Publications by authors named "Kathy McGraw"

The Myelodysplastic Syndromes (MDS) are heterogeneous stem cell malignancies clinically characterized by bone marrow dysplasia, peripheral blood cytopenias, and a high risk for transformation to acute myeloid leukemia. In early stages of disease, differentiation defects and maturation blocks result in deficient hematopoiesis. In higher risk disease, unrestricted proliferation of immature blast cells leads to leukemogenesis.

View Article and Find Full Text PDF

The intestinal microbiome has been mechanistically linked with health and many disease processes. Cancer is no exception. Both in solid tumors and hematologic malignancies, there is increasing evidence supporting the involvement of the intestinal microbiome in tumor development, disease progression, response to treatment, and treatment toxicity.

View Article and Find Full Text PDF

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) experience a wide range of symptoms due both to their underlying disease and the effects of treatment. Designing early phase trials to explore effective therapies in these patients should not only examine anti-tumor activity, but also consider the effects of treatments on how patients feel and function. Assessing symptomatic toxicities associated with new therapies in early phase trials from the patient perspective is best measured using patient-reported outcomes (PROs) and offers valuable insight and complementary information to the traditional adverse event reporting in cancer clinical trials.

View Article and Find Full Text PDF

This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

View Article and Find Full Text PDF
Article Synopsis
  • * The study employs genetic analysis methods (polygenic risk score and Mendelian randomization) to explore the relationship between genetically predicted leukocyte telomere length and the risk of AML and MDS.
  • * A significant association was found: a higher predicted telomere length increases the risk of AML, with various genetic instruments showing different odds ratios for this relationship.
View Article and Find Full Text PDF

Pyroptosis is an immunological response to infection and cellular stresses initiated by inflammasome oligomerization resulting in the release of pro-inflammatory factors including cytokines and other immune stimuli into the extracellular matrix. In order to understand the role of inflammasome activation and subsequent pyroptosis in human infection and disease pathogenesis and to explore markers of these signaling events as potential disease or response biomarkers, we must utilize quantitative, reliable, and reproducible assays to readily investigate these pathways in primary specimens. Here, we describe two methods using imaging flow cytometry for evaluation of inflammasome ASC specks in homogeneous peripheral blood monocytes and in bulk, heterogeneous peripheral blood mononuclear cells.

View Article and Find Full Text PDF

NLRP3 inflammasome and IFN-stimulated gene (ISG) induction are key biological drivers of ineffective hematopoiesis and inflammation in myelodysplastic syndromes (MDSs). Gene mutations involving mRNA splicing and epigenetic regulatory pathways induce inflammasome activation and myeloid lineage skewing in MDSs through undefined mechanisms. Using immortalized murine hematopoietic stem and progenitor cells harboring these somatic gene mutations and primary MDS BM specimens, we showed accumulation of unresolved R-loops and micronuclei with concurrent activation of the cytosolic sensor cyclic GMP-AMP synthase.

View Article and Find Full Text PDF
Article Synopsis
  • * Researchers identified mutations in aged rhesus macaques that mirror those found in human CH, confirming DNMT3A as the most common mutation, and created a CH model by gene editing young macaques' stem cells.
  • * The study found that macaques with TET2 mutations had abnormal bone marrow and heightened inflammation, and blocking IL-6 with a drug slowed the expansion of these mutated cells, offering insights into potential treatments for CH.
View Article and Find Full Text PDF

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)-inflammasome-induced pyroptotic cell death.

View Article and Find Full Text PDF

MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism and tumorigenesis. A variety of alterations drive expression in acute myeloid leukemia (AML) and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy-lysosome pathway.

View Article and Find Full Text PDF

Purpose: Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin.

Methods: In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment.

View Article and Find Full Text PDF
Article Synopsis
  • U2AF1, a protein involved in splicing, forms a complex with U2AF2 to help select 3' splice sites and has mutations linked to cancers, especially in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML).
  • The most common mutation, S34F, causes misregulation of translation initiation and ribosome production, leading to increased mRNA translation in affected cells.
  • The mutated U2AF1 enhances the production of Nucleophosmin 1 (NPM1), which drives myeloid cancer; reducing NPM1 levels decreases the mutant cells' viability and disrupts ribosomal RNA processing.
View Article and Find Full Text PDF

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated.

View Article and Find Full Text PDF
Article Synopsis
  • - The study investigates the genetic profiles and prognosis of 118 patients with acute myeloid leukemia (AML), specifically focusing on those with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) versus standard AML.
  • - Results indicate AML-MRC patients with certain mutations have significantly shorter overall survival (11 months) compared to AML patients with those same mutations (19 months) and a group of AML patients without these mutations.
  • - Specific mutations (e.g., FLT3, TP53) negatively impacted survival rates in AML-MRC, while different concurrent mutations affected survival in standard AML, highlighting the complexity of genetic influences on outcomes in these leukemia subtypes.
View Article and Find Full Text PDF
Article Synopsis
  • Myelodysplastic syndromes (MDS) are blood disorders linked to abnormal stem cells, with known risk factors including genetic mutations, therapies, aging, and chronic inflammation.
  • A study identified 8 genetic locations associated with MDS in a European population, focusing on gene expression differences in bone marrow cells from MDS patients versus healthy controls.
  • Higher expression of the gene PLA2G4A and lower expression of EYA2 were connected to worse survival rates, indicating their roles in MDS and suggesting that these genes impact immune regulation and could have clinical significance for treatment.
View Article and Find Full Text PDF
Article Synopsis
  • Myelodysplastic syndromes (MDS) with deletion of chromosome 7q are linked to poor patient outcomes, and reduced DOCK4 protein levels hinder hematopoietic stem cell differentiation in these cases.
  • Research identified that decreased DOCK4 leads to increased phosphorylation of certain proteins, particularly LYN kinase and phosphatases SHP1 and SHIP1, which negatively affect HSC function and differentiation.
  • Therapeutic inhibition of SHP1 has the potential to restore normal differentiation and migration in HSCs with low DOCK4, making it a promising target for treating -7/(del)7q MDS.
View Article and Find Full Text PDF

Hypomethylating agent (HMA) failure myelodysplastic syndrome (MDS) patients have poor outcomes and urgent need for novel therapies. Hedgehog pathway signaling upregulation plays a central role in myeloid neoplasm pathogenesis and leukemia stem cell survival. We evaluated the efficacy and safety of the smoothened inhibitor glasdegib in HMA-failure MDS (n = 35, median age 73 years).

View Article and Find Full Text PDF

Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964.

View Article and Find Full Text PDF

Background: NLRP3 inflammasome-directed pyroptotic cell death drives ineffective haemopoiesis in myelodysplastic syndromes. During inflammasome assembly, the apoptosis-associated speck-like protein containing a CARD (PYCARD, commonly known as ASC) adaptor protein polymerises into large, filamentous clusters termed ASC specks that are released upon cytolysis. Specks are resistant to proteolytic degradation because of their prion-like structure, and therefore might serve as a biomarker for pyroptotic cell death in myelodysplastic syndromes.

View Article and Find Full Text PDF