BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis

Deregulated BCL6 is not only linked to PE but also to endometriosis, a common disorder of the uterine endometrium. The uterine endometrium, the inner uterine cell layer, is composed of two layers, the functionalis and the basalis, the latter being responsible for regeneration of the former during the proliferative phase ( Cooke et al. , 2013 ). Depending on the phases of the menstrual cycle, the endometrium undergoes cyclical regeneration, differentiation and shedding in response to the steroid hormones estrogen and progesterone under the control of the hypothalamic-pituitary-ovarian axis ( Jabbour et al. , 2006 ; Hawkins and Matzuk, 2008 ; Garry et al. , 2009 ). While estrogen induces mitosis of endometrial cells including luminal and glandular epithelial cells, stromal fibroblasts and vascular components throughout the proliferative phase, progesterone causes secretory transformation of epithelial cells and differentiation of stromal fibroblasts after ovulation. In addition to the regulation by the steroid hormones, these dynamic processes of the endometrium are supported by cytokines/chemokines, such as IL6, IL10 and monocyte chemotactic protein 1, produced by endometrial stromal cells ( Large and DeMayo, 2012 ; Vallve-Juanico et al. , 2019 ). The extraordinarily high regenerative capacity of the endometrium indicates the presence of stem cell-like endometrial cell populations capable of self-renewal and differentiation. Indeed, numerous studies have demonstrated the presence of a stem cell population in the basalis of the endometrium, which is responsible for the formation of endometrial stromal fibroblasts ( Schwab and Gargett, 2007 ; Masuda et al. , 2012 ; Yin et al. , 2019 ). Additionally, several putative endometrial stem cell-like populations have been identified, including side population cells, endometrial mesenchymal stem cells (eMSCs), and bone marrow mesenchymal stem cells (BM-MSCs) ( Yilmaz and Bulun 2019 ). The side population may represent endometrial stem cells coffering migration and angiogenesis abilities ( Masuda et al. , 2010 ), whereas eMSCs are self-renewing, multipotent and clonogenic mesenchymal stem cells giving rise to mesodermal lineages in vitro ( Gargett et al. , 2016 ). Additionally, BM-MSCs may improve endometrial regeneration through secreting paracrine factors to stimulate resident endometrial stem cells ( Yilmaz and Bulun, 2019 ). The co-ordinated regulation of these self-renewal and differentiation populations is essential for dynamic endometrial tissue regeneration and homeostasis. In recent years, enormous progress has been made in the generation and application of self-organizing 3D organoids. 3D organoids of normal and decidualized human endometrium have been established and these organoids were able to differentiate upon treatment with reproductive hormones ( Turco et al. , 2017 ). Functionally, human endometrial organoids were successfully used to study ciliogenesis of multi-ciliated endometrial cells ( Haider et al. , 2019 ). Recently, a 3D model of the human decidua, consisting of hormone-responsive endometrial stromal fibroblasts and endometrial epithelial cells, was reported ( Cheung et al. , 2021 ). These technical developments are of importance in elucidating the pathogenesis of endometrium-related diseases such as endometriosis. Endometriosis is an estrogen-dependent inflammatory disorder of the uterine endometrium ( Bulun et al. , 2019 ). About 5–10% of women of reproductive age are affected and up to 50% of these women are infertile ( Bulun, 2009 ; de Ziegler et al. , 2010 ; Taylor et al. , 2021 ). The etiology of endometriosis remains to be defined. Among several hypotheses, ‘retrograde menstruation’ ( Sampson, 1927a , b ) is believed to be the primary mechanism of lesion formation ( Smolarz et al. , 2021 ). Important features of endometriosis are the high production of estrogen and deregulated expression of its receptors in endometriotic regions ( Chantalat et al. , 2020 ), and progesterone resistance ( Patel et al. , 2017 ). Endometriosis is characterized by endometrial-like tissue outside its normal location lining the uterus ( Giudice, 2010 ). Depending on its location, endometriosis can be classified as peritoneal endometriotic implants, rectovaginal nodules and ovarian endometriomas ( Bulun et al. , 2019 ; Kuan et al. , 2021 ). The symptoms of endometriosis are dysmenorrhea, dyspareunia, non-cyclic chronic pelvic pain and infertility ( Bulun, 2009 ; Bulun et al. , 2019 ). Its treatment includes pharmacological and surgical therapy ( Brichant et al. , 2021 ; Taylor et al. , 2021 ). Endometriosis is associated with infertility owing to numerous factors such as distorted anatomy, local inflammatory effects on oocyte quality and an inhospitable endometrial environment for embryo implantation ( Vallve-Juanico et al. , 2019 ). It is likely that ≤50% of infertile women ( Meuleman et al. , 2009 ) and ≤70% of women with endometriosis will not have a live birth ( Bulletti et al. , 2010 ). Moreover, a larger study, based on fertilized sibling oocytes transferred into women with and without endometriosis, demonstrated reduced implantation, clinical pregnancy, ongoing pregnancy and live birth rates in women with endometriosis ( Prapas et al. , 2012 ). These findings highlight that endometriosis is associated with infertility and failure of IVF. Despite the high incidence of endometriosis, its cellular and molecular mechanisms are poorly understood. The growth of endometriotic tissue outside the uterine cavity requires degradation of the ECM, peritoneal invasion and the growth of ectopic endometrial stromal and glandular cells ( Santanam et al. , 2002 ; Van Langendonckt et al. , 2002 ). The biological alterations in endometriotic lesions include increased proliferation, enhanced inflammation, decreased apoptosis, a deregulated immune response and progesterone resistance ( Young and Lessey, 2010 ). It is generally regarded that genetic, epigenetic, environmental, autoimmune and allergic factors are among the etiological factors ( Smolarz et al. , 2021 ). Specifically, the endometrium of patients with endometriosis exhibited aberrant global DNA-methylation profiles and altered gene expression ( Houshdaran et al. , 2016 ). The deregulated immune response and inflammatory regulation, systemically and locally, were reported to play central roles in its etiology and pathophysiology ( Vallve-Juanico et al. , 2019 ; Giacomini et al. , 2021 ). In fact, the endometriotic stromal cells, including stromal fibroblasts and immune cells, expressed and secreted large amounts of immune molecules such as IL1β, IL6 and TNFα ( Tseng et al. , 1996 ; Hornung et al. , 2001 ). High estrogen production is of paramount importance in the pathogenesis of endometriosis, as it promotes endometriotic cell survival, inflammation and lesion progression ( Bulun, 2009 ; Yilmaz and Bulun, 2019 ). Moreover, the underlying pathologic mechanisms include defectively programmed endometrial mesenchymal progenitor/stem cells ( Bulun et al. , 2019 ). Studies also highlight the involvement of the MAPK and the WNT/β-catenin signaling pathway in the pathogenesis of endometriosis through multiple mechanisms, including proliferation, apoptosis, migration and angiogenesis ( Giacomini et al. , 2021 ). Furthermore, many factors have been investigated as potential biomarkers for the diagnosis of endometriosis, such as IL6, IL8, hepatocyte growth factor, fibroblast growth factor, epidermal growth factor, VEGF- and platelet-derived growth factor ( Smolarz et al. , 2021 ). These growth factors and cytokines promote proliferation, invasion and angiogenesis. Notably, among these factors, IL6 is the most characteristic of endometriosis, with a sensitivity of 63% and a specificity of 69% ( Nisenblat et al. , 2016 ). IL6 impacts various vital cellular activities, including proliferation and migration by mediating the phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3) ( Yuan et al. , 1994 ; Heinrich et al. , 2003 ). Indeed, increased phosphorylated STAT3 was observed in endometriotic lesions ( Kim et al. , 2015 ). Interestingly, BCL6 is upregulated by STAT3 ( Arguni et al. , 2006 ; Walker et al. , 2013 ), suggesting a likelihood that BCL6 could be highly expressed in endometriotic lesions. BCL6 is upregulated at both mRNA and protein levels in the endometrium of women with endometriosis and is considered to be a potential diagnostic marker for endometriosis ( Table II ) ( Evans-Hoeker et al. , 2016 ; Almquist et al. , 2017 ; Gong et al. , 2017 ; Yoo et al. , 2017 ; Likes et al. , 2019 ; Nezhat et al. , 2020 ; Sansone et al. , 2021 ; Shen et al. , 2021 ). The first work came from Evans-Hoeker and colleagues reporting that BCL6 was expressed in endometrial cells during the secretory phase of the menstrual cycle and was overexpressed in eutopic endometrium from women with endometriosis ( Evans-Hoeker et al. , 2016 ). The authors reported that aberrant BCL6 expression had a high sensitivity and specificity for the diagnosis of all stages of endometriosis, indicative of BCL6 as a biomarker for endometriosis. In support of this finding, another large cohort study showed a high positive predictive value of BCL6 expression for the diagnosis of endometriosis ( Nezhat et al. , 2020 ). In combination with Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer, BCL6 was shown to be increased in endometrial cells of women with endometriosis ( Yoo et al. , 2017 ). In addition, BCL6 was upregulated together with ERK1/ERK2 in endometriotic tissues from rats with experimentally induced endometriosis ( Nahari and Razi, 2018 ). BCL6 expression in human endometriosis. n   =   20 fertile controls. n   =   29 endometriosis at laparoscopy. n   =   28 fertile controls. n   =   119 women with UI. Exclusion criteria were age ≥40, pelvic infection/inflammation, PCOS, or fibroid tumors. BCL6 expression by qPCR (Gene Expression Assays; Applied Biosystems (Foster City, CA)—assay HS00153368); IHC and HSCORE with BCL6 antibody clone LN22 (Leica Biosystems). BCL6 was significantly higher in the secretory phase of patients with endometriosis versus controls ( P < 0.0001). Both BCL6 mRNA and protein were increased in endometrial epithelium of women with endometriosis. 93.8% of BCL6 positive patients had endometriosis. A cutoff of 1.4 in HSCORE provided a likelihood ratio of 15.4 and 0.04 for positive and negative results, respectively. Women with UI for >1 year. n   =   69: n   =   20 pregnant, age 36.3 ± 3.2 n   =   49 non-pregnant, age 34.5 ± 3.9. Groups based on BCL6 expression: n   =   17 normal expression (age 35.6 ± 3.1; n   =   11 pregnant/n   =   6 non-pregnant); n   =   52 high expression (age 34.8 ± 3.9; n   =   9 pregnant/n   =   43 non-pregnant). Clinical pregnancy rate and live birth rate per transfer were compared between women with positive or negative BCL6 staining. A high BCL6 expression was defined by a histologic score (>1.4) and strongly associated with poor reproductive outcomes in IVF cycles in women with UI BCL6 expression, median (range) was 0.9 (0–4) in the pregnant group and 2.1 (0.5–4.0) in the non-pregnant group ( P  =   0.01). Staining for BCL6 was predominantly localized in the nucleus. 75.3% of patients with UI-tested positive for BCL6. n   =   30 controls (age 32.77 ± 4.7). n   =   30 RIF (age 33.23 ± 5.06). Age 18–45. For control: 21 samples from proliferative (n   =   5) and secretory phase (n   =   16) for WB and 23 samples from the proliferative (n   =   6) and secretory (n   =   17) phase for IHC. For endometriosis: 54 samples from proliferative (n   =   16) and secretory (n   =   38) phase for WB and 57 samples for IHC. BCL6, KRAS and SIRT1 were co-ordinately over-expressed in eutopic endometrium of women with endometriosis and likely participated in the pathogenesis of endometriosis BCL6 and SIRT1 were co-localized in the nuclei of endometrial cells, bound to and suppressed the promoter of GLI1 , suggesting its role in progesterone action. Age 27–42, n   =   85 cycles. Three groups: medical suppression (n   =   10), laparoscopy (n   =   20), controls (n   =   54). Prospective cohort study. At least 1 year of UI, underwent endometrial biopsy, and IHC for BCL6 (clone LN22, Leica Biosystems), prior to embryo transfer during an ART cycle. Subjects had elevated BCL6 (HSCORE ≥ 1.4). Patients with positive endometrial BCL6, defined as an HSCORE >1.4, were associated with poor IVF outcomes and recurrent miscarriage. Increased endometrial BCL6 was associated with worse reproductive outcomes after embryo transfer, compared with women with endometriosis and treated with medical or laparoscopy. Age 29–47. n   =   72 endometriosis. n   =   3 with other pathologies. Inclusion criteria: women of reproductive age undergoing IVF with a diagnosis of UI or recurrent pregnancy loss, endometrial biopsy with ReceptivaDx™. Retrospective cohort study. Patients with endometrial BCL6 overexpression underwent laparoscopic surgery for treatment of suspected endometriosis. The positive predictive value of BCL6 testing for endometriosis was 96%. This could help to identify a patient population that may require surgical treatment before embryo transfer. Women with other pathologies (n   =   3) also had endometrial BCL6 overexpression. Age 18–42. n   =   10 control. n = 10, stages I/II endometriosis. n = 10, stages III/IV endometriosis. Patients were of reproductive age, had regular menstrual cycles, without (PCOS) or hormonal birth control. No differences in BCL6 levels were found between patients with endometriosis and controls. No differences in BCL6 levels were found between Stages I/II and III/IV. Levels of SIRT1 in sera were significantly elevated in women with Stages III/IV compared with controls and Stages I/II. Age ≤40. n   =   6. Blood and/or endometrial samples from the mid-luteal phase of the menstrual cycle. BCL6, B-cell lymphoma 6; GC, germinal center; GLI1 , glioma-associated oncogene homolog 1; HSCORE, a method for quantifying the staining intensity and the percentage of stained cells in IHC; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma viral oncogene homolog; qPCR, quantitative PCR; RIF, repeated implantation failure; SIRT1, Sirtuin 1; T FH , T follicular helper cells; UI, unexplained infertility; WB, western blot analysis. Endometriosis is associated with infertility and IVF failure ( Prapas et al. , 2012 ). Intriguingly, the prevalence of elevated endometrial BCL6 in women with unexplained infertility (UI) has been reported to be 75.3% ( Almquist et al. , 2017 ) and 80% ( Evans-Hoeker et al. , 2016 ). A prospective study in patients with UI following IVF showed a live birth rate of 11.5% versus 58% in patients with and without elevated BCL6, respectively ( Almquist et al. , 2017 ). It was also reported that the mRNA and protein levels of endometrial BCL6, along with IL21 and CXCR5 (chemokine receptor type 5), were significantly increased in women with repeated implantation failure ( Gong et al. , 2017 ). In support of these observations, Likes et al. (2019 ) reported that women with suspected endometriosis and aberrant endometrial BCL6 expression had worse reproductive outcomes following embryo transfer, including a high miscarriage rate, poor implantation rate, and low live birth rate and clinical pregnancy rate. Increased endometrial BCL6 is thus considered to be a negative predictor for patients with endometriosis undergoing IVF ( Nezhat et al. , 2020 ). Although more investigations are required, these findings demonstrate an association of upregulated BCL6 with endometriosis, its related infertility and IVF failure. At the molecular level, BCL6 and SIRT1 have been shown to co-localize in the nuclei of endometriotic cells, interact with each other and bind to and repress the promoter of GLI1 ( Yoo et al. , 2017 ), a critical mediator of progesterone action in the Indian Hedgehog pathway ( Wei et al. , 2010 ). Similarly, the BCL6/BCOR/SIRT1 complex was observed to affect the growth of human medulloblastoma cells by suppressing GLI1 and GLI2 of the Sonic Hedgehog pathway ( Tiberi et al. , 2014 ). These data indicate that BCL6 is an important regulator of the Hedgehog pathway, which renders upregulated BCL6 as a prime candidate driving the progesterone resistance that is crucial in the pathophysiology of endometriosis ( Yoo et al. , 2017 ). In addition, among the immune cells, T FH and GC B cells, controlled by BCL6 ( Hatzi and Melnick, 2014 ; Alterauge et al. , 2020 ), were present in the endometrium ( Shen et al. , 2021 ), suggesting the importance of these cells through GC reactions. Among these observations, the association of increased endometrial BCL6 with progesterone resistance ( Yoo et al. , 2017 ) is of particular importance. Progesterone is the key hormone for adequate decidualization, proper implantation and successful pregnancy, as it is crucial for preparing the endometrium for implantation by blocking the proliferative effect of estrogen and by inducing genes permitting embryo attachment, as well as for regulating trophoblast invasion and migration by controlling MMP activity ( Halasz and Szekeres-Bartho, 2013 ; Nagy et al. , 2021 ). Abnormal endometrial BCL6-associated progesterone resistance and its other cellular activities, including deregulated proliferation, invasion and immune modulation, may be responsible for a defective endometrium, deficient endometrial receptivity, poor reproductive outcomes, and failed IVF. These data also suggest a potential involvement of BCL6 in endometrial-blastocyst cross talk during implantation. As in trophoblasts ( Fig. 2 ), BCL6 may be overexpressed and stabilized in endometriotic tissues by diverse causes, including altered epigenetic regulation, increased IL6/STAT3, other cytokines, stress factors, miRNAs, lncRNAs and miscellaneous protein post-translational modifications. Increased BCL6 may regulate multiple signaling pathways including FAK, MAPK/ERK, PI3K/AKT, WNT and Hedgehog pathways in endometriotic cells, as occurs in lymphoma cells ( Basso et al. , 2010 ). This might affect vital cellular activities such as cell proliferation, survival, differentiation, migration, invasion, immune response and inflammation regulation ( Basso et al. , 2010 ; Louwen et al. , 2014 ; Muschol-Steinmetz et al. , 2016 ; Jasmer et al. , 2017 ; Ritter et al. , 2020 ), impact various functionalities of endometriotic cells, including glandular epithelial cells, stromal fibroblasts, stromal GC B and T FH cells and stem/progenitor cells, and contribute to the pathophysiology of endometriosis and its related infertility ( Fig. 5 ). Increased BCL6 in endometriosis. Schematic illustration shows that various factors may upregulate and stabilize BCL6, which may impact vital cellular activities in diverse cell types of endometrial tissues through multiple signaling pathways, affecting the pathogenesis of endometriosis and its related infertility. ECM, extracellular matrix; FAK, focal adhesion kinase; GC, germinal center; IL6, interleukin 6; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; STAT3, signal transducer and activator of transcription 3; T FH cells, T follicular helper cells.

B-cell lymphoma 6 (BCL6), a key oncogene, is a master regulator of humoral immunity and lymphoma survival ( Bunting and Melnick, 2013 ; Cardenas et al. , 2017 ). Interestingly, recent studies show that it has important functions in trophoblastic cells ( Louwen et al. , 2014 ; Muschol-Steinmetz et al. , 2016 ; Jasmer et al. , 2017 ; Ritter et al. , 2020 ) and is upregulated in pre-eclamptic placenta ( Enquobahrie et al. , 2008 ; Sitras et al. , 2009 ; Winn et al. , 2009 ; Nishizawa et al. , 2011 ; Xiang et al. , 2013 ; Louwen et al. , 2014 ; Trifonova et al. , 2014 ; Sober et al. , 2015 ; Than et al. , 2018 ; Guo et al. , 2021a ; Ren et al. , 2021 ) as well as in endometriotic lesions ( Evans-Hoeker et al. , 2016 ; Almquist et al. , 2017 ; Gong et al. , 2017 ; Yoo et al. , 2017 ; Likes et al. , 2019 ; Nezhat et al. , 2020 ; Sansone et al. , 2021 ; Shen et al. , 2021 ). These interesting observations provide evidence that this key oncogene may play physiological and pathological roles in the placenta and the endometrium. BCL6 was identified as a locus affected by chromosomal translocations in diffuse large B-cell lymphomas ( Ye et al. , 1993 ). It plays a major role in many lymphomas independent of genetic lesions, where it drives the malignant phenotype by promoting proliferation, deactivating DNA damage checkpoints, and inhibiting cell terminal differentiation ( Cardenas et al. , 2017 ). BCL6 is a master regulator of B cell differentiation in germinal centers (GCs), being critical for the initiation and maintenance of GC reactions, and a key oncogene in B-cell lymphomagenesis ( Basso and Dalla-Favera, 2010 ; Hatzi and Melnick, 2014 ). Beside B cells in GCs, BCL6 is also selectively expressed in follicular helper T cells (T FH ) ( Nurieva et al. , 2009 ). There is compelling evidence demonstrating that BCL6 is a lineage-defining transcription factor essential for T FH differentiation ( Nurieva et al. , 2009 ) and maintenance ( Alterauge et al. , 2020 ). BCL6 binds to canonical DNA sequences in the regulatory region of diverse target genes and recruits corepressor complexes that repress gene transcription. It consists of an N-terminal BTB/POZ domain mediating transcriptional repression, an unstructured middle region containing a second repression domain (RD2), and a series of six C 2 H 2 zinc fingers at the C-terminus that bind to DNA sequences and other proteins ( Hatzi and Melnick, 2014 ). To mediate repression, its N-terminal BTB domain recruits the corepressor proteins SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), NCOR (nuclear receptor corepressor) and BCOR (BCL6 interacting corepressor) to an extended groove motif along the BTB dimer interface ( Ahmad et al. , 2003 ; Ghetu et al. , 2008 ), whereas the central RD2 region interacts with CtBP (C-terminal binding protein), NuRD (nucleosome remodeling domain), MTA2 (metastasis-associated protein 2) and HDAC2 (histone deacetylase 2) to assist the repression of genes ( Huang et al. , 2014 ). These interactions enable BCL6 to repress the transcription of diverse genes ( Basso et al. , 2010 ; Basso and Dalla-Favera, 2012 ; Hatzi and Melnick, 2014 ), including proliferation inhibitors such as CDKN1A (cyclin-dependent kinase inhibitor 1A), CDKN1B , CDKN2A and CDKN2B , DNA damage response regulators like ATR ( ataxia telangiectasia and rad3-related protein ), CHEK1 (checkpoint kinase 1 ) and TP53 (tumor protein 53) and cell differentiation suppressors including IRF4 ( interferon regulatory factor 4 ) and PRDM1 (positive regulatory domain containing 1) ( Hatzi and Melnick, 2014 ). As BCL6 is also found in various tissues including skeletal muscle, breast and prostate ( Bajalica-Lagercrantz et al. , 1998 ; Logarajah et al. , 2003 ), it is not surprising that numerous studies demonstrate its involvement in solid tumors. Increased BCL6 expression has been reported in breast cancer ( Bos et al. , 2003 ; Logarajah et al. , 2003 ; Walker et al. , 2015 ), gastric cancer ( Hirata et al. , 2009 ), ovarian cancer ( Wang et al. , 2015 ), non-small-cell lung cancer ( Sun et al. , 2016 ) and glioblastoma ( Ruggieri et al. , 2014 ; Song et al. , 2018 ), which is associated with a range of malignant characteristics including tumor cell proliferation, survival, migration, invasion and therapy resistance ( Bos et al. , 2003 ; Hurtz et al. , 2011 ; Walker et al. , 2015 ; Cardenas et al. , 2017 ; Guo et al. , 2021b ). These observations highlight that BCL6 is also an important oncoprotein in solid tumors, although the precise molecular mechanisms remain to be elucidated. Intriguingly, BCL6 is richly expressed in the human placenta, and its increased expression is associated with the common disease of pregnancy, pre-eclampsia (PE) ( Enquobahrie et al. , 2008 ; Winn et al. , 2009 ; Sitras et al. , 2009 ; Nishizawa et al. , 2011 ; Xiang et al. , 2013 ; Louwen et al. , 2014 ; Trifonova et al. , 2014 ; Sober et al. , 2015 ; Than et al. , 2018 ; Guo et al. , 2021a ; Ren et al. , 2021 ). Recent studies also demonstrate that BCL6 is a diagnostic marker for endometriosis and its associated infertility ( Evans-Hoeker et al. , 2016 ; Almquist et al. , 2017 ; Gong et al. , 2017 ; Yoo et al. , 2017 ; Likes et al. , 2019 ; Nezhat et al. , 2020 ; Sansone et al. , 2021 ; Shen et al. , 2021 ). These data suggest that BCL6 is an important player in normal development as well as in disease of the placenta and the endometrium. In this narrative review, we have summarized the available data and discussed the pathophysiological roles of BCL6 in these two reproductive organs.

A comprehensive search of the PubMed database was conducted for this narrative review to identify peer-reviewed publications in English until October 2021, focused on the expression and roles of BCL6 in the human placenta, and the pathogenesis of PE and endometriosis. The search included the keywords BCL6, proliferation, migration, invasion, differentiation, fusion, inflammation and infertility, either alone or in combination with ‘placenta’, ‘pre-eclampsia’, ‘endometrium’, ‘endometriosis’ or ‘ in vitro fertilization’.

We have summarized the current data from bench to clinic showing BCL6’s potential function in the placenta and its critical involvement in PE and endometriosis. BCL6 is significantly increased in pre-eclamptic placentas as well as in endometriotic lesions. Upregulated BCL6 regulates a variety of cellular activities, including proliferation, migration and invasion, and may also influence stem/progenitor cell differentiation in pre-eclamptic placentas as well as in endometriotic lesions. Increased endometrial BCL6 is considered to be a diagnostic marker for endometriosis and a predictor for poor IVF outcomes. Proper regulation of BCL6 may be crucial to orchestrate endometrial decidualization, implantation and placentation for a successful pregnancy. Although some work has been done, the detailed molecular mechanisms by which BCL6 exerts multiple functions in the placenta as well as in the endometrium have not been completely elucidated. It is paramount to explore whether increased BCL6 is one of the causes for the initiation of PE and endometriosis owing to epigenetic modifications, or a pathological consequence of the disease-related high-stress conditions such as chronic hypoxia, inflammation and oxidation. Further investigations are warranted to examine whether BCL6 is able to co-determine the fate of various stem/progenitor cells in the placenta and the endometrium. Recent progress in the establishment of human trophoblast stem cells ( Okae et al. , 2018 ), placental organoids ( Haider et al. , 2018 ; Turco et al. , 2018 ) and endometrial organoids ( Turco et al. , 2017 ; Cheung et al. , 2021 ; Song and Fazleabas, 2021 ) has provided novel tools to study the molecular regulatory network of placentation, the endometrial cycle and the pathophysiology of gestational and reproductive diseases like PE and endometriosis. These new models, in combination with specific small molecule inhibitors targeting BCL6 or gene editing, will allow us to explore the individual roles of BCL6 in stemness and differentiation of trophoblastic and endometrial stem/progenitor cells. New omics technologies ( Cao et al. , 2017 ; Habib et al. , 2017 ) will be of great help to delineate the gene landscapes controlled by BCL6 in diverse trophoblastic and endometrial cell types. Being equipped with these novel tools and techniques, we are just at the beginning of a journey to unveil the multifaceted roles of BCL6 in placental development, endometrial homeostasis, and the pathogenesis of PE and endometriosis.