ORCID Profile
0000-0001-6550-0637
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: Elsevier BV
Date: 11-2020
DOI: 10.1016/J.XFSS.2020.08.001
Abstract: To determine the importance of testis-specific, Y-encoded-like 1 (TSPYL1) in survival and male factor fertility in mice. Experimental prospective study. Research laboratories in a university medical faculty. We generated Tspyl1 knockout (KO) mouse lines by CRISPR/Cas9. The lines were maintained by pairing heterozygous mice to provide wild-type control and KO males for comparison. None. Mendelian ratio, body and testis weight, histology, sperm motility, mating tests, pregnancy outcome, transcript levels of genes for testosterone production, and serum testosterone level. A variable percentage of Tspyl1 KO mice survived beyond weaning depending on the genetic background. Growth around weaning was retarded in KO mice, but the testes-to-body weight ratio remained normal and complete spermatogenesis was revealed in testis histology. Sperm was collected from the cauda epididymis, and a significantly smaller percentage of sperm was progressively motile (22.3% ± 18.3%, n = 14 s les) compared with wild type (58.9% ± 11.5%, 11 s les). All 11 KO mice tested had defective mounting behavior. From 11 KO males paired with a total of 88 females, only one litter was born, compared with 53 litters sired by 11 age-matched wild-type males. Expression of Star, Cyp11a1, Cyp17a1, Hsd3b6, and Hsd17b3 in the KO testis was significantly reduced, while serum testosterone level was within the normal range. TSPYL1 is critical for survival and reproductive success in mice. TSPYL1 enhances the expression of key steroidogenic genes in the mouse testis.
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1111/PPL.12018
Abstract: The development of pollen wall with proper sporopollenin deposition is essential for pollen viability and male fertility in flowering plants. Sporopollenin is a complex biopolymer synthesized from fatty acid and phenolic derivatives. Recent investigations in Arabidopsis have identified a number of anther-specific genes involved in the production of fatty-acyl monomers potentially required for exine formation. The existence of ancient biochemical pathways for sporopollenin biosynthesis has been widely proposed but experimental evidence from plant species other than Arabidopsis is not extensively available. Here, we investigated the metabolic steps catalyzed by the anther-specific acyl-CoA synthetase (ACOS), polyketide synthase (PKS) and tetraketide α-pyrone reductase (TKPR). Using fatty acids as starting substrates, sequential activities of heterologously expressed tobacco enzymes NtACOS1, NtPKS1 and NtTKPR1 resulted in the production of reduced tetraketide α-pyrones. Transgenic RNA interference lines were then generated for the different tobacco genes which were demonstrated to be indispensable for normal pollen development and male fertility. Similarly, recombinant rice OsPKS1 and OsTKPR1 were shown to function as downstream enzymes of NtACOS1. In addition, insertion mutant lines for these rice genes displayed different levels of impaired pollen and seed formation. Taken together, reduced tetraketide α-pyrones appear to represent common sporopollenin fatty-acyl precursors essential for male fertility in taxonomically distinct plant species.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2018
Publisher: Springer Science and Business Media LLC
Date: 22-03-2019
DOI: 10.1038/S41467-019-09250-6
Abstract: The BCL6 Corepressor (BCOR) is a component of a variant Polycomb repressive complex 1 (PRC1) that is essential for normal development. Recurrent mutations in the BCOR gene have been identified in acute myeloid leukaemia and myelodysplastic syndrome among other cancers however, its function remains poorly understood. Here we examine the role of BCOR in haematopoiesis in vivo using a conditional mouse model that mimics the mutations observed in haematological malignancies. Inactivation of Bcor in haematopoietic stem cells (HSCs) results in expansion of myeloid progenitors and co-operates with oncogenic Kras G12D in the initiation of an aggressive and fully transplantable acute leukaemia. Gene expression analysis and chromatin immunoprecipitation sequencing reveals differential regulation of a subset of PRC1-target genes including HSC-associated transcription factors such as Hoxa7/9 . This study provides mechanistic understanding of how BCOR regulates cell fate decisions and how loss of function contributes to the development of leukaemia.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2022
DOI: 10.1038/S41375-022-01571-8
Abstract: Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1–5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOA G17V mutations associated with improved PFS (median 5.47 vs . 1.35 months Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
Publisher: Cold Spring Harbor Laboratory
Date: 08-04-2022
DOI: 10.1101/2022.04.06.487420
Abstract: Acute myeloid leukemias (AML) are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain- of-function mutations in IDH1 or IDH2 that result in over-production of the onco-metabolite 2-HG. Although IDH inhibitors can induce complete morphological remission, almost all patients eventually relapse. Analysis of clinical s les suggests that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that AG-120 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although IDH1 inhibition alone was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non- genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials. Inhibition of mutant IDH1 in AML is insufficient to eliminate the disease but promotes proliferation of quiescent leukemic stem cells. Our data provide a mechanistic explanation for the observed synergy between IDH inhibitors and azacitidine and suggest that IDH inhibitors may also synergize with other drugs that preferentially target actively iding cells.
Publisher: EMBO
Date: 06-05-2022
No related grants have been discovered for Joan So.