Fms-like tyrosine kinase 3 is a key factor of male fertility

Kwon, Woosung; Kim, Yeji; Ryu, Do-Yeal; Kwon, Ki-Jin; Song, Won-Hee; Rahman, Saidur; Pang, Myung-Geol

doi:10.1016/j.theriogenology.2018.12.019

Cited by 11 publications

(4 citation statements)

References 31 publications

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“…This suggests that downstream effects of FLT3 signalling may be influenced by sex variation. This hypothesis has been substantiated by studies demonstrating functional relevance of FLT3 expression in germinal tissue [39,40] and by investigation of the oestrogen receptor in FLT3‐positive haematopoietic cells, progenitor cells and mature cellular subsets like dendritic cells [8,41]. Together, these observations suggest inter‐regulatory pathways between sex steroid receptors and FLT3.…”

Section: Discussionmentioning

confidence: 86%

“…What is plausible, however, is that sex is an important contextual contributor in determining the translational effect in comparative fitness of novel gene variants. Interestingly, one of the very first papers characterising the FLT3 receptor suggested FLT3-mediated regulatory function not only in the haematopoietic compartment but also in the gonads, placenta and brain [36]; tissues characterised by sexual dimorphism. This suggests that downstream effects of FLT3 signalling may be influenced by sex-variation.…”

Section: Accepted Articlementioning

confidence: 99%

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Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis

et al. 2021

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Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) is influenced by sex, but little attention has been directed at untangling sex-related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk is generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3-ITD) mutation and co-mutations with NPM1 and DNMT3A is overrepresented in female AML. Here, we investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: BeatAML, LAML-TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex-associated molecular differences. Cooccurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterised by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia-associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was only observed in female FLT3-ITD mutated AML. Thus, we suggest optimisation of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner, and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex-specific considerations.

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Section: Discussionmentioning

confidence: 86%

Section: Accepted Articlementioning

confidence: 99%

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis

et al. 2021

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“…This suggests that downstream effects of FLT3 signalling may be influenced by sex-variation. This hypothesis has been substantiated by studies demonstrating functional relevance of FLT3 expression in germinal tissue 36,37 and by investigation of the oestrogen receptor in FLT3 positive haematopoietic cells, progenitor cells and mature cellular subsets like dendritic cells. 8,38 Together, these observations suggest inter-regulatory pathways between sex-steroid receptors and FLT3.…”

Section: Discussionmentioning

confidence: 90%

Sex disparity in acute myeloid leukemia – evidence from a study of FLT3-ITD mutated patients

Engen¹,

Hellesøy²,

Grob³

et al. 2020

Preprint

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Little attention has been directed at untangling sex-related molecular and phenotypic differences in AML. While increased incidence and poor risk is generally associated with a male phenotype, FLT3-ITD, NPM1 and DNMT3A mutations are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity responses in four cohorts: the Beat AML cohort, the LAML-TCGA cohort and two independent HOVON/SAKK clinical trial-associated cohorts, comprising a total of 1755 AML patients. We found that sex-associated molecular differences were prevalent in FLT3-ITD mutated AML. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterised by additional mutations in genes involved in RNA splicing and epigenetic modification. Female and male FLT3-ITD mutated AML had diverging expression of multiple leukemia-associated genes, as well as discrepant ex vivo drug-responses, suggestive of discrete functional properties. Surprisingly, we found significant prognostication of FLT3-ITD only in female patients. Thus, we suggest optimisation of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner. We further hypothesize that prognostication, prediction and development of therapeutic strategies in AML can be improved by including sex-specific considerations.

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“…Besides, Fms-like tyrosine kinase 3 (FLT3) is a type III kinase enriched in seminal plasma and highly expressed in infertile men. Its inhibition can repress fertilization and early embryonic development through a PKA-dependent pathway, which indicates that FLT3 is a key factor for male fertility [ 105 ]. Alterations in distinct pathways can be induced by internal healthy state and external factors.…”

Section: Sp Factors and Related Pathwaysmentioning

confidence: 99%

The Vehicle Determines the Destination: The Significance of Seminal Plasma Factors for Male Fertility

Wang

Yang

Ouyang

et al. 2020

IJMS

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Of all human infertility cases, up to 50% show contributing factors leading to defects in the male reproductive physiology. Seminal plasma (SP) is the biological fluid derived from the male accessory sex gland which carries spermatozoa passing throughout the male and female reproductive tract during ejaculation. It contains a complicated set of heterogeneous molecular structures, including proteins, cell-free nucleic acid (DNA, microRNA and LncRNA), and small-molecule metabolites as well as inorganic chemicals (ions). For a long time, the substantial significance of seminal plasma factors’ functions has been underestimated, which is restricted to spermatozoa transport and protection. Notably, significant advancements have been made in dissecting seminal plasma components, revealing new insights into multiple aspects of sperm function, as well as fertilization and pregnancy outcomes in recent years. In this review, we summarize the state-of-art discoveries regarding SP compositions and their implications in male fertility, particularly describing the novel understanding of seminal plasma components and related modifications using “omics” approaches and mainly focusing on proteome and RNA-seq data in the latest decade. Meanwhile, we highlighted the proposed mechanism of the regulation of SP molecules on immunomodulation in the female reproductive tract. Moreover, we also discussed the proteins investigated as non-invasive diagnosis biomarkers for male infertility in the clinic.

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Fms-like tyrosine kinase 3 is a key factor of male fertility

Cited by 11 publications

References 31 publications

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis

Sex disparity in acute myeloid leukemia – evidence from a study of FLT3-ITD mutated patients

The Vehicle Determines the Destination: The Significance of Seminal Plasma Factors for Male Fertility

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