Outcomes of Preoperative Medical Therapy for Thyroidectomy in Autoimmune Thyroid Disease.

INTRODUCTION: Thyroidectomy provides definitive treatment for autoimmune thyroid disease (AITD) often resulting in improved quality of life. Historically, patients with AITD undergoing thyroidectomy have increased rates of postoperative hypoparathyroidism and recurrent laryngeal nerve palsy. We investigated the outcomes of preoperative medications in patients with AITD undergoing thyroidectomy. METHODS: We performed a retrospective analysis of patients who underwent thyroidectomy for AITD at a single institution from 2015 to 2021. Surgical outcomes and perioperative laboratory values were analyzed by type of AITD and type of preoperative medical treatment: none, saturated solution of potassium iodide (SSKI), corticosteroids, or both SSKI and corticosteroids. RESULTS: A total of 123 patients underwent thyroidectomy for AITD and were included in analysis: 50 received no preoperative medications, 40 received SSKI, 20 received corticosteroids, and 13 received both. Seventy-six patients had Graves' disease and 47 had Hashimoto's thyroiditis. There were no significant differences in blood loss, operative time, wound complications, hematoma, or recurrent laryngeal nerve injury for patients treated with preoperative corticosteroids compared to those who were not. Patients who received corticosteroids and patients with Graves' disease more commonly had at least one instance of hypocalcemia postoperatively (P < 0.01, P = 0.01), although only on postoperative day 1 was mean calcium < 8.5 mg/dL. There was no difference in rate of transient or permanent hypoparathyroidism. CONCLUSIONS: Patients who received corticosteroids preoperatively had no increased risk of complications. They did have mildly lower calcium levels in the early postoperative period, although no difference in hypoparathyroidism. Further exploration is warranted to investigate the impact of preoperative corticosteroids on operative difficulty, quality of life, and autoantibody clearance.

Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Primary Whole-gland Ablation for the Treatment of Clinically Localized Prostate Cancer: A Focal Therapy Society Best Practice Statement.

CONTEXT: Whole-gland ablation is a feasible and effective minimally invasive treatment for localized prostate cancer (PCa). Previous systematic reviews supported evidence for favorable functional outcomes, but oncological outcomes were inconclusive owing to limited follow-up. OBJECTIVE: To evaluate the real-world data on the mid- to long-term oncological and functional outcomes of whole-gland cryoablation and high-intensity focused ultrasound (HIFU) in patients with clinically localized PCa, and to provide expert recommendations and commentary on these findings. EVIDENCE ACQUISITION: We performed a systematic review of PubMed, Embase, and Cochrane Library publications through February 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. As endpoints, baseline clinical characteristics, and oncological and functional outcomes were assessed. To estimate the pooled prevalence of oncological, functional, and toxicity outcomes, and to quantify and explain the heterogeneity, random-effect meta-analyses and meta-regression analyses were performed. EVIDENCE SYNTHESIS: Twenty-nine studies were identified, including 14 on cryoablation and 15 on HIFU with a median follow-up of 72 mo. Most of the studies were retrospective (n = 23), with IDEAL (idea, development, exploration, assessment, and long-term study) stage 2b (n = 20) being most common. Biochemical recurrence-free survival, cancer-specific survival, overall survival, recurrence-free survival, and metastasis-free survival rates at 10 yr were 58%, 96%, 63%, 71-79%, and 84%, respectively. Erectile function was preserved in 37% of cases, and overall pad-free continence was achieved in 96% of cases, with a 1-yr rate of 97.4-98.8%. The rates of stricture, urinary retention, urinary tract infection, rectourethral fistula, and sepsis were observed to be 11%, 9.5%, 8%, 0.7%, and 0.8%, respectively. CONCLUSIONS: The mid- to long-term real-world data, and the safety profiles of cryoablation and HIFU are sound to support and be offered as primary treatment for appropriate patients with localized PCa. When compared with other existing treatment modalities for PCa, these ablative therapies provide nearly equivalent intermediate- to long-term oncological and toxicity outcomes, as well as excellent pad-free continence rates in the primary setting. This real-world clinical evidence provides long-term oncological and functional outcomes that enhance shared decision-making when balancing risks and expected outcomes that reflect patient preferences and values. PATIENT SUMMARY: Cryoablation and high-intensity focused ultrasound are minimally invasive treatments available to selectively treat localized prostate cancer, considering their nearly comparable intermediate- to long term cancer control and preservation of urinary continence to other radical treatments in the primary setting. However, a well-informed decision should be made based on one's values and preferences.

Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

[This corrects the article DOI: 10.3389/fendo.2021.662865.].

Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

Introduction/Purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and Methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

H1 histones control the epigenetic landscape by local chromatin compaction.

H1 linker histones are the most abundant chromatin-binding proteins1. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood2. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape.

Evaluation and Active Treatment versus Active Surveillance of Localized Prostate Cancer in Renal Transplant Patients in the Era of Low and Very Low Risk Prostate Cancer.

PURPOSE: Current trends in renal transplantation, such as improved allograft/recipient survival and expanded organ transplantation eligibility criteria in older recipients, are concomitant with increasingly detected low risk prostate cancer in candidates for or recipients of renal transplantation. We reviewed the evidence regarding prostate cancer screening, diagnosis and management in renal transplant candidates and recipients. We focused on published reports of prostate cancer incidence and diagnosis in patients with end stage renal disease, pretransplant screening recommendations, and recommendations regarding waiting time between treatment and active wait listing after the prostate cancer diagnosis in renal transplant candidates. In addition, we examined the natural history of prostate cancer development after renal transplantation in the setting of standard immunosuppression. MATERIALS AND METHODS: We reviewed the English language literature using search terms including prostate cancer, end stage renal disease, renal transplantation, prostate cancer screening, prostate specific antigen, prostate cancer treatment and active surveillance in various combinations. RESULTS: Prostate cancer screening is still widely done in almost all patients with end stage renal disease before and after transplantation. Active treatment of any patients with prostate cancer and a 5-year waiting period before transplantation can negatively affect the collective pool of participants and the overall survival of patients on dialysis. Several groups have proposed a shorter waiting time to kidney transplantation in patients with low risk prostate cancer. CONCLUSIONS: There are no standardized guidelines for screening and management of prostate cancer before and after transplantation. In the era of low risk prostate cancer end stage renal disease is a significant competing mortality risk factor. The role of active surveillance in these complex cases has yet to be well investigated. Further studies and nomograms are urged to integrate risk stratified screening and treatment protocols before and after renal transplantation.

microRNA-22 promotes megakaryocyte differentiation through repression of its target, GFI1.

Precise control of microRNA expression contributes to development and the establishment of tissue identity, including in proper hematopoietic commitment and differentiation, whereas aberrant expression of various microRNAs has been implicated in malignant transformation. A small number of microRNAs are upregulated in megakaryocytes, among them is microRNA-22 (miR-22). Dysregulation of miR-22 leads to various hematologic malignancies and disorders, but its role in hematopoiesis is not yet well established. Here we show that upregulation of miR-22 is a critical step in megakaryocyte differentiation. Megakaryocytic differentiation in cell lines is promoted upon overexpression of miR-22, whereas differentiation is disrupted in CRISPR/Cas9-generated miR-22 knockout cell lines, confirming that miR-22 is an essential mediator of this process. RNA-sequencing reveals that miR-22 loss results in downregulation of megakaryocyte-associated genes. Mechanistically, we identify the repressive transcription factor, GFI1, as the direct target of miR-22, and upregulation of GFI1 in the absence of miR-22 inhibits megakaryocyte differentiation. Knocking down aberrant GFI1 expression restores megakaryocytic differentiation in miR-22 knockout cells. Furthermore, we have characterized hematopoiesis in miR-22 knockout animals and confirmed that megakaryocyte differentiation is similarly impaired in vivo and upon ex vivo megakaryocyte differentiation. Consistently, repression of Gfi1 is incomplete in the megakaryocyte lineage in miR-22 knockout mice and Gfi1 is aberrantly expressed upon forced megakaryocyte differentiation in explanted bone marrow from miR-22 knockout animals. This study identifies a positive role for miR-22 in hematopoiesis, specifically in promoting megakaryocyte differentiation through repression of GFI1, a target antagonistic to this process.

British Neuropathological Society and International Society of Forensic Radiology and Imaging expert consensus statement for post mortem neurological imaging.

AIMS: To develop an expert consensus statement regarding appropriate clinical and forensic post mortem neurological imaging. METHODS: An expert panel of clinicians were recruited from registered members of the British Neuropathological Society (BNS) and the International Society of Forensic Radiology and Imaging (ISFRI) with post mortem expertise. Following a focus group meeting, 16 core statements were incorporated into an online modified Delphi survey and each panellist was asked to score their level of agreement. Following the first iteration, two statements that failed to reach consensus were modified and re-rated. Consensus was predefined as 75% agreement across responders. RESULTS: Seventeen experts joined the panel and 12 (70.6%) attended the focus group meeting; 14 (82%) completed both iterations of the survey. Consensus was reached for need of adequate clinical history, multidisciplinary discussion, establishment of special interest groups to discuss cases, gathering further evidence to inform imaging choices, establishment of methods for quality assessment in reporting standards and adequate funding for imaging services. The panel agreed that pathologists should be responsible for neuroimaging referrals, collating results of ancillary tests, and producing the final post mortem report. Areas requiring further discussion include the impact of double reporting, indications for neuroimaging and utilities of three-dimensional printing. CONCLUSION: The BNS/ISFRI statement represents current views of an expert panel of health professionals engaged in post-mortem neuroimaging. We hope this provides a working guideline for less experienced operators, stimulates discussion and highlights the most pressing clinical and research questions.

A Macro View of MicroRNAs: The Discovery of MicroRNAs and Their Role in Hematopoiesis and Hematologic Disease.

MicroRNAs (MiRNAs) are a class of endogenously encoded ~22 nucleotide, noncoding, single-stranded RNAs that contribute to development, body planning, stem cell differentiation, and tissue identity through posttranscriptional regulation and degradation of transcripts. Given their importance, it is predictable that dysregulation of MiRNAs, which target a wide variety of transcripts, can result in malignant transformation. In this review, we explore the discovery of MiRNAs, their mechanism of action, and the tools that aid in their discovery and study. Strikingly, many of the studies that have expanded our understanding of the contributions of MiRNAs to normal physiology and in the development of diseases have come from studies in the hematopoietic system and hematologic malignancies, with some of the earliest identified functions for mammalian MiRNAs coming from observations made in leukemias. So, with a special focus on the hematologic system, we will discuss how MiRNAs contribute to differentiation of stem cells and how dysregulation of MiRNAs contributes to the development of malignancy, by providing examples of specific MiRNAs that function as oncogenes or tumor suppressors, as well as of defects in MiRNA processing. Finally, we will discuss the promise of MiRNA-based therapeutics and challenges for the future study of disease-causing MiRNAs.

Salvage high-intensity focused ultrasound (HIFU) for locally recurrent prostate cancer after failed radiation therapy: Multi-institutional analysis of 418 patients.

OBJECTIVE: To report the oncological outcome of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after external beam radiotherapy (EBRT) from a multicentre database. PATIENTS AND METHODS: This retrospective study comprises patients from nine centres with local recurrent disease after EBRT treated with S-HIFU from 1995 to 2009. The biochemical failure-free survival (bFFS) rate was based on the 'Phoenix' definition (PSA nadir + 2 ng/mL). Secondary endpoints included progression to metastasis and cancer-specific death. Kaplan-Meier analysis was performed examining overall (OS), cancer-specific (CSS) and metastasis-free survival (MFS). Adverse events and quality of life status are reported. RESULTS: In all, 418 patients with a mean (SD) follow-up of 3.5 (2.5) years were included. The mean (SD) age was 68.6 (5.8) years and the PSA level before S-HIFU was 6.8 (7.8) ng/mL. The median PSA nadir after S-HIFU was 0.19 ng/mL. The OS, CSS and MFS rates at 7 years were 72%, 82% and 81%, respectively. At 5 years the bFFS rate was 58%, 51% and 36% for pre-EBRT low-, intermediate- and high-risk patients, respectively. The 5-year bFFS rate was 67%, 42% and 22% for pre-S-HIFU PSA level ≤4, 4-10 and ≥10 ng/mL, respectively. Complication rates decreased after the introduction of specific post-RT parameters: incontinence (grade II or III) from 32% to 19% (P = 0.002); bladder outlet obstruction or stenosis from 30% to 15% (P = 0.003); recto-urethral fistula decreased from 9% to 0.6% (P < 0.001). Study limitations include being a retrospective analysis from a registry with no control group. CONCLUSION: S-HIFU for locally recurrent prostate cancer after failed EBRT is associated with 7-year CSS and MFS rates of >80% at a price of significant morbidity. S-HIFU should be initiated early following EBRT failure.

High-intensity focused ultrasound for focal therapy: reality or pitfall?

PURPOSE OF REVIEW: Progress in imaging, fusion software, and ablative modalities has fostered growth of the latest image-guided generation of high-intensity focused ultrasound (HIFU) for focal treatment of prostate cancer. Although early reports are encouraging, important questions remain regarding candidate selection, treatment, and outcomes. We review contemporary considerations for the use of HIFU for focal treatment of primary and radio-recurrent prostate cancer. RECENT FINDINGS: HIFU has been used to treat prostate cancer for over two decades. More recently, stage migration from screening and improvements in pelvic imaging and fusion technology has resulted in wider clinical application of focal HIFU as a first-line treatment for localized prostate cancer. Advanced imaging has also improved targeting for focal salvage therapy of radio-recurrent disease. Proponents point to the minimally invasive nature, limited morbidity profile, and ability to perform retreatments in the future. Critics emphasize positive post-treatment biopsies, nonuniform treatment protocols, and absence of long-term follow-up. Thus, a review of clinical considerations and recently published data is warranted. SUMMARY: Recent advances have strengthened support for the use of focal HIFU. Although HIFU has great potential, it must be applied judiciously, maintaining appropriate oncologic principles in the setting of standardized trials to determine its true clinical value.

DNA damage: a sensible mediator of the differentiation decision in hematopoietic stem cells and in leukemia.

In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche.

Development of an objective tool for the diagnosis of myxedema coma.

Myxedema coma, a rare entity, with a reported 25%-65% mortality had no objective criteria for making the diagnosis when we began our study. We developed an objective screening tool for myxedema coma to more easily identify patients and examine the best treatment method in future prospective studies to reduce the mortality of this entity. We conducted a retrospective chart review to find all patients aged ≥18 years admitted with myxedema coma from January 1, 2005 through June 13, 2010 at Indiana University Health Methodist Hospital. On the basis of both our retrospective chart review and on literature accounts, we identified 6 criteria to diagnose myxedema coma. We identified 10 patients initially diagnosed with myxedema coma and established a control group consisting of 13 patients identified with altered mental status and increased thyroid-stimulating hormone (TSH) levels. The 6 variables we created for the screening tool were heart rate, temperature, Glasgow coma scale, TSH, free thyroxine, and precipitating factors. The screening tool has a sensitivity and specificity of about 80%. We ran a logistic regression model using the 10 study patients and 13 controls with the 6 variables. No variables alone significantly contributed to the model. However, the overall model was highly significant (P = 0.012), providing strong support for a scoring system that uses these variables simultaneously. This screening tool enables physicians to rapidly diagnose myxedema coma to expedite treatment. A more refined diagnostic tool may be used in future clinical studies designed to determine the optimal treatment.

Temporal occurrences and recurrence patterns of hypoglycemia during hospitalization.

OBJECTIVE: To describe the temporal distribution of hypoglycemia and its rate of recurrence during hospitalization to aid in the development of strategies to prevent hypoglycemia in hospitalized patients. METHODS: Retrospective review of hypoglycemia (blood glucose <50 mg/dL) audit data in adult hospitalized patients at 2 academic hospitals. Demographics, timing, and blood glucose values were recorded. Antihyperglycemic medications, number of recurrent events, and change in basal insulin dose following the hypoglycemic event were also extracted. RESULTS: A total of 274 index occurrences of hypoglycemia were analyzed. The mean age of the patients was 53.8 years, with roughly equal gender distributions. Twenty-eight percent of the events occurred in the absence of antihyperglycemic therapy. The incidence of hypoglycemia peaked between midnight and 6 AM. There were 36 instances of recurrent hypoglycemia associated with antihyperglycemic therapy, with 78% (n = 28) cases involving basal insulin. Patients on basal insulin who developed hypoglycemia did not have their dose changed prior to the time of the next administration in 75% of the cases. CONCLUSION: Hypoglycemia in hospitalized patients may occur with greater frequency overnight. Although cumbersome, routine nocturnal glycemic testing should be considered. Education regarding insulin management in the hospital and improved communication between night and day staff may aid in decreasing subsequent hypoglycemic events.

Does the multidisciplinary approach improve oncological outcomes in men undergoing surgical treatment for prostate cancer?

OBJECTIVES: To determine whether oncological outcomes are improved in prostate cancer patients by using a multidisciplinary strategy as compared with a standard clinic paradigm, and whether time to treatment is delayed when using a multidisciplinary approach. METHODS: We retrospectively analyzed patients who were evaluated and pursued radical prostatectomy as primary treatment, by the same surgeons, in the prostate cancer multidisciplinary clinic (n = 194) and standard urology clinic (n = 741) at Duke University Medical Center from 2005 to 2009. Comparisons of baseline characteristics were examined using rank sum and χ(2) -tests. Differences in time to radical prostatectomy and oncological outcomes were evaluated using multivariate linear and Cox regression, respectively. RESULTS: A greater proportion of high-risk patients (D'Amico criteria) were evaluated at the multidisciplinary clinic compared with the urology clinic (23.2% vs 15.6%, P = 0.014). Mean-adjusted time from biopsy to radical prostatectomy was shorter for multidisciplinary clinic patients (85.6 vs 96.8 days, P = 0.006). After a median follow up of 21 months, no significant difference was found between the multidisciplinary clinic and urology clinic in the risk of biochemical recurrence after radical prostatectomy, whether controlling for clinical (hazard ratio 0.71, P = 0.249) or pathological variables (hazard ratio 0.75, P = 0.349). CONCLUSIONS: Despite higher-risk disease, men evaluated using the multidisciplinary approach have similar oncological outcomes compared with men undergoing standard evaluation. Furthermore, time to radical prostatectomy is not delayed by the multidisciplinary management of these patients.

The role of PML in hematopoietic and leukemic stem cell maintenance.

The tumor suppressor promyelocytic leukemia (PML) was first identified as a component of PML-RARα fusion protein, one of the initiating cytogenetic abnormalities in acute promyelocytic leukemia. PML is now known to have diverse functions regulating the DNA-damage response, apoptosis, senescence, and angiogenesis. Recent investigations have identified PML as a regulator of metabolic pathways in stem cell compartments, including the hematopoietic system, and have provided researchers with new strategies for controlling stem cell maintenance and differentiation. Studies of PML in leukemia-initiating cells demonstrate that PML is also an essential component of their maintenance, which has drawn tremendous attention to PML from scientists in various stem cell fields. Here, we review research into PML and its associated pathways, including recent studies of PML as it relates to stem cell biology, as well as our finding that PML regulates fatty acid oxidation, which is essential to the maintenance of normal hematopoietic stem cells. We also discuss the therapeutic potential of controlling PML-associated pathways. In particular, we describe promising evidence for the use of arsenic trioxide in the treatment of chronic myeloid leukemia.