Publications by authors named "Elizabeth Eklund"

Fanconi anemia (FA) is an inherited disorder of DNA repair due to mutation in one of 20+ interrelated genes that repair intrastrand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia may also occur. In prior studies, we found that Fanconi DNA repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response.

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As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1) AML comprising a third of all AML patients.

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Unlabelled: Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival.

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Age-associated bone marrow changes include myeloid skewing and mutations that lead to clonal hematopoiesis. Molecular mechanisms for these events are ill defined, but decreased expression of Irf8/Icsbp (interferon regulatory factor 8/interferon consensus sequence binding protein) in aging hematopoietic stem cells may contribute. Irf8 functions as a leukemia suppressor for chronic myeloid leukemia, and young Irf8 mice have neutrophilia with progression to acute myeloid leukemia (AML) with aging.

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Article Synopsis
  • - The study investigates the role of dynamins, specifically DNM2, in hematopoiesis and its impact on blood cell development, revealing that reduced DNM2 levels in female mice can lead to neutropenia and other blood-related issues as they age.
  • - Conditional deletion of Dnm2 in mice leads to decreased levels of granulocyte-monocyte progenitors and altered migration patterns of bone marrow neutrophils, indicating that DNM2 is crucial for normal blood cell development and function.
  • - The findings suggest that decreased DNM2 can contribute to chronic idiopathic neutropenia, a condition often seen in middle-aged women, by impairing the production and migration of essential blood cells.
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Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown.

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Background: Prenatal screening for common trisomies via cell-free (cfDNA) is usually implemented by technologies utilizing massively parallel sequencing, stringent environmental controls, complex bioinformatics, and molecular expertise. An alternative and less complex methodology utilizes rolling circle amplification (RCA). Further evaluation of its performance and related requirements are warranted.

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Fanconi anemia (FA) is an inherited disorder of DNA repair with hematologic manifestations that range from anemia to bone marrow failure to acute myeloid leukemia. In a murine model of FA (Fancc mice), we found bone marrow failure was accelerated by repeated attempts to induce emergency (stress) granulopoiesis, the process for granulocyte production during the innate immune response. Fancc mice exhibited an impaired granulocytosis response and died with profound anemia during repeated challenge.

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Background: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported.

Objective: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies.

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  • * A study using RNA sequencing revealed 567 differentially expressed genes in pediatric CML CD34+ cells compared to healthy controls, and 398 genes unique to pediatric CML when compared to adult CML.
  • * Notable gene differences include upregulation of VAV2 and ARHGAP27 in adult CML, while DLC1 was significantly upregulated in pediatric CML, highlighting distinct molecular characteristics that may influence clinical outcomes for these two age groups.
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The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for acute myeloid leukemia (AML). We evaluated the therapeutic potential of the highly-selective MNK1/2 inhibitor Tomivosertib on AML cells. Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells.

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Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation, and inhibition of proapoptotic pathways. In spite of a relatively homogeneous clinical disease presentation, risk of long-term survival in AML varies from 20% to 80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia Net (ELN) and WHO classification systems now incorporate cytogenetics and increasing numbers of gene mutations into AML prognostication.

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Background: There is conflicting evidence regarding the association between a history of depression and risk of early menopause. In a cohort of premenopausal women, we investigated the association between depression history and ovarian reserve, as measured by anti-müllerian hormone (AMH).

Methods: The Harvard Study of Moods and Cycles (HSMC) was a prospective cohort study of women living in the Boston, MA metropolitan-area (1995-1999).

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Acute myeloid leukemia (AML) with mixed lineage leukemia 1 () gene rearrangement is characterized by increased expression of a set of homeodomain transcription factors, including homeobox A9 (HOXA9) and HOXA10. The target genes for these regulators include fibroblast growth factor 2 () and Ariadne RBR E3 ubiquitin ligase 2 (). FGF2 induces leukemia stem cell expansion in MLL1-rearranged AML.

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Chronic myeloid leukemia (CML) is characterized by expression of the tyrosine kinase oncogene, Bcr-abl. Tyrosine kinase inhibitors (TKI) induce prolonged remission in CML, and therapy discontinuation is an accepted approach to patients with reduction in Bcr-abl transcripts of four logs or greater. Half such individuals sustain a therapy free remission, but molecular mechanisms predicting relapse are undefined.

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MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells.

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Objective: To determine whether differences exist in angiogenic placental growth factor (PlGF) and antiangiogenic soluble vascular endothelial growth factor receptor 1 (sVEGFR-1; both being early markers of placental ischemic disease) in oocyte-donation (OD) pregnancies, compared with autologous in vitro fertilization (aIVF) and spontaneous pregnancies.

Design: Case-control study of residual second-trimester serum samples from women undergoing prenatal screening.

Setting: Academic medical center.

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  • The study examines the challenges of distinguishing between malignant and benign pelvic masses in women, particularly focusing on the effectiveness of serum biomarkers like HE4 and CA125 in detecting epithelial ovarian cancer (EOC).
  • It involved a clinical trial with 184 patients, measuring various serum biomarkers and analyzing their effectiveness in differentiating EOC from benign conditions using logistic regression and ROC curves.
  • The results showed that while combining additional biomarkers with HE4 and CA125 improved detection accuracy to some extent, it didn't significantly outperform the HE4 and CA125 combination alone for diagnosing EOC.
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  • The study investigates the relationship between maternal body mass index (BMI) and peripheral deiodinase activity, especially focusing on how these factors relate to glucose and C-peptide levels in pregnant women.
  • It analyzes data from a subset of 600 non-Hispanic white women, assessing thyroid hormone levels and comparing outcomes in women with and without gestational diabetes mellitus (GDM).
  • Findings reveal that higher maternal BMI correlates with increased deiodinase activity and higher levels of glucose, indicating that while deiodinase activity contributes to glucose levels, it only accounts for a small portion of the variation.
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Aberrant activation of mTOR signaling in acute myeloid leukemia (AML) results in a survival advantage that promotes the malignant phenotype. To improve our understanding of factors that contribute to mammalian target of rapamycin (mTOR) signaling activation and identify novel therapeutic targets, we searched for unique interactors of mTOR complexes through proteomics analyses. We identify cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8.

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  • Megakaryocyte (MK) migration from the bone marrow to blood vessels is essential for releasing platelets, yet the exact mechanisms behind this process are not well understood.
  • The study reveals that inhibiting dynamins (specifically DNM2 and DNM3) impairs MK movement by reducing actin polymerization and affecting the activity of RhoA, a protein involved in cell shape and movement.
  • Additionally, the research indicates that targeting dynamins alters the expression and recycling of specific receptors like CXCR4 and β1 integrin, which are important for MK migration in response to signaling molecules like SDF-1α.
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Background: High maternal weight is known to associate with both low free thyroxine and gestational diabetes mellitus. We explore a deiodinase-related mechanism that may help explain these associations.

Methods: Among 108 women receiving routine oral glucose tolerance testing for gestational diabetes mellitus, we collected biophysical data and measured free thyroxine and total triiodothyronine, using residual plasma samples.

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Introduction: Snoring, the symptom of partial airway obstruction during sleep, is a common complaint during pregnancy and is associated with adverse perinatal outcomes. Mechanisms underlying this association have not been studied. We investigated the relationship between snoring in pregnancy and maternal serum markers of feto-placental wellbeing.

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Fas associated phosphatase 1 (Fap1) is a ubiquitously expressed protein tyrosine phosphatase. Fap1 substrates include Fas and Gsk3β, suggesting a role in regulating cell survival. Consistent with this, increased Fap1 expression is associated with resistance to Fas or platinum induced apoptosis in some human colon cancer tumors or cell lines.

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Chromosomal translocations involving the MLL1 gene characterize a poor prognosis subset of acute myeloid leukemia (AML), referred to as 11q23-AML. Transcription of the HOXA9 and HOXA10 genes is enhanced in hematopoietic stem and progenitor cells in these leukemias. We previously found the ARIH2 gene was repressed by HoxA9 in myeloid progenitors, but activated by HoxA10 during granulopoiesis.

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