Upregulated SPAG6 promotes acute myeloid leukemia progression through MYO1D that regulates the EGFR family expression

Abstract

Chromosomal aberrations and gene mutations have been considered to be the major reasons for high recurrence rates and poor survival among AML patients. However, the underlying molecular mechanism of AML gene mutation remains largely unclear. Here, we show that sperm-associated antigen 6 (SPAG6), one of the most markedly increased SPAG genes in AML, significantly contributed to the proliferation and migration of leukemic cells. SPAG6 was highly expressed in AML and its upregulation was negatively correlated with the prognosis of the disease. In vitro, SPAG6 promoted the proliferation and migration of leukemia cells and promoted cell cycle progression from G1 phase to S phase. In vivo, low expression of SPAG6 reduced the proliferation and infiltration of leukemia cells and prolonged the survival of xenograft tumor mice. Furthermore, immunoprecipitation and mass spectrometry analysis showed that SPAG6 interacts with MYO1D. Specifically, overexpression of SPAG6 promoted the translocation of MYO1D into the cell membrane, thus upgrading the expression level of the EGFR family and thereby promoting the progression of AML. Overall, our study found that SPAG6 combined with MYO1D and translocated MYO1D from the cytosol to the cytomembrane, which induced the PI3K/AKT signaling and ERK signaling pathway to regulate the growth and prognosis of AML. SPAG6 may become a new target gene for the treatment of AML.

Upregulated SPAG6 correlates with increased STAT1 and is associated with reduced sensitivity of interferon‐α response in BCR::ABL1 negative myeloproliferative neoplasms

“…The BMMCs collected from 34 patients of newly diagnosed ET and 11 patients of newly diagnosed PV were cultured and treated with INF‐α of the same concentrations of 50 ng.mL −1 for 48 h. At the same time, RT‐qPCR was carried out using RNA extracted from whole bone marrow cells of the above 45 patients and 20 IDA cases (Figure 4E). The SPAG6 mRNA expression in IDA cases was comparable to healthy donors and used as the experimental control for this study 21 . The results revealed that SPAG6 mRNA expression levels were significantly upregulated in patients with MPN compared to controls ( p < 0.01).…”

“…[14][15][16][17] Notably, the expression levels of SPAG6 in hematological malignancies have been reported to be upregulated compared with common types of solid tumors. [18][19][20][21] Our previous studies on various leukemia cell lines showed that SPAG6 promoted the growth of hematologic malignant cells by affecting different signaling pathways and connoted with the worse clinical prognosis of MDS and AML patients. 18,21,27 The present study found that SPAG6 was that the expressions of JAK1 (Figure S1) and STAT1 were decreased following SPAG6 knockdown, which might be caused by reduced reactivation of the JAK-STAT pathway due to reduced cytokine release (Figure 8).…”

“…[18][19][20][21] Our previous studies on various leukemia cell lines showed that SPAG6 promoted the growth of hematologic malignant cells by affecting different signaling pathways and connoted with the worse clinical prognosis of MDS and AML patients. 18,21,27 The present study found that SPAG6 was that the expressions of JAK1 (Figure S1) and STAT1 were decreased following SPAG6 knockdown, which might be caused by reduced reactivation of the JAK-STAT pathway due to reduced cytokine release (Figure 8). Thus, the secretion of inflammatory cytokines was further reduced, forming a positive feedback loop.…”

“…In contrast, the expression levels of SPAG6 in hematological malignancies MDS, 18 MPN, 19 lymphoma, 20 and AML 21 have been reported to be upregulated. Aberrant expression of SPAG6 could affect the occurrence and development of human cancer by regulating the apoptosis, proliferation, metastasis, and invasion of tumor cells and confers a worse clinical prognosis.…”

“…Some studies have indicated that the promoter of SPAG6 genes is methylated in bladder, lung, and breast cancers and neuroblastoma cell lines, 14–17 resulting in gene silencing. In contrast, the expression levels of SPAG6 in hematological malignancies MDS, 18 MPN, 19 lymphoma, 20 and AML 21 have been reported to be upregulated. Aberrant expression of SPAG6 could affect the occurrence and development of human cancer by regulating the apoptosis, proliferation, metastasis, and invasion of tumor cells and confers a worse clinical prognosis 21–24 .…”