Use Of All-trans Retinoic Acid Research Articles

Gaillardin exerts potent antileukemic effects on HL-60 cells and intensifies arsenic trioxide cytotoxicity: Providing new insight into sesquiterpene lactones in leukaemia treatment.

The use of all-trans retinoic acid and arsenic trioxide resulted in favourable therapeutic responses in standard-risk acute promyelocytic leukaemia (APL) patients. However, resistance to these agents has made treating the high-risk subgroup more problematic, and possible side effects limit their clinical dosages. Numerous studies have proven the cytotoxic properties of Gaillardin, one of the Inula oculus-christi-derived sesquiterpene lactones. Due to the adverse effects of arsenic trioxide on the high-risk subgroup of APL patients, we aimed to assess the cytotoxic effect of Gaillardin on HL-60 cells as a single or combined-form approach. The results of the trypan blue and MTT assays outlined the potent cytotoxic properties of Gaillardin. The flow cytometric analysis and the mRNA expression levels revealed that Gaillardin attenuated the proliferative capacity of HL-60 cells through cell cycle arrest and induced apoptosis via reactive oxygen species generation. Moreover, the results of synergistic experiments indicated that this sesquiterpene lactone sensitizes HL-60 cells to the cytotoxic effects of arsenic trioxide. Taken together, the findings of the present investigation highlighted the antileukemic characteristics of Gaillardin by inducing G1 cell cycle arrest and triggering apoptosis. Gaillardin acts as an antileukemic metabolite against HL-60 cells and this study provides new insight into treating APL patients, especially in the high-risk subgroup.

Integrated Analysis Focusing on Genome-Wide DNA Methylation in Pediatric Acute Promyelocytic Leukemia: The Jccg Study, JPLSG AML-P05

Introduction: Pediatric acute promyelocytic leukemia (APL) represents approximately 5%-10% of all acute myeloid leukemia (AML). While the prognosis of APL patients has dramatically improved with the use of all-trans retinoic acid and arsenic trioxide, cases of relapse still exist. Moreover, the molecular biological basis of pediatric APL remains unknown. In adult and pediatric AML, to predict prognosis, DNA methylation patterns have been proposed as biomarkers. In this study, we aimed to investigate the molecular biological basis of pediatric APL and validate biomarkers associated with prognosis using an integrated analysis, including DNA methylation analysis, targeted deep sequencing, and RNA sequencing, in patients enrolled in the Japanese AML-P05 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Methods: Pediatric de novo APL patients (n = 38) who participated in the JPLSG AML-P05 trial from 2006 to 2009 were analyzed. Genome-wide DNA methylation analysis (n = 34), targeted deep sequencing (n = 35), RNA sequencing (n = 34), and motif analysis (n = 34) were performed. In the DNA methylation analysis, the Infinium MethylationEPIC v2.0 Kit (Illumina) was used. Results: Based on the most variable 1,000 DNA methylation values between patients, unsupervised hierarchical clustering classified APL patients into four clusters (cluster 1, 2a, 2b, and 3). Clusters 1 and 2a (n = 15) demonstrated a significantly higher DNA methylation levels at 87 CpG sites out of 1,000 compared to clusters 2b and 3 (n = 19). A part of the 87 CpG sites locate on the genes, such as CPM, GRB10 and BAALC, which have been reported to be associated with APL prognosis. A significant DNA methylation difference was found between the “high” (cluster 1 and 2a) and “low” (cluster 2b and 3) methylation groups at 2,372 CpG sites (Figure). Patients in the high methylation group presented with significantly worse outcomes compared to those in the low methylation group (3-year overall survival: 80% vs. 100%, p = 0.043; 3-year event-free survival: 73.3% vs. 94.7%, p = 0.049). Additionally, among the 2,372 CpG sites, motif analysis was performed for 783 CpG sites with an average methylation difference of 0.3 or higher. The binding domain of EBF1 was enriched among them. EBF1 is a critical transcriptional factor for B-cell differentiation. In the high methylation group, an aberrant B-cell differentiation was considered as a characteristic of APL. Gene expression analysis between the high and low methylation groups revealed significant differences in expression of 600 genes with more than twofold changes. Gene ontology analysis of the 600 genes revealed that their genes were enriched in T-cell and B-cell linage differentiation. In the targeted deep sequencing analysis, a total of 41 mutations in 21 genes in 25 patients were identified. The most frequent mutation was NRAS. Interestingly, previously unreported mutations in EP300 and BRCA2 were identified in APL, with EP300 mutations detected only in the high methylation group. Conclusions: DNA methylation analysis suggests that DNA methylation levels at specific CpG sites are effective biomarkers for the prognosis of pediatric APL. The presence of the EBF1 binding motif in the vicinity of these CpG sites suggests the involvement of EBF1 in prognosis.

Anti-tumor activity of all-trans retinoic acid in gastric-cancer: gene-networks and molecular mechanisms

BackgroundGastric-cancer is a heterogeneous type of neoplastic disease and it lacks appropriate therapeutic options. There is an urgent need for the development of innovative pharmacological strategies, particularly in consideration of the potential stratified/personalized treatment of this tumor. All-Trans Retinoic-acid (ATRA) is one of the active metabolites of vitamin-A. This natural compound is the first example of clinically approved cyto-differentiating agent, being used in the treatment of acute promyelocytic leukemia. ATRA may have significant therapeutic potential also in the context of solid tumors, including gastric-cancer. The present study provides pre-clinical evidence supporting the use of ATRA in the treatment of gastric-cancer using high-throughput approaches.MethodsWe evaluated the anti-proliferative action of ATRA in 27 gastric-cancer cell-lines and tissue-slice cultures from 13 gastric-cancer patients. We performed RNA-sequencing studies in 13 cell-lines exposed to ATRA. We used these and the gastric-cancer RNA-sequencing data of the TCGA/CCLE datasets to conduct multiple computational analyses.ResultsProfiling of our large panel of gastric-cancer cell-lines for their quantitative response to the anti-proliferative effects of ATRA indicate that approximately half of the cell-lines are characterized by sensitivity to the retinoid. The constitutive transcriptomic profiles of these cell-lines permitted the construction of a model consisting of 42 genes, whose expression correlates with ATRA-sensitivity. The model predicts that 45% of the TCGA gastric-cancers are sensitive to ATRA. RNA-sequencing studies performed in retinoid-treated gastric-cancer cell-lines provide insights into the gene-networks underlying ATRA anti-tumor activity. In addition, our data demonstrate that ATRA exerts significant immune-modulatory effects, which seem to be largely controlled by IRF1 up-regulation. Finally, we provide evidence of a feed-back loop between IRF1 and DHRS3, another gene which is up-regulated by ATRA.ConclusionsATRA is endowed with significant therapeutic potential in the stratified/personalized treatment gastric-cancer. Our data represent the fundaments for the design of clinical trials focusing on the use of ATRA in the personalized treatment of this heterogeneous tumor. Our gene-expression model will permit the development of a predictive tool for the selection of ATRA-sensitive gastric-cancer patients. The immune-regulatory responses activated by ATRA suggest that the retinoid and immune-checkpoint inhibitors constitute rational combinations for the management of gastric-cancer.

ATRA ameliorates fibrosis by suppressing the pro-fibrotic molecule Fra2/AP-1 in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to irreversible fibrosis of the skin and the internal organs. The etiology of SSc is complex, its pathophysiology is poorly understood, and clinical therapeutic options are restricted. Thus, research into medications and targets for treating fibrosis is essential and urgent. Fos-related antigen 2 (Fra2) is a transcription factor that is a member of the activator protein-1 family. Fra2 transgenic mice were shown to have spontaneous fibrosis. All-trans retinoic acid (ATRA) is a vitamin A intermediate metabolite and ligand for the retinoic acid receptor (RAR), which possesses anti-inflammatory and anti-proliferative properties. Recent research has demonstrated that ATRA also has an anti-fibrotic effect. However, the exact mechanism is not fully understood. Interestingly, we identified potential binding sites for the transcription factor RARα to the promoter region of the FRA2 gene through JASPAR and PROMO databases. In this study, the pro-fibrotic effect of Fra2 in SSc is confirmed. SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc animals exhibit increased levels of Fra2. Inhibition of Fra2 expression in SSc dermal fibroblasts with Fra2 siRNA markedly decreased collagen I expression. ATRA reduced the expressions of Fra2, collagen I, and α-smooth muscle actin(α-SMA) in SSc dermal fibroblasts and bleomycin-induced fibrotic tissues of SSc mice. In addition, chromatin immunoprecipitation and dual-luciferase assays demonstrated that retinoic acid receptor RARα binds to the FRA2 promoter and modulates its transcriptional activity. ATRA decreases collagen I expression both in vivo and in vitro via the reduction of Fra2 expression. This work establishes the rationale for expanding the use of ATRA in the treatment of SSc and indicates that Fra2 can be used as an anti-fibrotic target.

All Trans Retinoic Acid: A Cerebral Friend or Foe? (P3-5.002)

<h3>Objective:</h3> NA <h3>Background:</h3> All-trans retinoic acid (ATRA) is an initial treatment for acute promyelocytic leukemia (APL). Studies suggest that ATRA has neuroprotective effects since it reduces atherosclerosis and neural inflammation. We present a case series of patients that developed acute recurrent ischemic strokes and demonstrated rapid progression of intracranial and extracranial stenosis in the setting of ATRA therapy. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case 1:</h3> A 47-year-old female with a history of hypertension presented with symptoms concerning for myocardial infarction, deep venous thrombosis, and thrombocytopenia which led to a diagnosis of APL. She was treated with ATRA and two days later developed left gaze deviation, facial droop, and left hemiparesis. Vessel imaging revealed a right middle cerebral artery (MCA) occlusion. Despite successful thrombectomy, the patient continued to decline. Repeat imaging showed re-occlusion of the right MCA as well as a new left MCA infarct. She later developed diffuse cerebral edema and fatal herniation. <h3>Case 2:</h3> A 41-year-old female with a history of hypertension and APL treated with ATRA had multiple recent strokes involving bilateral frontal, left occipital and watershed territories. Vessel imaging during the first admission did not show any stenosis. Over the course of the next seven months, she had multiple admissions for recurrent strokes with rapid progression and worsening of her intracranial stenosis despite dual antiplatelet and statin therapy. Cerebrospinal fluid analysis including cell count, protein, cytology and flow cytometry was unremarkable. She subsequently developed extensor posturing with paraparesis due to malignant cerebral edema and died. <h3>Conclusions:</h3> The underlying mechanism of accelerated vessel stenosis in the above cases is unknown. Further research should explore whether ATRA use in APL is indeed associated with the progression and/or poor clinical outcomes in the setting of acute ischemic stroke. Clinicians should remain vigilant about the concomitant use of ATRA in patients with a history of vascular risk factors. <b>Disclosure:</b> Mannyam, MD (Jackson, MS); Maryam

Potential antitumour effect of all-trans retinoic acid on regorafenib-treated human colon cancer cell lines.

Colorectal cancer (CRC) is a significant contributor to cancer-related mortality worldwide, ranking as the second leading cause of such deaths. Central to the progression of this malignancy is angiogenesis - a complex process orchestrated by vascular endothelial growth factor (VEGF). Regorafenib, a potent multikinase inhibitor, acts as a critical antagonist of multiple kinases involved in angiogenesis, proliferation, and metastasis. Conversely, all-trans retinoic acid (ATRA) has demonstrated compelling antitumour effects across various cancer types. This study aims to comprehensively evaluate the combined antitumour potential of ATRA and regorafenib in human colon cancer cell lines while elucidating the intricate molecular mechanisms that underlie their action. Our investigative approach involved an enzyme-linked immunosorbent assay to meticulously analyse the levels of key players in the VEGF signalling pathway, including VEGF itself, activated protein kinase (AMPK), extracellular signal-regulated protein kinase 1 (ERK1), and nuclear factor kappa B (NF-κB). Additionally, we assessed caspase-3 activity as a fundamental marker of apoptosis. The combined use of ATRA and regorafenib exhibited a remarkable augmentation in both AMPK and caspase-3 activities. This was accompanied by a significant reduction in VEGF, ERK1, and NF-κB levels within human colon cancer cell lines subjected to regorafenib treatment. Our findings underscore the remarkable antiproliferative, antiangiogenic, and proapoptotic effects resulting from the combined use of ATRA and regorafenib in the context of CRC. This modulation of tumourigenic processes is predominantly mediated through the VEGF signalling axis.

Intracranial hypertension associated with treatment of acute promyelocytic leukemia with all-trans retinoic acid (ATRA): a case report

Case presentation&#x0D; Female, 18 years-old, without relevant family history, referred to Neurology by Hematology for headache. 3 years ago, she was diagnosed with Acute Promyelocytic Leukemia (APL) currently on maintenance therapy with All-Trans Retinoic Acid (ATRA). The patient reports that in all previous cycles presented headache with the following characters: one-side temporal location, pulsating quality, moderate intensity, with nausea and vomiting, photophobia and phonophobia, uncertain duration, with simple analgesics response. In the current cycle, she relates continuous pain, severe intensity and unresponsive to medication. On examination, there were no focal neurological findings and on funduscopic examination there was no papilledema. MRI and laboratorial tests were normal. Cerebrospinal fluid (CSF) opening pressure was 35 cmH2O, no other alterations. 15 milliliters of CSF were removed, with a closing pressure of 25 cmH2O. A hypothesis of Intracranial Hypertension associated with use of ATRA was made. Afterwards, there was important improvement of the headache, with residual pain of mild intensity. Therefore, Acetazolamide was started at a dose of 250 milligrams every 12 hours with complete resolution of symptoms.&#x0D; &#x0D; Discussion&#x0D; Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood cell cancers that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variant of AML. APL is classified as acute promyelocytic leukemia with PML-RARA. The cytogenetic hallmark of APL is a translocation involving RARA, the retinoic acid receptor alpha locus on chromosome 17. Without treatment, APL is the most malignant form of AML, with a median survival of less than one month.&#x0D; (To see the complete abstract, please, check out the PDF).

P542: REAL WORLD OUTCOMES FOR PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA IN BRITISH COLUMBIA (BC): EXCELLENT OUTCOMES WITH LOW EARLY DEATH RATE AND HIGH OVERALL SURVIVAL IN A POPULATION BASED STUDY

Background: Acute promyelocytic leukaemia (APL) therapy has significantly improved with the use of All trans retinoic acid (ATRA) and Arsenic Trioxide (ATO) for low risk disease (Lo-Coco 2013). Treatment of high risk disease remains more challenging with a higher risk of early mortality & greater concern of relapse. All patients (pts) with APL in British Columbia, Canada are treated by the Leukemia/BMT Program at Vancouver General Hospital, Vancouver. Since 2014, all pts have received ATRA/ATO based therapy based on the Le-Coco study. Pts with high risk disease (WCC > 10 x 109/L at presentation) also receive a 3 day course of doxorubicin (60mg/m2) for induction only. Aims: We sought to review treatment outcomes since initiating these treatment protocols with emphasis on drug toxicities, dose modifications & management of high risk & elderly patients in order to describe real world outcomes. Methods: Ethics was approved by the board of the BCCA and UBC. Data was collected by chart reviews, hospital databases & collated on a central file. Demographics, risk stratification, treatment received, adverse events & survival was collected & analysis performed on Microsoft excel v16.57 & SPSS Statistics v28.0.1.1. Kaplan Meier curves were performed for PFS & OS, student t and chi squared tests were performed to assess differences between subgroups. Results: We identified 67 pts with APL during the study period. 40% were male 60% female, the median age was 61 yrs. (21-83yo). 36(54%) pts were > 60 yrs at diagnosis. The median duration of follow up was 2.9 yrs. All had molecular confirmation of disease. 16(24%) pts had high risk disease at diagnosis. At time of censor overall survival was 97% and PFS 94%. 55(82%) pts had a documented toxicity. Common toxicities included differentiation syndrome (DS) in 27(40%) pts, hepatotoxicity 17 (25%), QTc prolongation 13(19%) & neurological effects 9 (13%). Infections were documented in 40(59%) pts including bacterial infections in 25 patients (37%), culture negative febrile neutropenia in 12 (20%), viral infections in 5 (7%) & fungal infections in 1 (1.5%). Clinically significant bleeding was documented in 10 (15%) of patients, 5 of which were CNS/retinal bleeds. DS was more common in high risk disease though this difference was not statistically significant (p=0.365). 8(30%) pts with DS needed ICU admission. There were 2 early deaths, in the cohort, both in pts > 75 yo with high risk disease due to multi-organ failure and bleeding within 5 days of presentation. Dose modifications were assessed in 64 pts (2 deaths & one lost to follow up). 37 (58%) were described as having had a dose modification. 13 (20%) had a reduction in treatment dose, 16(25%) had doses/days of drug omitted. 6(9%) had reductions in dose and omissions. The most common reasons for dose modifications were DS 12(19%), QTc prolongation 10 (15%) & hepatotoxicity 8 (12%). Pts over 60yo were more likely to have a dose modification than pts below 60yo (73% vs 43% p = 0.014). 65 pts diagnosed achieved morphological remission & 64 a molecular remission at the end of planned therapy. 2 relapses occurred in our cohort, 1 had a concomitant cytogenetic abnormality incorporating a Tp53 deletion. The second initially received ATRA only induction due to age & comorbidity. Summary/Conclusion: This real world, population based data for patients with APL in BC confirms high response rates, survival and relatively low early death rate and acceptable toxicity even in older patients with high risk disease and comorbidities. In our cohort appropriate dose modifications did not impact remission or relapse rates.

Inhibition of myeloid-derived suppressive cell function with all-trans retinoic acid enhanced anti-PD-L1 efficacy in cervical cancer

PD-1/PD-L1 inhibitor treatments are relatively inefficacious in advanced cervical cancer patients. The presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment may be one significant barrier to efficacy. It has been shown that all-trans retinoic acid (ATRA) can differentiate MDSCs into mature myeloid cells. However, whether ATRA suppression of MDSCs function could enhance PD-L1 blockade-mediated tumor immunotherapy remains unknown. Here, the frequency of tumor-infiltrating MDSCs in cervical cancer patients was measured. ATRA was used to target MDSCs both in vitro and in tumor-bearing mice. The impact of ATRA on the human cell line HeLa was also investigated. The frequency of MDSCs and T cells was determined by flow cytometry. The expression of immunosuppressive genes was measured with quantitative real time-PCR and infiltration of immune cells was assessed by immunohistochemical examination. We found that tumor-infiltrating PD-L1+ MDSCs were more prevalent in cervical cancer patients. Blockade of PD-L1 expression in MDSCs with anti-PD-L1 antibody cannot relieve the suppressive activity of MDSCs induced by HeLa cells, while ATRA efficiently abrogated the suppressive activity of MDSCs. Furthermore, ATRA had no effect on PD-L1 expression in HeLa cells in vitro. In in vivo treatment, ATRA decreased MDSCs accumulation and increased the frequency of CD8+ T cells in BALB/C mice with U14 cervical tumors. Importantly, a combination treatment of ATRA and anti-PD-L1 antibody further delayed U14 tumor growth and increased the proportion of CD62L−CD8+ T cells, CD62L−CD4+ T cells, CD107a+CD8+ T cells as well as IFN-γ and TNF-α levels in tumors. Our results provide a rationale for the use of ATRA to suppress MDSCs and enhance anti-PD-L1 cancer immunotherapy in cervical cancer.

Extracellular Traps Increase Burden of Bleeding by Damaging Endothelial Cell in Acute Promyelocytic Leukaemia.

The rate of complete remission of acute promyelocytic leukemia (APL) is currently over 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). However, hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission. Neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells. We have previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin, termed ETosis/NETosis. However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown. Here, we analysed the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL. Importantly, the effect of ETs on vascular endothelium in APL was discussed. Our results showed that the ability of immature neutrophils to release ETs was impaired in APL, whereas mature neutrophils produced ETs, which were associated with activated PLTs. Moreover, ATRA+ATO induced immature neutrophil differentiation, as well as increased the release of ETs from mature neutrophils. The excessive ETs damaged endothelial cells, causing blood cell leakage. Removing ETs using DNase 1 alleviated endothelial damage and improved blood cells leakage. Our results indicate that vascular endothelial injury is at least partially associated with ETs in APL, and that targeting ETs production may be an effective approach for relieving vascular leakage and reducing the burden of bleeding in APL.

Low specificity of HLA-DR expression for diagnosis of acute promyelocytic leukemia

Contemporary therapy of acute promyelocytic leukemia (APL) is based on the use of all-trans retinoic acid, which is effective against tumor cells harboring RARa gene rearrangements (most common – t(15;17)(q24;q21)/PML::RARa). In several studies, it was suggested to use typical immunophenotypic features of APL (HLA-DR-negativity, etc) for prediction of RARa rearrangements presence. In this study, we aimed to evaluate the range of genetic aberrations that could be found in the HLA-DR-negative acute myeloid leukemia (AML). Our study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Among studied 806 pediatric AML patients, HLA-DR-negativity was found in 253 cases. Only in 45.4% of them t(15;17)(q24;q21)/PML::RARa was found, while in remaining 54.6% normal karyotype or other genetic aberrations without RARa involvement. Frequency of the most common immunophenotypic features of APL, such as total CD117, CD33 and MPO expression with the lack of CD34, was higher in patients with t(15;17)(q24;q21)/PML::RARa, although only two thirds of APL cases were found to have all these signs. Moreover, the percentage of cells positive or negative for mentioned antigens varied significantly in APL group. Thus we can conclude, that all “typical” immunophenotypic characteristics of APL including HLA-DR-negativity, are very unspecific and cannot be used for reliable prediction of presence of t(15;17)(q24;q21)/PML::RARa.

The treatment with all-trans retinoic acid causes apoptosis without chromosomal instability in adipose-derived stem cells and might act starting the browning process

Introduction: The knowledge about the biology of obesity and apoptosis induction of adipose-derived stem cells (ADSCs) may support in the development of new therapies. Objective: The present research aimed to investigate the toxicogenic effect of all-trans retinoic acid (ATRA) as well as its influence in the adipogenic differentiation and expression of genes related to DNA damage, cell cycle and thermogenesis. Methodology: Cell cultures of human adipose-derived stem cells were treated for 12 hours with ATRA (20.75 μM) and were performed the adipogenic differentiation, comet assay, micronucleous, cell death, cell cycle and qPCR. Results: The ATRA treatment decreased the capacity of adipogenic differentiation of ADSCs. The comet assay demonstrated increase in nucleoid frequency with genomic damage and scoring. However, these damages were not fixed at the chromosome level, since the tail moment was not significant. The treatment with ATRA increased cytotoxicity and increased cell death by apoptosis. The relative expression of CHEK-1, CHEK-2, CDC25A, CDC25C, ATM and ATR decreased and only UCP1 increased significantly. Conclusion: The results of the present study demonstrate that the use of ATRA induces genomic damage in ADSCs, although it was eliminated in the apoptosis process. Therefore, administration of ATRA in ADSCs did not cause chromosomal instability, which suggests toxicogenic safety. Also it was considered that ATRA might active the browning effect. Thus, this compound is considered a promising candidate for the development of novel therapies for the treatment of obesity and / or localized fat by the use of mesotherapy.

Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4β7 Integrin and Direct Their Migration In Vitro.

Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4β7 via binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to function. However, the unstable nature and toxicity of ATRA limit its use as a widespread treatment modality for mucosal diseases. Therefore, identifying alternatives that could reduce or eliminate the use of ATRA are needed. Rexinoids are synthetically derived compounds structurally similar to ATRA. Originally named for their ability to bind RXRs, rexinoids can enhance RAR-mediated gene transcription. Furthermore, rexinoids are more stable than ATRA and possess an improved safety profile, making them attractive candidates for use in clinical settings. Here we show that select novel rexinoids act as ATRA mimics, as they cause increased CCR9 and α4β7 expression and enhanced migration to the CCR9 ligand, CCL25 in vitro, even in the absence of ATRA. Conversely, other rexinoids act synergistically with ATRA, as culturing cells with suboptimal doses of both compounds resulted in CCR9 expression and migration to CCL25. Overall, our findings show that rexinoids can be used independently or synergistically with ATRA to promote mucosal homing of T cells in vitro, and lends support for the prospective clinical use of these compounds in immunotherapeutic approaches for pathogenic infections or cancers at mucosal surfaces.

Update on acute promyelocytic leukemia in the pediatric population

Acute promyelocytic leukemia (APL) has shown differences in incidence around the world, it has a characteristic molecular, pathogenic and clinical development mechanism. Despite being a low incidence acute myeloid leukemia (AML) compared to other AML and having a good response to therapy, it continues to be of interest due to the toxicities of its current treatment, to mutations that have shown resistance to those drugs, and to the few possibilities of alternative treatment with all-trans retinoic acid (ATRA) and anthracyclines in the pediatric population. Furthermore, the description of new mutations that originate APL produced by LPA generates new interest in studies that may shed light on their effects on the disease’s incidence, prognoses, and response to treatment. This article aims to review different studies that describe findings of APL in terms of incidences, treatments, side effects, survival, especially in the pediatric population. Different studies propose the use of ATRA - arsenic trioxide (ATO) as the first line of treatment, however, few have been carried out in the pediatric population and the use of ATO is not recommended in children under 5 years of age. On the other hand, the differentiation syndrome (DS) has been d

Impact of sociodemographic factors on early mortality in acute promyelocytic leukemia in the United States: A time-trend analysis.

The survival of patients with acute promyelocytic leukemia (APL) has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, because of the complexity of the initial management, early mortality (EM) remains a major contributor to treatment failure. It is less known whether advances in treatment, urgent access to specialized care, and broad availability of ATRA/ATO have reduced EM in the last 2 decades. Furthermore, the influence of sociodemographic factors on the risk of EM also remains unclear. This study used the Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on the rates of EM and overall survival (OS) in patients with APL diagnosed between 1992 and 2015. In all, 2224 cases were identified (895 who were younger than 40 years and 1329 who were 40 years old or older); 47.9% had a county-level median household income of $59,630 or higher, 49.0% belonged to counties where more than 31% of adults held at least a bachelor's degree, and 86.0% resided in urban areas. The rate of EM declined from 31.5% in 1992-1995 to 15.9% in 2012-2015 for all patients. It improved for patients younger than 40 years (27.4% in 1992-1995 vs 5.4% in 2012-2015; P < .001) and for patients 40 years old or older but not to the same extent (35.2% in 1992-1995 vs 22.2% in 2012-2015; P = .02). Importantly, improvements in EM were not seen among patients residing in rural areas, with the rate remaining higher than 20% in 2012-2015. The 3-year OS rate was 49.2% for patients with APL diagnosed in 1992-1995 and 76.4% for patients diagnosed in 2012-2015. These findings confirm consistent improvements in EM and OS for patients with APL and point to the challenge of further extending these improvements in EM rates to older patients and to those living in rural areas.

Rate of Differentiation Syndrome in Patients Based on Timing of Initial All-Trans Retinoic Acid Administration

Rate of Differentiation Syndrome in Patients Based on Timing of Initial All-Trans Retinoic Acid Administration

Impact of insurance status on the survival of younger patients diagnosed with acute promyelocytic leukemia in the United States.

Survival among patients diagnosed with acute promyelocytic leukemia (APL) has significantly improved with the use of all-trans retinoic acid and arsenic trioxide. However, the need for immediate diagnosis and access to specialized care and the cost associated with APL management can potentially act as barriers for disadvantaged patients. The influence of sociodemographic factors on the outcomes of patients with APL remains unclear. The authors used the National Cancer Institute's Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on survival in patients younger than 65 years with APL. The authors identified 1787 cases: 816 who were younger than 40 years and 971 who were 40 years old or older. Insured patients who were younger than 40 years had an improved 5-year overall survival (OS) rate in comparison with patients without insurance. Among patients who were 40 years or older, having insurance (other than Medicaid) was associated with better survival than being a Medicaid beneficiary or being uninsured, whereas patients with Medicaid had improved 5-year OS in comparison with uninsured patients. In a multivariate analysis of patients younger than 40 years, a higher risk of death was associated with being male, being diagnosed in earlier years, and being uninsured. For patients who were 40 years old or older, mortality increased with increasing age and for both Medicaid and uninsured patients in comparison with insured patients. Despite the high cure rate experienced by patients with APL, patients younger than 65 years without insurance and those 40 years old or older with Medicaid are at a significant disadvantage in comparison with patients with insurance. These findings point to an opportunity to improve survival in APL by addressing access to care.

Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy.

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of pseudotumor cerebri and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term sequelae.

Walking a Tightrope: Dosage Modifications and Treatment Outcomes of All-Trans-Retinoic Acid, Arsenic Trioxide, and Daunorubicin for High-Risk Acute Promyelocytic Leukemia.

PURPOSEThe use of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) in the treatment of low- and intermediate-risk acute promyelocytic leukemia (APL) is the standard of care. We report the combined use of ATRA, ATO, and daunorubicin (DNR) in patients newly diagnosed with high-risk APL. The primary focus was to describe the drug dosage modifications made in the real-world scenario.METHODSIn this descriptive study, we included 16 out of 28 patients with high-risk APL from two tertiary care centers in South India (Vijayawada and Trichy) between January 2015 and December 2018. A unique approach of initiating ATRA at a dose of 25 mg/m2 on day 1 and escalation to 45 mg/m2 after cytoreduction with DNR and hydroxyurea was followed in all patients to avert differentiation syndrome, in the setting of hyperleukocytosis at presentation.RESULTSAll patients who survived the first 3 days of admission achieved complete remission after a median duration of 29 days. There were no deaths during induction or consolidation, and the regimen was well tolerated; two patients developed grade 3/4 peripheral neuropathy requiring treatment modification. After a median follow-up duration of 1.9 years, there were no hematologic or molecular relapses.CONCLUSIONThe study sheds light on the modifications made to recommended dosages of ATRA, ATO, and DNR to optimize outcomes in high-risk APL and reaffirms the importance of ATO use in the front-line setting to achieve durable responses with minimal toxicity.

Effect of endoplasmic reticulum stress induced by all-trans retinoic acid on apoptosis of FLT3-ITD mutated leukemia cells by activating autophagy in FLT3-ITD mutated protein

目的以内质网应激（ERS）为切入点，深入研究全反式维甲酸（ATRA）调控FLT3-ITD突变蛋白表达下降，导致FLT3-ITD突变阳性白血病细胞凋亡的分子机制。方法ATRA处理FLT3-ITD突变阳性白血病细胞株（MV4-11和MOLM13），流式细胞术检测细胞凋亡，实时荧光定量PCR和Western blot法分别检测细胞ERS相关和（或）自噬相关基因及蛋白的表达。结果低剂量ATRA可提高FLT3-ITD突变阳性白血病细胞的ERS水平；ATRA作用于ERS相关的PERK/eif2ɑ信号通路，使FLT3-ITD突变阳性细胞的ERS水平持续升高，CHOP基因表达上调；FLT3-ITD突变阳性细胞经ATRA处理后，FLT3-ITD蛋白表达水平降低；细胞内与ERS有关的并且主要的两个蛋白降解途径中，与内质网关联降解（ERAD）相关的蛋白ATF6表达无明显变化，而与内质网激活自噬（ERAA）相关的自噬相关蛋白Atg5和Atg7表达明显升高。结论ATRA通过激活PERK/eif2ɑ信号通路持续上调FLT3-ITD突变阳性细胞的ERS水平，通过ERAA途径自噬降解FLT3-ITD蛋白，促进白血病细胞凋亡。研究结果为临床应用ATRA治疗难治性FLT3-ITD突变阳性白血病提供了初步实验依据。