The Emerging Role of Sperm-Associated Antigen 6 Gene in the Microtubule Function of Cells and Cancer

Zheng, Dafang; Wang, Qi; Wang, Jingping; Bao, Zhengqi; Wu, Shiwu; Ma, Li; Chai, Damin; Wang, Z. Peter; Tao, Yisheng

doi:10.1016/j.omto.2019.08.011

Cited by 17 publications

(29 citation statements)

References 75 publications

(205 reference statements)

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“…COMMD3 levels are elevated in prostate cancer, and have been demonstrated to upregulate C‐MYC expression, promoting proliferation in prostate cancer models 74 . SPAG6 is a member of the cancer‐testis antigen family primarily involved in regulation of the microtubule system, with secondary roles associated with inhibition of the Akt and p53 pathways 75 . High expression levels of SPAG6 occur in numerous malignancies including myelodysplastic syndrome, and genetic knockdown of SPAG6 inhibits cell proliferation of myeloid leukemia cell lines, but pharmacological inhibitors of SPAG6 are not yet available 76 …”

Section: The Role Of Mllt10 In Mllt10r‐mediated Leukemogenesismentioning

confidence: 99%

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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Rearrangements of the MLLT10 gene occur in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), most commonly T-lineage ALL (T-ALL), in patients of all ages. MLLT10 rearranged (MLLT10r) acute leukemia presents a complex diagnostic and therapeutic challenge due to frequent presentation of immature or mixed phenotype, and a lack of consensus regarding optimal therapy. Cases of MLLT10r AML or TALL bearing immature phenotype are at high risk of poor outcome, but the underlying molecular mechanisms and sensitivity to targeted therapies remain poorly characterized. This review addresses the incidence and prognostic significance of MLLT10r in acute leukemia, and how the aberrant gene expression profile of this disease can inform potential targeted therapeutic strategies. Understanding the underlying genomics of MLLT10r acute leukemia, both clinically and molecularly, will improve prognostic stratification and accelerate the development of targeted therapeutic strategies, to improve patient outcomes.

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Section: The Role Of Mllt10 In Mllt10r‐mediated Leukemogenesismentioning

confidence: 99%

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Forgione

McClure

Yeung

et al. 2020

Genes Chromosomes & Cancer

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“…7A). The interaction with SPAG6 was particularly intriguing due to a number of phenotypic and functional similarities as CCDC103: mouse Spag6 mutants display ciliary defects and many phenotypic hallmarks of PCD (Sapiro et al ., 2002); Spag6 can promote effective migration of cortical neurons and proliferation and migration of mouse embryonic fibroblasts (Sapiro et al ., 2002; Li, Mukherjee, Wu, Zhang, Maria E Teves, et al ., 2015; Alciaturi et al ., 2019) (Li, et al 2015) (Alciaturi et al ., 2019); Spag6 has increased expression in myeloid leukemia lines (Cooley et al, 2016; Yang et al, 2015; Yin et al, 2018); and Spag6 can promote microtubule stability (Zheng et al ., 2019). To validate these protein-protein interactions, we used the bioluminescent resonance transfer assay (BRET)-based LuTHy system (Trepte et al ., 2018).…”

Section: Resultsmentioning

confidence: 99%

“…In light of reports implicating SPAG6 in myeloid proliferation and cell migration (Sapiro et al ., 2002; Jiang et al ., 2019; Zheng et al ., 2019), we interrogated the requirement of Spag6 in zebrafish myeloid cells. RT-PCR from flow-sorted spi1b:EGFP cells showed that zebrafish spag6 is expressed in myeloid cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…One reason it was an attractive candidate is because of the large body of literature indicating Spag6 promotes the same cellular processes as Ccdc103 in both ciliated and non-ciliated cells. Broadly, Spag6 has been shown to regulate cilia assembly, microtubule stability, proliferation, and migration (Li et al 2015b; Zheng et al 2019). While mutations in SPAG6 have not as yet been identified as underlying cases of PCD in humans, Spag6 KO mice have a higher incidence of neonatal death with ∼50% showing hydrocephalus (Sapiro et al ., 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the correlations in ciliated cells within the literature, our data support that zebrafish smh and spag6 mutants both have previously unrecognized defects in myeloid proliferation and directed migration that are consistent with decreased microtubule stability. Increased SPAG6 expression is found in a broad range of myeloid cancers and myelodysplastic syndromes (Zheng et al 2019; Steinbach et al 2015; Yin et al 2018b). Depletion of SPAG6 is associated with reduced proliferation of these leukemia lines, implying its increased expression contributes to their hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Cilia-independent requirements for Ccdc103 promoting proliferation and migration of myeloid cells

Falkenberg

Beckman

Ravisankar

et al. 2020

Preprint

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The pathology of primary ciliary dyskinesia (PCD) is predominantly attributed to impairment of motile cilia. However, PCD patients also have perplexing functional defects in myeloid cells, which lack motile cilia. Here, we show Coiled-coiled domain containing protein 103 (CCDC103), mutations in which underlie PCD, is required for the proliferation and directed migration of myeloid cells. CCDC103 co-localizes with cytoplasmic microtubules in human myeloid cells. Zebrafish ccdc103/schmalhans (smh) mutants have reduced macrophage and neutrophil proliferation, rounded cell morphology, and an inability to migrate efficiently to the site of sterile wounds. Furthermore, we demonstrate that direct interactions between CCDC103 and Sperm associated antigen 6 (SPAG6), which also promotes microtubule stability, are abrogated by CCDC103 mutations from PCD patients, and that spag6 zebrafish mutants recapitulate the myeloid defects of smh mutants. In summary, we have illuminated a mechanism, independent of motile cilia, to explain functional defects in myeloid cells from PCD patients.Summary StatementWe show Ccdc103 regulates myeloid migration and proliferation independent of cilia in zebrafish and that mutations in CCDC103 that cause primary ciliary dyskinesia abrogate interactions with the microtubule-stabilizing protein SPAG6.

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Generation of floxed Spag6l mice and disruption of the gene by crossing to a Hprt‐Cre line

Man

Yap

et al. 2023

Genesis

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Mouse sperm-associated antigen 6 like (SPAG6L) is an axoneme central apparatus protein, essential for the normal function of the ependymal cell and lung cilia, and sperm flagella. Accumulated evidence has disclosed multiple biological functions of SPAG6L, including ciliary/flagellar biogenesis and polarization, neurogenesis, and neuronal migration. Conventional Spag6l knockout mice died of hydrocephalus, which impedes further investigation of the function of the gene in vivo. To overcome the limitation of the short lifespan of conventional knockout mice, we developed a conditional allele by inserting two loxP sites in the genome flanking exon 3 of the Spag6l gene. By crossing the floxed Spag6l mice to a Hrpt-Cre line which expresses Cre recombinase ubiquitously in vivo, mutant mice that are missing SPAG6L globally were obtained. Homozygous mutant Spag6l mice showed normal appearance within the first week after birth, but reduced body size was observed after 1 week, and all developed hydrocephalus and died within 4 weeks of age. The phenotype mirrored that of the conventional Spag6l knockout mice. The newly established floxed Spag6l model provides a powerful tool to further investigate the role of the Spag6l gene in individual cell types and tissues.

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The Emerging Role of Sperm-Associated Antigen 6 Gene in the Microtubule Function of Cells and Cancer

Cited by 17 publications

References 75 publications

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

Cilia-independent requirements for Ccdc103 promoting proliferation and migration of myeloid cells

Generation of floxed Spag6l mice and disruption of the gene by crossing to a Hprt‐Cre line

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