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

doi:10.1186/s12967-021-02733-5

. 2021 Feb 12;19(1):65.

doi: 10.1186/s12967-021-02733-5.

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

Caixia Han¹, Shujiao He¹, Ruiqi Wang², Xuefeng Gao¹, Hong Wang², Jingqiao Qiao¹, Xiangyu Meng¹, Yonghui Li³, Li Yu⁴

Affiliations

¹ Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China.
² Medicine School, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
³ Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China. Yonghuililab@163.com.
⁴ Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China. liyu301@vip.163.com.

PMID: 33579308
PMCID: PMC7881617
DOI: 10.1186/s12967-021-02733-5

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

Caixia Han et al. J Transl Med. 2021.

. 2021 Feb 12;19(1):65.

doi: 10.1186/s12967-021-02733-5.

Authors

Caixia Han¹, Shujiao He¹, Ruiqi Wang², Xuefeng Gao¹, Hong Wang², Jingqiao Qiao¹, Xiangyu Meng¹, Yonghui Li³, Li Yu⁴

Affiliations

¹ Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China.
² Medicine School, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
³ Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China. Yonghuililab@163.com.
⁴ Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China. liyu301@vip.163.com.

PMID: 33579308
PMCID: PMC7881617
DOI: 10.1186/s12967-021-02733-5

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 ARHGAP9^low group, the ARHGAP9^high 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 ARHGAP9^high 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.

Keywords: AML; ARHGAP9; Auto/allo-HSCT; Chemotherapy; Prognosis; t(15;17).

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
ARHGAP9 expression in cell lines. a ARHGAP9 expression in leukemia cell lines, analyzed by HPA. b The expression of ARHGAP9 in leukemia Cell Lines, analyzed by CCLE

**Fig. 2**
ARHGAP9 expression in AML. a ARHGAP9 expression in pan-cancer, analyzed by UALCAN. b ARHGAP9 expression in various cancer tissues and normal tissues analyzed by GEPIA; The height of the bar represents the median expression of a certain tumor type or normal tissue. c ARHGAP9 expression in AML and normal tissues analyzed by GEPIA. d and e ARHGAP9 expression in AML with various chromosomal abnormalities in the microarray data of GSE14468 and GSE13159 from the GEO database, respectively

**Fig. 3**
Effect of ARHGAP9 on the survival of AML patients. a Prognostic value of ARHGAP9 mRNA level in AML, analyzed by GEPIA. b Prognostic value of ARHGAP9 mRNA level in AML, analyzed by LinkedOmics. c Survival curves of EFS in AML patients from the TCGA cohort

**Fig. 4**
Prognostic values of ARHGAP9 with different factors on the survival of AML patients from the TCGA cohort. a OS and b EFS in CN-AML. c OS and d EFS of patients undergoing chemotherapy. e OS and f EFS of patients treated with auto/allo-HSCT. g OS and h EFS of patients in the ARHGAP9^high group

**Fig. 5**
Genome-wide genes associated with ARHGAP9 expression. a Volcano plot of different gene-expression profiles between the ARHGAP9^low and ARHGAP9^high groups. b Volcano plots for the analysis of the co-expression genes associated with ARHGAP9 expression (LinkedOmics). c Overlapping genes between positively correlated genes and significantly increased genes. d Overlapping genes between negatively correlated genes and significantly reduced genes

**Fig. 6**
Enrichment of functions and signaling pathways of the overlapping genes in AML. a Analysis of GO and KEGG pathway associated with ARHGAP9 expression. b Enrichment of differentially expressed genes in tissues and cells. c Enrichment of overlapping genes in diseases

**Fig. 7**
PPI network of the overlapping genes. a Network view of PPI for the overlapping genes. b MCODE analysis of the most significant interactions from a (MCODE score = 29.806); c Prognostic value of hub genes in AML, analyzed by GEPIA. d KIF20A expression in AML patients and healthy tissues, analyzed by GEPIA

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References

1. Burnett A, Stone R. AML: New Drugs but New Challenges. Clin Lymphoma Myeloma Leuk. 2020;20:341–350. doi: 10.1016/j.clml.2020.02.005. - DOI - PubMed
1. Thol F, Ganser A. Treatment of Relapsed Acute Myeloid Leukemia. Curr Treat Options Oncol. 2020;21:66. doi: 10.1007/s11864-020-00765-5. - DOI - PMC - PubMed
1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136–1152. doi: 10.1056/NEJMra1406184. - DOI - PubMed
1. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701. doi: 10.1038/nrm2476. - DOI - PubMed
1. Humphries BA, Wang Z, Yang C: MicroRNA Regulation of the Small Rho GTPase Regulators-Complexities and Opportunities in Targeting Cancer Metastasis. Cancers (Basel) 2020, 12. - PMC - PubMed

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[1] Burnett A, Stone R. AML: New Drugs but New Challenges. Clin Lymphoma Myeloma Leuk. 2020;20:341–350. doi: 10.1016/j.clml.2020.02.005. - DOI - PubMed

[2] Burnett A, Stone R. AML: New Drugs but New Challenges. Clin Lymphoma Myeloma Leuk. 2020;20:341–350. doi: 10.1016/j.clml.2020.02.005. - DOI - PubMed

[3] Thol F, Ganser A. Treatment of Relapsed Acute Myeloid Leukemia. Curr Treat Options Oncol. 2020;21:66. doi: 10.1007/s11864-020-00765-5. - DOI - PMC - PubMed

[4] Thol F, Ganser A. Treatment of Relapsed Acute Myeloid Leukemia. Curr Treat Options Oncol. 2020;21:66. doi: 10.1007/s11864-020-00765-5. - DOI - PMC - PubMed

[5] Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136–1152. doi: 10.1056/NEJMra1406184. - DOI - PubMed

[6] Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136–1152. doi: 10.1056/NEJMra1406184. - DOI - PubMed

[7] Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701. doi: 10.1038/nrm2476. - DOI - PubMed

[8] Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701. doi: 10.1038/nrm2476. - DOI - PubMed

[9] Humphries BA, Wang Z, Yang C: MicroRNA Regulation of the Small Rho GTPase Regulators-Complexities and Opportunities in Targeting Cancer Metastasis. Cancers (Basel) 2020, 12. - PMC - PubMed

[10] Humphries BA, Wang Z, Yang C: MicroRNA Regulation of the Small Rho GTPase Regulators-Complexities and Opportunities in Targeting Cancer Metastasis. Cancers (Basel) 2020, 12. - PMC - PubMed

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

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

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