scholarly journals High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Li ◽  
Zheng Ge

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

2019 ◽  
Vol 20 (9) ◽  
pp. 2625-2631
Author(s):  
Mortaza Raeisi ◽  
Ali Reza Nikhanfar ◽  
Babak Nejate ◽  
Ali Akabr Movassaghpour Akbari ◽  
Roya Dolatkhah ◽  
...  

2019 ◽  
Vol 10 (1) ◽  
pp. 178-185 ◽  
Author(s):  
Ning Hu ◽  
Zhiheng Cheng ◽  
Yifan Pang ◽  
Hongmian Zhao ◽  
Li Chen ◽  
...  

2012 ◽  
Vol 209 (10) ◽  
pp. 1883-1899 ◽  
Author(s):  
Alexandre P.A. Theocharides ◽  
Liqing Jin ◽  
Po-Yan Cheng ◽  
Tatiana K. Prasolava ◽  
Andrei V. Malko ◽  
...  

Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPα signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPα-Fc fusion protein to disrupt SIRPα–CD47 engagement. Treatment with SIRPα-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPα-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.


2017 ◽  
Vol 7 (1) ◽  
Author(s):  
A. F. O. Costa ◽  
D. L. Menezes ◽  
L. H. S. Pinheiro ◽  
A. F. Sandes ◽  
M. A. P. Nunes ◽  
...  

Aging ◽  
2021 ◽  
Author(s):  
Kongfei Li ◽  
Lieguang Chen ◽  
Hua Zhang ◽  
Lu Wang ◽  
Keya Sha ◽  
...  

2020 ◽  
Vol 10 ◽  
Author(s):  
Cong Lu ◽  
Jiang Zhu ◽  
Xiangjun Chen ◽  
Yanjie Hu ◽  
Wei Xie ◽  
...  

The role of CXC chemokine receptors in tumors has been an increasingly researched focus in recent years. However, significant prognostic values of CXCR members in acute myeloid leukemia are yet to be explored profoundly. In this study, we firstly made an analysis of the relationship of CXCR family members and AML using samples from TCGA. Our results suggested that transcriptional expressions of CXCRs serve an important role in AML. CXCR transcript expressions, except CXCR1 expression, were significantly increased in AML. It displayed the expression pattern of CXCR members in different AML subtypes according to FAB classification. The correlations of CXCR transcript expression with different genotypes and karyotypes were also present. High CXCR2 expression was found to have a significantly worse prognosis compared with that of low CXCR2 expression, and CXCR2 was also found to be an independent prognostic factor. We also established a CXCR signature to identify high-risk subgroups of patients with AML. It was an independent prognostic factor and could become a powerful method to predict the survival rate of patients.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2994-2994
Author(s):  
Valeria Biggio ◽  
Selim Corm ◽  
Hugues Leroy ◽  
Stephane De Botton ◽  
Christophe Roumier ◽  
...  

Abstract Cytogenetics remain the most powerful prognostic factor in acute myeloid leukemia (AML). However, 50–60 % of those patients (pts) are included in intermediate or unknown karyotypic risk groups. Molecular markers might improve risk classification and recently, 2 groups have reported that the expression of BAALC and EVI1 might be associated with a poor outcome, especially in pts with normal karyotype (Blood.2003;102:1613; Blood2003;101:837). Thus, we retrospectively analyzed the prognostic significance of the expressions level of these genes, by real time quantitative PCR (RQ-PCR) in AML. Patients and methods: 189 adult pts were analyzed: median age was 49 years (range, 19-65), median WBC counts 19 Giga/L (range, 0-602). FAB classification was: M0=22, M1=41,M2=44,M4=37,M5=26,M6=7,M7=1 and unclassified =11. Karyotype was prognostically favorable (n=28), intermediate (n=115, including 80 normal), unfavorable (n=39) and unknown (n=7). All pts received anthracycline-AraC chemotherapy according to French ALFA group multicenter trials (Castaigne et al, Blood 2004; May 13, Epub ahead of print). Complete remission rate was 83 %, median overall survival: 22 months, range 0.1 to 123. RQ-PCR was performed according to the 2 previous paper recommendations. However the housekeeping gene used in this work was TBP (TF2D). Results were expressed using ΔCt method. High levels of EVI1 were defined by ΔCt lower than 11. BAALC (+) pts and (−) pts were defined by ΔCt value lower or higher than 2.45 (ie the median ΔCt for BAALC expression). Results: 24/189 (13%) pts had high expression of EVI1. By comparison to pts without high EVI1 expression, pretreatment variables other than karyotype (including age, WBC counts, FAB classification) were similar in pts with high EVI1 expression. Patients with high EVI1 expression had significantly worse karyotype: none had favorable karyotype, only 4 (17%) had 3q26 abnormalities ((associated with other adverse abnormalities in 3 cases (i.e. -7/7q-)), 3 had 11q23 abnormalities and 9/24 (37.5%) pts normal karyotype. No significant diferencies between pts with high and low EVI1 expression was found for CR rates and DFS, but high EVI1 expression was associated with poorer overall survival ( median:11.7 months versus 26.9 months; p=0.0372). No pretreatment parameters, including karyotype, differed between BAALC (+) (ie pts with BAALC expression lower than the ΔCt median value) and BAALC (−) pts (ie pts with expression greater than the ΔCt median value). Overall CR rate, DFS, OS were similar in BAALC (+) and BAALC (−) pts. However, in the intermediate cytogenetic subgroup (n=115 pts), BAALC (+) pts had lower median DFS (9.7 months versus 19.8 months; p=0.0316) and EFS (4.1 months versus 11.8 months; p=0.0027) than BAALC (−) pts and a trend for poorer OS:16 months versus 27 months (p=0.07). In conclusion: In adult AML patients, high expression of EVI and BAALC are associated with poorer outcome. Determination at diagnosis of the level of those two genes could be helpful for treatment adjustment, especially in the intermediate cytogenetic subgroup. Correlation between EVI1 and BAALC results and those of other molecular markers (CEBPA, RAS, FLT3) mutations will be presented.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4191-4191
Author(s):  
Kathleen Wren Phelan ◽  
Sucha Nand ◽  
Laura C Michaelis

Abstract Abstract 4191 Background: Performance status is traditionally used to judge fitness in cancer patients. It is often a key factor in determining appropriateness for chemotherapy and entry into clinical trials. Most research on PS has been in solid tumor patients, but it is generally assumed to be valid in hematologic malignancies as well. However, PS assessment can be problematic, especially in patients who have become ill quickly or where there are conflicting parameters; e.g. patients whose function is limited but who are still actively working. We explored the role of PS in patients with AML to determine if alternative, more objectively determined parameters, could predict PS. We evaluated the relationship between PS and rates of complete remission (CR) and duration of overall survival (OS) as well as the relationship between objectively determined pretreatment parameters and these outcomes. Methods: Approval for retrospective data collection was obtained by the institutional IRB. A randomly selected cohort of 145 patients with newly diagnosed AML was identified using pharmacy records of treatment with induction agents cytarabine, daunorubicin or azacitidine. We excluded patients with acute promyelocytic leukemia. Pretreatment data was collected from the electronic medical record of each subject, including AML subtype, age, gender, PS, presence of infection at diagnosis, peripheral blood white blood cell count, peripheral blood blast percentage, hemoglobin, lactate dehydrogenase, aspartate transaminase, alanine transaminase, creatinine, albumin, left ventricular ejection fraction (LVEF), bone marrow cellularity, bone marrow blast percentage and cytogenetics. Achievement of complete remission was assessed and overall survival was calculated in months from diagnosis to either death or date of censorship. PS was obtained from physician notes and documented as a Zubrod score. In the absence of documentation, the authors reviewed medical records for presenting symptoms, mobility and functional status and made an assignment. Retrospective assignment of PS was reviewed and confirmed by at least two of the authors. Logistic regression was performed to examine the relationship between pretreatment characteristics and CR, and the effect of pretreatment characteristics and the assignment of PS, dichotomized as good (0–1) vs. poor (2–4). Linear regression analysis was used to investigate the relationship between pretreatment characteristics and OS. Results: A total of 120/145 (83%) were assigned a PS of 0, 1. Twenty patients were considered to have a PS of 2 and five patients had a PS of 3. There was a statistically significant relationship between a good PS assignment and a higher albumin level (OR 5.32, p=0.000, 95% CI 2.32, 12.22). There was no significant relationship between the remaining clinical parameters and PS assignment, including age at diagnosis. Ninety-three patients (64%) achieved a CR. There was no relationship between PS, assigned either contemporarily or retrospectively, with the achievement of CR. The median overall survival was 15 months (range 0 to 92 months). PS did not predict the duration of OS. As is well reported, CR was significantly more likely in younger (< 60 yrs) patients and patients with favorable cytogenetics. Median OS was also prolonged in these patients. No additional pretreatment characteristics were significantly related to CR or OS except LVEF. Patients with an LVEF greater than 50% were more likely to achieve a CR (P=0.0001) and had a longer OS. Conclusions: We found that, among pretreatment characteristics, a higher albumin level was associated with a good performance status. Age was not a predictor of PS. Contrary to expectations, in this population of treated AML patients, PS did not predict either CR or OS. In addition to the association of younger age and favorable cytogenetics with better outcomes, we found that a higher LVEF is also associated with higher CR rates, but this is likely explained by choice of chemotherapeutic agents. Our data calls into question the use of PS as a tool to guide therapy in routine clinical management of acute myeloid leukemia. Prospective studies should evaluate the utility of more objective and more reliably documented clinical parameters than PS for predicting patient outcome. Disclosures: No relevant conflicts of interest to declare.


Haematologica ◽  
2015 ◽  
Vol 100 (5) ◽  
pp. e183-e185 ◽  
Author(s):  
E. Barragan ◽  
M. C. Chillon ◽  
R. Castello-Cros ◽  
N. Marcotegui ◽  
M. I. Prieto ◽  
...  

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