scholarly journals The role of ARHGAP9: clinical implication and potential function in acute myeloid leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Caixia Han ◽  
Shujiao He ◽  
Ruiqi Wang ◽  
Xuefeng Gao ◽  
Hong Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Differentially Expressed Genes ◽  
Myeloid Leukemia ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Clinicopathological Parameters ◽  
Hub Genes ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background Rho GTPase activating protein 9 (ARHGAP9) is expressed in various types of cancers and can inactivate Rho GTPases that mainly regulate cytoskeletal dynamics. However, the exact role of ARHGAP9 in acute myeloid leukemia (AML) has yet to be clarified. Methods We compared the transcriptional expression, prognosis, differentially expressed genes, functional enrichment, and hub genes in AML patients on the basis of the data published in the following databases: UALCAN, GEPIA, Gene Expression Omnibus, the Human Protein Atlas, Cancer Cell Line Encyclopedia, LinkedOmics, Metascape, and String. Data from the Cancer Genome Atlas database was used to evaluate the correlations between ARHGAP9 expression and various clinicopathological parameters, as well as the significantly different genes associated with ARHGAP9 expression. Results We found that ARHGAP9 expression was higher in the tissues and cell lines extracted from patients with AML than corresponding control tissues and other cancer types. ARHGAP9 overexpression was associated with decreased overall survival (OS) in AML. Compared with the ARHGAP9low group, the ARHGAP9high group, which received only chemotherapy, showed significantly worse OS and event-free survival (EFS); however, no significant difference was observed after treatment with autologous or allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT). The ARHGAP9high patients undergoing auto/allo-HSCT also had a significantly better prognosis with respect to OS and EFS than those receiving only chemotherapy. Most overlapping genes of the significantly different genes and co-expression genes exhibited enriched immune functions, suggesting the immune regulation potential of ARHGAP9 in AML. A total of 32 hub genes were identified from the differentially expressed genes, within which the KIF20A had a significant prognostic value for AML. Conclusions ARHGAP9 overexpression was associated with poor OS in AML patients and can be used as a prognostic biomarker. AML patients with ARHGAP9 overexpression can benefit from auto/allo-HSCT rather than chemotherapy.

scholarly journals The Role of ARHGAP9: Clinical Implication and Potential Function in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Caixia Han ◽  
Shujiao He ◽  
Ruiqi Wang ◽  
Xuefeng Gao ◽  
Hong Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinicopathological Parameters ◽  
Published Data ◽  
Hub Genes ◽  
Hematopoietic Stem ◽  
Over Expression ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background: Rho GTPase activating protein 9 (ARHGAP9) is expressed in many cancers and can inactivate Rho GTPases that are key regulators of cytoskeletal dynamics. However, the exact role of ARHGAP9 in acute myeloid leukemia (AML) is still unclear. Methods: We compared the transcriptional expression, prognosis, differentially expressed genes, function enrichment, and hub genes in AML patients based on published data in UALCAN, GEPIA, Gene Expression Omnibus (GEO), the Human Protein Atlas (HPA), Cancer Cell Line Encyclopedia (CCLE), LinkedOmics, Metascape, and String databases. Data from the Cancer Genome Atlas (TCGA) database was used to evaluate the correlations between ARHGAP9 expression and various clinicopathological parameters as well as the significantly different genes associated with ARHGAP9 expression.Results: We found that ARHGAP9 expression was higher in AML patient tissues and cell lines than the corresponding control tissues and other cancer types. Furthermore, ARHGAP9 over-expression was associated with shorter overall survival (OS) in AML patients. Compared with the ARHGAP9low group, ARHGAP9high patients received only chemotherapy showed the significantly worse OS and event-free survival (EFS), but no significant difference after treatment with autologous or allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT). In addition, ARHGAP9high patients undergoing auto/allo-HSCT had significantly better prognosis in OS and EFS than those receiving only chemotherapy. Because most of the overlapping gene between the significantly different genes and co-expression genes were enriched in the immune functions, suggesting an immune regulation potential of ARHGAP9 in AML. Thirty-two hub genes were identified from the differently expressed genes, within which the KIF20A had significant prognostic value for AML.Conclusions: Our results demonstrated that ARHGAP9 overexpression was associated with poor OS in AML patients and can be used as a prognosis biomarker. AML patients with ARHGAP9 over-expression could benefit from auto/allo-HSCT rather than chemotherapy.

scholarly journals TET2/IDH1/2/WT1 and NPM1 Mutations Influence the RUNX1 Expression Correlations in Acute Myeloid Leukemia

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 637
Author(s):  
Sergiu Pasca ◽  
Ancuta Jurj ◽  
Ciprian Tomuleasa ◽  
Mihnea Zdrenghea
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Runx1 Expression ◽  
Acute Myeloid

Background and objectives: Mutational analysis has led to a better understanding of acute myeloid leukemia (AML) biology and to an improvement in clinical management. Some of the most important mutations that affect AML biology are represented by mutations in genes related to methylation, more specifically: TET2, IDH1, IDH2 and WT1. Because it has been shown in numerous studies that mutations in these genes lead to similar expression profiles and phenotypes in AML, we decided to assess if mutations in any of those genes interact with other genes important for AML. Materials and Methods: We downloaded the clinical data, mutational profile and expression profile from the TCGA LAML dataset via cBioPortal. Data were analyzed using classical statistical methods and functional enrichment analysis software represented by STRING and GOrilla. Results: The first step we took was to assess the 196 AML cases that had a mutational profile available and observe the mutations that overlapped with TET2/IDH1/2/WT1 mutations. We observed that RUNX1 mutations significantly overlap with TET2/IDH1/2/WT1 mutations. Because of this, we decided to further investigate the role of RUNX1 mutations in modulating the level of RUNX1 mRNA and observed that RUNX1 mutant cases presented higher levels of RUNX1 mRNA. Because there were only 16 cases of RUNX1 mutant samples and that mutations in this gene determined a change in mRNA expression, we further observed the correlation between RUNX1 and other mRNAs in subgroups regarding the presence of hypermethylating mutations and NPM1. Here, we observed that both TET2/IDH1/2/WT1 and NPM1 mutations increase the number of genes negatively correlated with RUNX1 and that these genes were significantly linked to myeloid activation. Conclusions: In the current study, we have shown that NPM1 and TET2/IDH1/2/WT1 mutations increase the number of negative correlations of RUNX1 with other transcripts involved in myeloid differentiation.

scholarly journals Th1 Cytokine Polymorphism Gene: TNF-Alpha -857C/T Affects the Pathogenesis and Progression of Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1431-1431
Author(s):  
Kana Soma ◽  
Gotoh Nanami ◽  
Tetsuhiro Kasamatsu ◽  
Yuki Murakami ◽  
Rei Ishihara ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Features ◽  
Myeloid Leukemia ◽  
Control Group ◽  
Target Cells ◽  
Tnf Α ◽  
Significant Difference ◽  
Th1 Cytokine ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a hematological malignancy characterized by the autonomous growth of immature myeloid cells with impaired differentiation and maturation. Cytokines are low-molecular-weight proteins that play a basic and fundamental role in communication within the immune system. Cytokines induce various effects such as differentiation, proliferation, hematopoiesis, and inflammation of target cells. AML is also closely associated with cytokine networks in terms of proliferation, apoptosis, and differentiation of leukemic cells. Cytokines produced by Th1 involved in cell-mediated immunity are called Th1 cytokines. Th1 cytokine includes TNF-α and IL-2. Several studies have reported that TNF-α is highly expressed in leukemia cells with AML patients. Other studies have also reported that high serum level of TNF-α of AML patients is associated with poor survival outcome. However, the association between Th1 cytokine polymorphisms: TNF-α -857C/T and IL-2-330T/G and the pathogenesis of AML is unclear. Therefore, we investigated the role of these polymorphisms in AML. Materials and Methods: This study included 101 patients with AML [male/female, 56/45; age, 15-86 years; median age, 58 years; MRC classification favorable (n = 38), intermediate (n =56), and adverse (n = 7)] and 202 healthy race-matched controls. All participants provided written informed consent. This study was approved by the Institutional Review Board of Gunma University Hospital. Genotyping was performed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. Genotype and allele frequency were compared between patient group and control group by χ2-test. Clinical features were compared using Student's t and χ2 tests. Overall survival (OS) and leukemia free survival (LFS) were calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Analyses were performed using the SPSS software package ver. 25 (IBM, Armonk, NY, USA). P < 0.05 was considered to represent statistical significance. Results: TNF-α -857 C/T nonCC genotype (higher producer type) increases the risk of AML (AML vs. controls = 39.6% vs. 28.2%, OR = 1.67, 95% CI = 1.01-2.75, p = 0.045). Moreover, the frequency of TNF-α -857 C/T T allele (higher producer type) was higher in AML patients compared to controls (AML vs. controls = 24.8% vs. 16.8%, OR = 1.625, 95%CI = 1.078-2.451 p = 0.02). There was no significant difference between AML patients and controls in genotype and allele frequencies of IL-2 -330 T/G. In the analysis of clinical features, the average platelet count was significantly lower in TNF-α -857 C/T TT genotype (higher producer type) (TT vs. nonTT = 2.4±1.4 vs. 4.4±5.9, p < 0.01). TT genotype (higher producer type) was also significantly higher in frequency of MRC classification adverse (TT vs. nonTT = 30.0% vs. 4.4%, p = 0.02) and history of tumor (TT vs. nonTT = 30.0% vs. 6.6%. p =0.04). Moreover, in survival time analysis, patients with TNF-α -857 C/T TT genotype (higher producer type) had significantly shortened OS compared with patients with nonTT genotype (lower producer type) (TT vs. nonTT = 17.2 months vs not reached, p < 0.01). Patients with TT genotype (high producer type) also experienced significantly shortened LFS (TT vs. nonTT = 24.0 months vs not reached, p = 0.04). Furthermore, multivariate analysis of OS revealed TNF-α -857 C/T TT genotype (higher producer type) as an independent prognostic factor (HR = 3.01, 95% CI = 1.04-8.69, p = 0.04), like age and white blood cell count. Conclusion: These results suggest that TNF-α-857 C/T T allele (higher producer type) increases the risk of AML. Furthermore, TNF-α-857 C/T TT genotype (higher producer type) affects the poor prognosis. Therefore, these data suggest the new role of TNF-α polymorphism in AML leukemogenesis. Figure Disclosures Handa: Ono: Research Funding.

Bone Marrow Small Adipocytes in Acute Myeloid Leukemia Correlate with Prognosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2874-2874
Author(s):  
Wei Lu ◽  
Jun Shi
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Solid Tumors ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Biopsy Specimens ◽  
Brown Adipose ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Introduction: Adipocytes have a substantial effect on the outcome and progression of certain solid tumors. However, little attention has been paid to the role of bone marrow (BM) adipocytes in acute myeloid leukemia (AML) because it is difficult to observe adipocytes through clinical BM aspiration. Although it was reported that adipocytes affected the behavior of leukemia cells in vitro, there is still no direct in vivo evidence. In the present study, we investigated the influence of adipocytes by focusing on their changing size in BM from primary AML patients. Methods: We retrospectively analyzed the biopsy specimens of BM from 70 patients with newly diagnosed AML and 70 controls with lymphoma or solid tumors without infiltration of BM. The size and type of adipocytes were analyzed for average diameter (Ad.Dm) and area (Ad.Ar) by tracing each individual adipocyte with Image-Pro Plus 5.1. Then, AML patients were further divided into 32 patients with continuous complete remission and 38 patients who were refractory based on the treatment effects. Adipocyte number (Ad.N; per square millimeter) and the percentage of adipocyte volume per tissue volume (Ad.V/TV) were compared between these two groups. Furthermore, the prognostic impact of adipocytes on the overall survival (OS) and relapse-free survival (RFS) in AML patients was analyzed by Cox regression analysis and Kaplan-Meier curves. Finally, the phenotype of adipocytes was determined by immunohistochemistry of UCP-1 and Perilipin1 to further explore the possible mechanism of the effect of adipocytes on the prognosis. Results: The Ad.Dm and Ad.Ar in BM from AML patients were 38.3±14.7 µm and 559.4±271.9 µm2, respectively, and both values were significantly smaller than those for the controls (P<0.001). The Ad.Dm exhibited no relation to the number of blasts in BM, indicating that the decreased size of adipocytes in AML cannot be attributed to extensive marrow blasts. Adipocytes were classified as small, medium and large adipocytes according to the frequency distribution of Ad.Dm in BM from controls. A significant difference was detected only in the proportion of small adipocytes (Ad.Dm<42.6 µm) between AML patients and controls (43.9% vs 25%, P=0.005). Furthermore, the Ad.V/TV and Ad.N of the adipocytes in the refractory group were 6.70±3.18% and 31.56±11.72/mm2, respectively, which were significantly higher than those of the remission subjects (P<0.001). This outcome prompted us to further analyze the role of small adipocytes in AML. Patients with Ad.V/TV of small adipocytes≤ 2.3% exhibited a longer OS than patients with Ad.V/TV of small adipocytes >2.3% (P<.001). Similarly, the subjects with Ad.N of small adipocytes <10.6/mm2 (P<.001) had a longer OS. Meanwhile, for the remission AML patients, those with Ad.V/TV of small adipocytes ≤2.5% had a shorter RFS than patients with Ad.V/TV of small adipocytes >2.5% (P<.001), and similar significant differences were also found between patients with Ad.N of small adipocytes ≥9.2/mm2 and Ad.N of small adipocytes <9.2/mm2(P<.001). In the biopsy specimens of BM, the subgroup of small adipocytes exhibited expression of Perilipin1 but not mitochondrial membrane protein UCP-1. Combination with the unilocular lipid droplets in adipocytes indicated that small adipocytes did not play a role in the conversion to brown adipose tissue. Conclusions: We first defined a subpopulation of small adipocytes in BM and demonstrated that only these cells but not all adipocytes were related to a poor prognosis in AML patients. The morphological changes of marrow adipocytes could be helpful to judge the prognosis of leukemia and could lead to other therapeutic perspectives. Disclosures No relevant conflicts of interest to declare.

Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

2019 ◽  
Vol XIV (1) ◽  
Author(s):  
A.M. Radzhabova ◽  
S.V. Voloshin ◽  
I.S. Martynkevich ◽  
A.A. Kuzyaeva ◽  
V.A. Shuvaev ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Course Of Disease ◽  
Acute Myeloid

scholarly journals The clinical profile, management, and outcome of febrile neutropenia in acute myeloid leukemia from resource constraint settings

2021 ◽  
Vol 8 ◽  
pp. 204993612110365
Author(s):  
Kundan Mishra ◽  
Suman Kumar ◽  
Sandeep Ninawe ◽  
Rajat Bahl ◽  
Ashok Meshram ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Burkholderia Cepacia ◽  
Myeloid Leukemia ◽  
Tertiary Care ◽  
Care Hospital ◽  
Significant Difference ◽  
The Mean ◽  
Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is the commonest leukemia in adults. Mortality in thew first 30-days ranges from 6% to 43%, while infections account for 30–66% of early deaths. We aim to present our experience of infections in newly-diagnosed AML. Method: This prospective, observational study, was undertaken at a tertiary care hospital in Northern India. Patients with confirmed AML (bone marrow morphology and flow cytometry) and who had developed febrile neutropenia (FN), were included. Result: A total of fifty-five patients were included in the study. The median age of the patients was 47.1 years (12–71) and 28 (50.9%) were males. Fever (33, 60%) was the commonest presentation at the time of diagnosis. One or more comorbid conditions were present in 20 patients (36.36%). Infection at presentation was detected in 17 patients (30.9%). The mean duration to develop febrile neutropenia since the start of therapy was 11.24 days. With each ten-thousand increase in white blood cell (WBC) count, the mean number of days of FN development decreased by 0.35 days ( p = 0.029). Clinical and/or radiological localization was possible in 23 patients (41.81%). Thirty-four blood samples (34/242, 14.04%) from 26 patients (26/55, 47.3%) isolated one or more organisms. Gram negative bacilli (GNB) were isolated in 24 (70.58%) samples. Burkholderia cepacia (8/34, 23.52%) was the commonest organism. The number of days required to develop febrile neutropenia was inversely associated with overall survival (OS). However, when compared, there was no statistically significant difference in OS between patients developing fever on day-10 and day-25 ( p = 0.063). Thirteen patients (23.63%) died during the study period. Discussion: Low percentage of blood culture positivity and high incidence of MDR organisms are a matter of concern. Days to develop febrile neutropenia were inversely associated with overall survival (OS), emphasizing the importance of preventive measures against infections. Conclusion: Infections continues to be a major cause of morbidity and mortality among AML patients.

scholarly journals Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yiyi Yao ◽  
Fenglin Li ◽  
Jiansong Huang ◽  
Jie Jin ◽  
Huafeng Wang
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chemotherapy Resistance ◽  
Bone Marrow Microenvironment ◽  
Cytotoxic Effects ◽  
High Relapse Rate ◽  
Underlying Mechanisms ◽  
Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

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