Melissa M. Lee‐Sundlov

Glycosylation orchestrates megakaryocytic fate of hematopoietic stem cells via Wnt-MUC13 signaling

Alejandro Roisman, Leonardo Rivadeneyra, Lindsey Conroy, Natalia Weich et autres

Hematopoietic stem and progenitor cells (HSPCs) sustain blood production through tightly regulated fate decisions. Disruption of this control underlies disorders such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and inherited thrombocytopenias. While transcriptional and epigenetic regulation of HSPCs is well established, the …

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Remission of TP53 -Mutant AML After Transplantation With Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Followed by a Donor-Derived Anti-CD33 Chimeric Antigen Receptor T (VCAR33)

Guenther Koehne, Muhammad Umair Mushtaq, Lori Muffly, Manuel Menes et autres

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A CD33-Deleted Allograft (Trem-cel) Enables Post-Hematopoietic Cell Transplant (HCT) Maintenance Dosing of Gemtuzumab Ozogamicin (GO) with Therapeutic Levels of Drug Exposure and Low Hematologic and Hepatic Toxicity in Patients with High-Risk Acute Myeloid Leukemia (AML)

John F. DiPersio, Guenther Koehne, Nirali N. Shah, Alain Mina et autres

Background Maintenance therapy post-HCT is a strategy to reduce AML relapse , however use of GO (Mylotarg TM ), an anti-CD33 antibody-drug conjugate, for this purpose is limited by hepato- and hematologic toxicity. Tremtelectogene empogeditemcel (trem-cel, formerly VOR33) is a hematopoietic stem …

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Glycan-Mediated Mechanosensing Regulates Megakaryocyte-Biased Hematopoietic Stem Cell Subsets

Alejandro Roisman, Leonardo Rivadeneyra, Lindsey R. Conroy, Melissa M. Lee‐Sundlov et autres

SUMMARY Definitive hematopoietic stem and progenitor cells (HSPCs) development relies on intrinsic and extrinsic programs to meet homeostatic and stress-related demands. The comprehensive mechanisms governing HSPC’s fate remain poorly understood. Our study identifies B4GALT1, a glycosyltransferase essential for N-glycosylation, as a key …

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Serum O-Glycan Antigenicity in Pediatric Immune Thrombocytopenia Predicts Disease Persistence

Katelyn E. Rosenbalm, George F. Steinhardt, Melissa M. Lee‐Sundlov, Alejandro Roisman et autres

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count, leading to symptoms of bleeding and fatigue. While many cases are mild with limited mucocutaneous bleeding, severe and life-threatening bleeding can occur. ITP is a diagnosis of exclusion. It …

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A CD33-Deleted Allograft (Trem-cel) Enables Post-Hematopoietic Cell Transplant (HCT) Maintenance Dosing of Gemtuzumab Ozogamicin (GO) with Therapeutic Levels of Drug Exposure and Low Hematologic and Hepatic Toxicity in Patients with High-Risk Acute Myeloid Leukemia (AML)

John F. DiPersio, Guenther Koehne, Nirali N. Shah, Léa Bernard et autres

Background: Relapse is the leading cause of death for patients undergoing allogeneic HCT for AML. Strategies to reduce relapse including leukemia-directed maintenance therapies post-HCT have been largely ineffective. GO (MylotargTM) is an anti-CD33 antibody-drug conjugate approved for use in AML, but its …

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Characterization of the human platelet N- and O-glycome upon storage using tandem mass spectrometry

Katelyn E. Rosenbalm, Melissa M. Lee‐Sundlov, David J. Ashline, Renata Grozovsky et autres

Changes in surface glycan determinants, specifically sialic acid loss, determine platelet life span. The gradual loss of stored platelet quality is a complex process that fundamentally involves carbohydrate structures. Here, we applied lipophilic extraction and glycan release protocols to sequentially profile N- …

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Reduced platelet glycoprotein Ibα shedding accelerates thrombopoiesis and COX-1 recovery: implications for aspirin dosing regimen

Paola Simeone, Rossella Liani, Romina Tripaldi, Sonia Ciotti et autres

Cardiovascular (CV) disease prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet (PLT) cyclooxygenase (COX)-1 activity during the 24-hour dosing interval. We previously showed that incomplete suppression of TXA2 over 24 hours can be rescued …

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Trial in Progress: A First-in-Human Phase 1/2 Study of Hematopoietic Stem Cell Transplantation (HCT) with VOR33 (CD33-Deleted Allograft) Followed By Treatment with Gemtuzumab Ozogamicin (GO) in Patients with CD33+ Acute Myeloid Leukemia (AML) Who Are at High-Risk of Post-HCT Relapse

Brenda Cooper, Hyung C. Suh, Divya Koura, Guenther Koehne et autres

Background: Allogeneic HCT is the standard of care for eligible patients with AML harboring high-risk features such as adverse-risk cytogenetics or minimal residual disease (MRD). However, the majority of such patients still relapse post-HCT and have very poor outcomes. The use of …

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Endocytosis of the thrombopoietin receptor Mpl regulates megakaryocyte and erythroid maturation in mice

Nathan Eaton, Emily K. Boyd, Ratnashree Biswas, Melissa M. Lee‐Sundlov et autres

Dnm2 fl/fl Pf4-Cre ( Dnm2 Plt–/– ) mice lacking the endocytic GTPase dynamin 2 (DNM2) in platelets and megakaryocytes (MKs) develop hallmarks of myelofibrosis. At the cellular level, the tyrosine kinase JAK2 is constitutively active but decreased in expression in Dnm2 Plt–/– …

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Characterization of CD41+ cells in the lymph node

Li Dai, Mayuko Uehara, Xiaofei Li, Brenna A. LaBarre et autres

Lymph nodes (LNs) are the critical sites of immunity, and the stromal cells of LNs are crucial to their function. Our understanding of the stromal compartment of the LN has deepened recently with the characterization of nontraditional stromal cells. CD41 (integrin αIIb) …

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Sialic acid and platelet count regulation: Implications in immune thrombocytopenia

Melissa M. Lee‐Sundlov, Leonardo Rivadeneyra, Hervé Falet, Karin M. Hoffmeister et autres

Platelets are blood components that survive in circulation for 7 to 10 days in humans. Thus, platelet production by bone marrow (BM) megakaryocytes (MKs), and their removal from the blood circulation is precisely orchestrated to maintain an average platelet count. Abnormalities in …

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