was observed, probably associated with the delay in implementation of pediatric-inspired regimens and lack of access to ASCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Correlation of Sperm DNA Fragmentation Index With Seminal Plasma Biochemical Index and Semen Parameters in Infertile Men

2020 ◽  
Author(s):  
Kang-Sheng Liu ◽  
Xiao-Dong Mao ◽  
Feng Pan ◽  
Xinyuan Yang
Keyword(s):  
Survival Rate ◽  
Dna Fragmentation ◽  
Semen Quality ◽  
Semen Analysis ◽  
Sperm Concentration ◽  
Group Iii ◽  
Group I ◽  
Sperm Dna ◽  
Semen Volume ◽  
Sperm Survival

Abstract BackgroundAccording to world Health Organization guidelines, semen analysis by testing routine parameters is the main method for assessing male fertility.In general, routine semen analysis makes only limited predictions about a man's reproductive potential and is not always able to explain why he is infertile. In fact, many male infertility cases are caused by sperm DNA defects ,which routine semen quality analyses fail to detect.The relationship between sperm DFI , sperm parameters and their diagnostic value were analyzed and evaluated by observing the seminal parameters of infertile patients without accessory gonadal infection.MethodsSpecimens of 151 cases were collected from infertile patients who visited the male department of STD and reproductive specialty clinic of our hospital from August 2018 to September 2019. SCD test was performed to measure the DNA fragmentation in native. The routine semen analysis was performed with a semen quality detection system (WLJY-9000, Beijing Weili New century Science & Tech Dev .Co.Ltd) and supporting reagents. Seminal plasma malondialdehyde (MDA), and total antioxidant capacity (TAC) were assessed. Fructose(Fru) 、a-glucosidase (,a-glu), and zinc (Zn) levels are quantitatively detected by kehua-310, a fully automated biochemical tester provided by Nanjing Xindibio.ResultsAccording to DFI level, there were 31 cases in group I (DFI≤15%), 81 cases in group II (15% < DFI < 30%), and 39 cases in group III (DFI≥30%). Compared with group II, there were significant differences in sperm survival rate, PR% and Fru by non-parametric test (Z = -2.16 -2. 43. - 2. 20,respectively,P < 0. 05). There were significant differences in sperm survival rate and PR% between group I and group III (t = 4. 32, 4.25, respectively, P< 0.01). Compared with group III, there were significant differences in sperm survival rate and PR% by non-parametric test (Z= -3. 26, -3. 50, respectively).Sperm DFI was negatively correlated with sperm survival rate and PR%(R=-0.56,-0.46,P<0.01). DFI was positively correlated with MDA content (R=0.42, P<0.01) and negatively correlated with TAC (r=-0.40, P<0.01).There was no correlation with age ,abstinence days, semen volume, sperm concentration, percentage of normal form sperm, Fru, a-Glu, Zn (R= 0. 15, 0. 05,0.03,-0.03, -0.2, -0.16,- 0.20, 0.03, 0.15, p > 0.05).ConclusionThe survival rate and PR% of sperm decreased significantly with the increase of DFI level, antioxidant can decrease the rate of DNA fragmentation, antioxidant can decrease the rate of DNA fragmentation. Semen volume and sperm concentration were mainly related to the secretion volume of accessory gonads and total sperm count, but no correlation was found between them and DFI.

scholarly journals Targeting Nucleolin for Reversal of Chemotherapy Resistance in Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5058-5058
Author(s):  
Jianda Hu ◽  
Yanxin Chen ◽  
Zhengjun Wu ◽  
Lingyan Wang ◽  
Jingjing Wen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Drug Sensitivity ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Chemotherapy Resistance

Chemotherapy resistance is considered to be the principal cause of ineffective treatment in acute lymphoblastic leukemia (ALL). Nucleolin (NCL) is high expression andplays oncogenic roles in most cancers. However, less research on the role of NCL in hematologic malignancies was noted. Our previous studies have showed that overexpression of NCL was associated with worse prognosis in the patients with acute leukemia and NCL expressionwashigher in resistant HL-60/ADR than in sensitive HL-60 cells. The potential mechanisms of NCL in chemotherapy resistance have yet to be revealed. Here we presented that expression of NCL was associated positively with chemotherapy resistance and poor prognosis in ALL. Overexpressed NCL at both mRNA and protein level was relevant to a poorer overall survival (OS) and relapse free survival (RFS), indicating NCL as an independent prognostic marker in ALL. mRNA level of NCL in de novo ALL was quantitatively higher than in complete remission(CR) status, and refractory/relapse ALL had the highest level. Upon above clinical data, we further investigated the mechanism(s) by which NCL regulated drug resistance in ALL cells. Remarkably, NCL expression was higher in resistant ALL cells relative to sensitive parental cells. When treated with ADM, NCL level was decreased in sensitive parental cells while unchanged in resistant cells. Overexpressing NCL suppressed drug sensitivity, altered drug effluxion and decreased intracellular drug accumulation, while inhibition of NCL led to a completely reversed appearance, more intracellular Adriamycin(ADM) mean fluorescence intensity (MFI) and percentage of ADM accumulated cells population. Overexpression of NCL increased significantly the IC50 of ADM. The IC50 of ADM on Jurkat-NCL-overexpression(OE), Jurkat-NCL-knockdown(KD), Molt-4-NCL-OE, Molt-4-NCL-KD, Nalm-6-NCL-OE, Nalm-6-NCL-KD were 1.362±0.271μg/ml, 0.077±0.010μg/ml, 4.863±0.733μg/ml, 0.081±0.018μg/ml, 0.237±0.042μg/ml and 0.046±0.002μg/ml, respectively (P <0.05). Involvement of ATP-binding cassette (ABC) transporters was proved in NCL mediated drug resistance. Silencing NCL resulted in a decrease of P-gp, MRP1, LRP and BCRP in ALL cells, and NCL overexpression increased the MRP1, LRP and BCRP. The Akt/mTOR and ERK signaling pathways were involved in this procedure. Notably, co-IP assays confirmed the NCL-Ras, NCL-ERK and NCL-BCRP interaction. For intervention study, aptamer AS1411, a NCL inhibitor, could reduce drug resistance in ALL cell lines and primary ALL cells.Moreover, AS1411 treatment decreased BCRP protein expression. Furthermore, the ALL leukemia models that nude mice engrafted with Nalm-6 cells and NCG mice engrafted with Luc+ Nalm-6 cells were established, then treated with ADM plus AS1411 or control CRO for comparison drug sensitivity and survival. Growth of subcutaneous xenograft tumors was inhibited in those treated with AS1411 or ADM, compared to their respective controls treated with CRO or PBS. The stronger inhibition effect was observed in those treated with AS1411 combined with ADM. For Luc+Nalm-6 derived ALL model, leukemia progression was suppressed in mice treated with AS1411 and AS1411 combined with ADM. AS1411and ADM, especially combination of AS1411 and ADM, could improve survival of the leukemic mice compared to those treated with PBS. The results showed that NCL targeted by AS1411 sensitized ADM treatment and prolonged survival in vivo. In summary, our findings revealed NCL as a survival predictor and the novel role of NCL in ALL chemo-resistance. NCL may be a potential target for improving outcome in ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Early Deaths in Pediatric Acute Leukemia; A Challenge in Developing Countries

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5160-5160
Author(s):  
Hanafy Ahmed Hafez ◽  
Rawaa Solaiman ◽  
Dalia Bilal ◽  
Lobna m Shalaby
Keyword(s):  
Developing Countries ◽  
Acute Leukemia ◽  
Supportive Care ◽  
Death Rate ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Early Death ◽  
Response To Therapy ◽  
P Value

Abstract Background and objectives: The survival rates of children with acute leukemia is consistently improving, due to the lower relapse rates in addition to reducing treatment-related mortality, which is mainly a result of infectious causes. The aim of the study is to describe the incidence and risk factors associated with early deaths (first 42 days in treatment) among children with acute leukemia. Methods: This is a retrospective study included newly diagnosed patients with acute leukemia who presented to the National Cancer Institute, Cairo University between Jan. 2011 to Dec. 2013. Patients' data were collected from their files and analyzed for the total and early death rates and proposed causes of death. Results: The study included 370 patients, 253 with acute lymphoblastic leukemia (ALL), 100 with acute myeloid leukemia (AML) and 17 with mixed phenotypic acute leukemia (MPAL). The total death rate among the whole group was 40.5% (n=150) and induction death rate was 19.2% (n=71). AML was accompanied with higher rates of total and induction deaths as they were 58% and 25% respectively, compared to 33.6% and 17.4% in ALL. These early deaths were attributed mostly to infection 64.7% (n=46) and cerebrovascular accidents 18.3% (n=13). Early deaths were significantly higher in patients with age below 2 years old (p. value=0.008), and in those with poor response to therapy (p. value= 0.001). Using enhanced supportive care measures as better infection control, appropriate antibiotic guidelines and available intensive care unit during 2013 had significantly reduced the overall and induction mortality rates (27.8% and 13.8% respectively in 2013 versus 45% and 20.3% in 2011 and 49% and 25% in 2012). Conclusion: Induction deaths in pediatric acute leukemia remain a major challenge in developing countries and constitute an increasing fraction of all deaths. Accordingly, using a well equipped cancer centers with better supportive care guidelines is essential to further improve the survival in these group of patients. Key words: Acute Leukemia- Pediatrics- Early Death- Infection Disclosures No relevant conflicts of interest to declare.

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