Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response.

Regulation of the hematopoietic stem cell pool by C-Kit-associated trogocytosis.

Hematopoietic stem cells (HSCs) are routinely mobilized from the bone marrow (BM) to the blood circulation for clinical transplantation. However, the precise mechanisms by which individual stem cells exit the marrow are not understood. This study identified cell-extrinsic and molecular determinants of a mobilizable pool of blood-forming stem cells.

An iron rheostat controls hematopoietic stem cell fate.

Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis.

TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is initiated and sustained by a hierarchy of leukemia stem cells (LSCs), and elimination of this cell population is required for curative therapies. Here we show that transmembrane and immunoglobulin domain containing 2 (TMIGD2), a recently discovered co-stimulatory immune receptor, is aberrantly expressed by human AML cells, and can be used to identify and enrich functional LSCs. We demonstrate that TMIGD2 is required for the development and maintenance of AML and self-renewal of LSCs but is not essential for normal hematopoiesis.

Complete miRNA-15/16 loss in mice promotes hematopoietic progenitor expansion and a myeloid-biased hyperproliferative state.

Dysregulated apoptosis and proliferation are fundamental properties of cancer, and microRNAs (miRNA) are critical regulators of these processes. Loss of miR-15a/16-1 at chromosome 13q14 is the most common genomic aberration in chronic lymphocytic leukemia (CLL). Correspondingly, the deletion of either murine miR-15a/16-1 or miR-15b/16-2 locus in mice is linked to B cell lymphoproliferative malignancies.

Ciclopirox ethanolamine preserves the immature state of human HSCs by mediating intracellular iron content.

Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. To elucidate regulatory mechanisms governing the maintenance and propagation of human HSCs ex vivo, we screened libraries of annotated small molecules in human cord blood cells using an optimized assay for detection of functional HSCs during culture. We found that the antifungal agent ciclopirox ethanolamine (CPX) selectively supported immature CD34+CD90+ cells during culture and enhanced their long-term in vivo repopulation capacity.

Role of IL8 in myeloid malignancies.

Aberrant overexpression of Interleukin-8 (IL8) has been reported in Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), Myeloproliferative Neoplasms (MPNs) and other myeloid malignancies. IL8 (CXCL8) is a CXC chemokine that is secreted by aberrant hematopoietic stem and progenitors as well as other cells in the tumor microenvironment. IL8 can bind to CXCR1/CXCR2 receptors and activate oncogenic signaling pathways, and also increase the recruitment of myeloid derived suppressor cells to the tumor microenvironment.

Clinical outcomes: endoscopic resection of duodenal ampullary lesions.

Background: Ampullary adenomas are lesions at the duodenum's major papilla commonly associated with familial adenomatous polyposis (FAP) but may also occur sporadically. Historically, ampullary adenomas were removed surgically, however endoscopic resection has become the preferred method of resection. Most of the literature on management of ampullary adenomas are small single-center retrospective reviews.

Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses.

Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective GLS inhibitor, when combined with azacytidine (AZA), and , followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with telaglenastat/AZA led to an ORR of 70% with CR/mCRs in 53% patients and a median overall survival of 11.

The cost of competency?

Curtailed protein translation ensures stemness and multipotency in embryonic and adult tissue-specific stem cells. In this issue of Cell, a study led by Zhao and colleagues uncovered increased susceptibility of hematopoietic stem cells (HSC) to iron-dependent programmed necrotic cell death (ferroptosis) as a consequence of low protein synthesis.

Lenalidomide and Eltrombopag for Treatment of Low- or Intermediate-Risk Myelodysplastic Syndrome: Result of a Phase II Clinical Trial.

Purpose: Thrombocytopenia is a serious complication of myelodysplastic syndromes (MDS) associated with an increased bleeding risk and worse prognosis. Eltrombopag (ELT), a thrombopoietin receptor agonist, can increase platelet counts and reverse anti-megakaryopoietic effects of lenalidomide (LEN) in preclinical studies. We hypothesized ELT would reduce the incidence of thrombocytopenia in MDS.

Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.

Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant-ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia.

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.

Background: Mutations in the splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood.

Methods: RNA-seq data from mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 ( isoforms were determined.

PU.1-Dependent Enhancer Inhibition Separates Tet2-Deficient Hematopoiesis from Malignant Transformation.

Unlabelled: Cytosine hypermethylation in and around DNA-binding sites of master transcription factors, including PU.1, occurs in aging hematopoietic stem cells following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase ten-eleven translocation-2 (TET2), albeit functional relevance has been unclear. We show that Tet2-deficient mouse hematopoietic stem and progenitor cells undergo malignant transformation upon compromised gene regulation through heterozygous deletion of an upstream regulatory region (UREΔ/WT) of the PU.

Impact of aeroplane noise on mental and physical health: a quasi-experimental analysis.

Objectives: Historically, departures at New York City's LaGuardia airport flew over a large sports complex within a park. During the US Open tennis games, flights were diverted to fly over a heavily populated foreign-born neighbourhood for roughly 2 weeks out of the year so that the tennis match was not disturbed (the 'TNNIS' departure). In 2012, the use of the TNNIS departure became year-round to better optimise flight patterns around the metropolitan area.

Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia.

Dysregulation of innate immune signaling pathways is implicated in various hematologic malignancies. However, these pathways have not been systematically examined in acute myeloid leukemia (AML). We report that AML hematopoietic stem and progenitor cells (HSPCs) exhibit a high frequency of dysregulated innate immune-related and inflammatory pathways, referred to as oncogenic immune signaling states.

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster.

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.

SEPHguarding acute myeloid leukemia.

Adaptive aberrant gene regulation is a hallmark of malignant growth and therapy resistance in acute myeloid leukemia (AML). In this issue of Cell Stem Cell, Eagle et al. identified oncogenic enhancer-driven overexpression of selenophosphate synthetase 2 (SEPHS2) as an opportunity for targeted mitigation of malignant cell growth in AML.

Distractions when viewing in-hospital heart failure self-care videos and change in heart failure self-care knowledge.

Background: When viewing in-hospital heart failure (HF) education videos, internal and external distractions could interfere with understanding of educational content.

Objective: To examine if distractions when learning are associated with HF knowledge.

Methods: HF self-care knowledge was assessed using a validated HF knowledge instrument.

Correction: Proteome-wide analysis of chaperone-mediated autophagy targeting motifs.

[This corrects the article DOI: 10.1371/journal.pbio.

Anxiety and depression moderate the relationship between quality of life and self-care in patients with heart failure.

The purpose of this study was to determine perceptions of heart failure quality of life and its relationship to self-care as moderated by anxiety and depression. Older adults (n = 85) were surveyed using Kansas City Cardiomyopathy Questionnaire-12, Self-Care of Heart Failure Index V6.2, and Patient Reported Outcomes Measurement Information System Anxiety and Depression Short Forms 4a.

To Degrade or Not to Degrade DNMT3A.

Aberrant DNA cytosine methylation is a critical contributor to compromised tissue regeneration and malignant transformation, particularly during aging. In this issue of , Huang and colleagues define a new class of disease-associated DNA (cytosine-5-)-methyltransferase 3 alpha () variants with decreased DNA methylation activity due increased proteasomal degradation that are able to drive clonal expansion of hematopoietic stem cells..