Nakisha D Williams

Telomere content and genomics of myeloid neoplasia by whole-genome sequencing

Luca Guarnera, Adam Wahida, Carmelo Gurnari, Stephan Hütter et autres

ABSTRACT: Telomere length shortening has been associated with genomic instability and acquisition of molecular lesions, but these processes have not been systematically studied across large cohorts of myeloid neoplasia (MN). As proof of concept for a novel, cross-validated whole-genome sequencing-based method of …

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RAPID FIRE SESSION 01

Luca Guarnera, Adam Wahida, Carmelo Gurnari, Stephan Hütter et autres

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Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia

Carlos Bravo‐Pérez, Carmelo Gurnari, Jani Huuhtanen, Naomi Kawashima et autres

BACKGROUNDT cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents a unique model for the study of persistent CTL expansions. Albeit autoimmunity is implied, various paradoxical observations led us …

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Non canonical c-CBL mutations define a specific phenotype of myeloid neoplasia

Luca Guarnera, Carmelo Gurnari, Carlos Bravo‐Pérez, Arda Durmaz et autres

CBL proteins are a family of RING finger E3 ubiquitin ligases that regulate proliferative signals via ubiquitination and degradation of tyrosine-phosphorylated signaling proteins, such as KIT, CSF-1, FLT3 and PDGF [ 1 ]. We previously described c-CBL RING finger mutations in myeloid …

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Clonal hematopoiesis in large granular lymphocytic leukemia

Naomi Kawashima, Carmelo Gurnari, Carlos Bravo‐Pérez, Yasuo Kubota et autres

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Loss of TET2 Increases MHC Class I Expression in Acute Myeloid Leukemia

Xiaorong Gu, Songa Bae, Yahan Zhang, Nakisha D Williams et autres

Background: One of the major challenges in the treatment of acute myeloid leukemia (AML) is the elimination of undifferentiated immature blood cells, often referred to as leukemia stem and progenitor cells (LSPC). LSPCs persist after treatment and are considered a major cause …

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Developing a Therapeutic Strategy for Targeting Metabolic Vulnerability of TET2 Mutant Leukemia

Xiaorong Gu, Yahan Zhang, Songa Bae, Dongxu Jiang et autres

Background Loss-of-function TET2 mutations (TET2MT) occur in up to 30% of Myelodysplastic Syndrome and Acute Myeloid Leukemia. In Chronic Myelomonocytic Leukemia it is > 66%. Additionally, TET2MT is a founding lesion in myeloid neoplasms (MN), frequently appearing in clonal hematopoiesis of indeterminate …

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Distinct Phenotypes of Myeloid Neoplasia Associated with Truncating C-CBL Mutations

Luca Guarnera, Carmelo Gurnari, Carlos Bravo‐Pérez, Arda Durmaz et autres

Introduction. Canonical missense (MS) c-CBL mutations affecting linker and zinc finger domains impair protein ubiquitination function and are the most encountered in myeloid neoplasia (MN). However, c-CBL truncations can be also observed with consequential impairment of ubiquitin-association and PI3K/AKT activation function. Due …

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Dysregulation of the Ubiquitination Pathway: Insights on Autoinflammatory Conditions and Inborn Errors of Immunity in Bone Marrow Failure Disorders

Zachary Brady, Nakisha D Williams, Arda Durmaz, Luca Guarnera et autres

Genetic variants/dysregulation of the ubiquitination pathway have been described in various autoinflammatory disorders and in inborn errors of immunity leading to broad clinical manifestations including multisystem autoimmunity and hematologic malignancies. VEXAS syndrome is an example par excellence of such a clinical diagnosis …

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Telomere Content Diversity in Myeloid Neoplasia Could Inform on Differential Sensitivity to Telomerase Inhibitors

Luca Guarnera, Adam Wahida, Carmelo Gurnari, Stephan Hütter et autres

The recent FDA approval of Imetelstat, a new class of antineoplastic drugs for the treatment of MDS1 opens the question on whether telomere content (TC) and/or telomerase function might constitute therapeutic targets and diagnostic biomarkers. Early studies have not specifically delved in …

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Landscape of biallelic DNMT3A mutant myeloid neoplasms

Naomi Kawashima, Yasuo Kubota, Carlos Bravo‐Pérez, Luca Guarnera et autres

DNA methyltransferase 3 A mutations ( DNMT3A MT ) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3A MT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with …

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Non-canonical FLT3 alterations reveal novel germline FLT3 variants leading to somatic gene rescue mutations

J I Gordon, Carlos Bravo‐Pérez, Luca Guarnera, Serhan Ünlü et autres

FMS-like receptor tyrosine kinase 3 (FLT3) expression is almost exclusively found in the myeloid compartment [ 1 ]. The FLT3 protein consists of an extracellular region containing the ligand-binding site, a transmembrane domain, a cytoplasmic juxtamembrane domain, and a tyrosine kinase domain …

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